{"title":"Prescription lipid therapy trial evidence database","compiled":"2026-10-28","method":"Trials curated by drug class; primary report identified in PubMed; fields extracted from the PubMed abstract only; each record carries a verbatim supporting quote, and all numbers in result fields were checked automatically against the abstract text.","source":"PubMed (NCBI E-utilities)","records":[{"trial":"LRC-CPPT","drug_class":"Bile acid sequestrant","drug":"Cholestyramine","study_type":"Cardiovascular outcome trial","year":1984,"first_author":"","journal":"JAMA","title":"The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.","pmid":"6361299","doi":"10.1001/jama.1984.03340270029025","design":"multicenter, randomized, double-blind study","population":"3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia)","n":3806,"intervention":"cholestyramine resin (bile acid sequestrant)","comparator":"placebo","follow_up":"average of 7.4 years","primary_endpoint":"definite CHD death and/or definite nonfatal myocardial infarction","primary_result":"The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point; cumulative seven-year incidence was 7% in the cholestyramine group v 8.6% in the placebo group.","ldl_effect":"average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group","key_secondary_or_mortality":"24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction; incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively; risk of death from all causes was only slightly and not significantly reduced (7% decrease)","safety":"The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group.","result":"Benefit","bottom_line":"Lowering LDL-C with cholestyramine significantly reduced coronary heart disease events in high-risk hypercholesterolemic men, though it did not significantly reduce overall mortality.","us_status":"US-approved","evidence_quote":"The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction.","quote_verified":true,"slug":"lrc-cppt","family":"ezetimibe","outcome":"benefit"},{"trial":"Helsinki Heart Study","drug_class":"Fibrate","drug":"Gemfibrozil","study_type":"Cardiovascular outcome trial","year":1987,"first_author":"Frick","journal":"N Engl J Med","title":"Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.","pmid":"3313041","doi":"10.1056/NEJM198711123172001","design":"randomized, double-blind five-year trial","population":"4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements)","n":4081,"intervention":"600 mg of gemfibrozil twice daily (2051 men)","comparator":"placebo (2030 men)","follow_up":"five-year trial","primary_endpoint":"Incidence of coronary heart disease (cumulative rate of cardiac end points)","primary_result":"The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test).","ldl_effect":"Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides.","key_secondary_or_mortality":"There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates.","safety":"There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates.","result":"Benefit","bottom_line":"In middle-aged men with dyslipidemia, gemfibrozil raised HDL and lowered non-HDL cholesterol and significantly reduced coronary heart disease incidence over five years without affecting total mortality or cancer rates.","us_status":"US-approved","evidence_quote":"The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test).","quote_verified":true,"slug":"helsinki-heart-study","family":"fibrates-omega-3-niacin","outcome":"benefit"},{"trial":"4S","drug_class":"Statin","drug":"Simvastatin","study_type":"Cardiovascular outcome trial","year":1994,"first_author":"","journal":"Lancet","title":"Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).","pmid":"7968073","doi":"","design":"Randomised, double-blind, placebo-controlled trial","population":"Patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet","n":4444,"intervention":"Simvastatin","comparator":"Placebo","follow_up":"5.4 years median follow-up","primary_endpoint":"All-cause mortality","primary_result":"The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively.","ldl_effect":"-35% LDL cholesterol (total cholesterol -25%, HDL cholesterol +8%)","key_secondary_or_mortality":"There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularisation procedures.","safety":"Simvastatin produced the above lipid changes with few adverse effects; long-term treatment with simvastatin is safe.","result":"Benefit","bottom_line":"In patients with coronary heart disease and elevated cholesterol, simvastatin reduced the risk of death and major coronary events compared with placebo over about 5.4 years.","us_status":"US-approved","evidence_quote":"256 patients (12%) in the placebo group died, compared with 182 (8%) in the simvastatin group. The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003).","quote_verified":true,"slug":"4s","family":"statins","outcome":"benefit"},{"trial":"WOSCOPS","drug_class":"Statin","drug":"Pravastatin","study_type":"Cardiovascular outcome trial","year":1995,"first_author":"Shepherd","journal":"N Engl J Med","title":"Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.","pmid":"7566020","doi":"10.1056/NEJM199511163332001","design":"double-blind, randomized, placebo-controlled (primary prevention)","population":"Men, 45 to 64 years of age, with hypercholesterolemia (mean plasma cholesterol 272 +/- 23 mg/dl) and no history of myocardial infarction","n":6595,"intervention":"Pravastatin 40 mg each evening","comparator":"Placebo","follow_up":"4.9 years (average)","primary_endpoint":"Combined incidence of nonfatal myocardial infarction and death from coronary heart disease (definite coronary events)","primary_result":"There were 248 definite coronary events in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001).","ldl_effect":"Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo.","key_secondary_or_mortality":"22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051); 32 percent reduction in death from all cardiovascular causes (P = 0.033)","safety":"There was no excess of deaths from noncardiovascular causes in the pravastatin group.","result":"Benefit","bottom_line":"In middle-aged men with moderate hypercholesterolemia and no prior MI, pravastatin significantly reduced coronary events and cardiovascular death without increasing noncardiovascular deaths.","us_status":"US-approved","evidence_quote":"There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001).","quote_verified":true,"slug":"woscops","family":"statins","outcome":"benefit"},{"trial":"CARE","drug_class":"Statin","drug":"Pravastatin","study_type":"Cardiovascular outcome trial","year":1996,"first_author":"Sacks","journal":"N Engl J Med","title":"The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.","pmid":"8801446","doi":"10.1056/NEJM199610033351401","design":"double-blind trial","population":"Patients with myocardial infarction and plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and LDL cholesterol levels of 115 to 174 mg per deciliter (mean, 139); 3583 men and 576 women","n":4159,"intervention":"40 mg of pravastatin per day","comparator":"Placebo","follow_up":"five years","primary_endpoint":"A fatal coronary event or a nonfatal myocardial infarction","primary_result":"The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003).","ldl_effect":"LDL cholesterol levels of 115 to 174 mg per deciliter (mean, 139) at baseline","key_secondary_or_mortality":"There were no significant differences in overall mortality or mortality from noncardiovascular causes. Coronary bypass surgery was reduced by 26 percent (P=0.005), coronary angioplasty by 23 percent (P=0.01), and stroke by 31 percent (P=0.03).","safety":"There were no significant differences in overall mortality or mortality from noncardiovascular causes.","result":"Benefit","bottom_line":"In patients with average cholesterol levels after myocardial infarction, pravastatin significantly reduced the risk of fatal coronary events and nonfatal MI, as well as the need for revascularization and stroke, without a significant effect on overall mortality.","us_status":"US-approved","evidence_quote":"The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003).","quote_verified":true,"slug":"care","family":"statins","outcome":"benefit"},{"trial":"AFCAPS/TexCAPS","drug_class":"Statin","drug":"Lovastatin","study_type":"Cardiovascular outcome trial","year":1998,"first_author":"Downs","journal":"JAMA","title":"Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.","pmid":"9613910","doi":"10.1001/jama.279.20.1615","design":"A randomized, double-blind, placebo-controlled trial","population":"Men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C and below-average HDL-C levels","n":6605,"intervention":"Lovastatin (20-40 mg daily)","comparator":"Placebo","follow_up":"average follow-up of 5.2 years","primary_endpoint":"First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death","primary_result":"183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001","ldl_effect":"Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL).","key_secondary_or_mortality":"Myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003)","safety":"There were no clinically relevant differences in safety parameters between treatment groups.","result":"Benefit","bottom_line":"In men and women with average cholesterol but low HDL-C and no known heart disease, lovastatin substantially lowered the risk of a first major coronary event.","us_status":"US-approved","evidence_quote":"After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001)","quote_verified":true,"slug":"afcaps-texcaps","family":"statins","outcome":"benefit"},{"trial":"LIPID","drug_class":"Statin","drug":"Pravastatin","study_type":"Cardiovascular outcome trial","year":1998,"first_author":"Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group","journal":"N Engl J Med","title":"Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.","pmid":"9841303","doi":"10.1056/NEJM199811053391902","design":"double-blind, randomized trial","population":"Patients 31 to 75 years of age with a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter","n":9014,"intervention":"Pravastatin 40 mg daily","comparator":"Placebo","follow_up":"mean follow-up period of 6.1 years","primary_endpoint":"Mortality from coronary heart disease","primary_result":"Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001).","ldl_effect":"''","key_secondary_or_mortality":"Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001).","safety":"There were no clinically significant adverse effects of treatment with pravastatin.","result":"Benefit","bottom_line":"In patients with coronary heart disease and a broad range of cholesterol levels, pravastatin reduced death from coronary heart disease, overall mortality, and other cardiovascular events compared with placebo.","us_status":"US-approved","evidence_quote":"Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001).","quote_verified":true,"slug":"lipid","family":"statins","outcome":"benefit"},{"trial":"VA-HIT","drug_class":"Fibrate","drug":"Gemfibrozil","study_type":"Cardiovascular outcome trial","year":1999,"first_author":"Rubins","journal":"N Engl J Med","title":"Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.","pmid":"10438259","doi":"10.1056/NEJM199908053410604","design":"double-blind trial","population":"Men with coronary heart disease, HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less","n":2531,"intervention":"Gemfibrozil (1200 mg per day)","comparator":"Placebo","follow_up":"median follow-up was 5.1 years","primary_endpoint":"Nonfatal myocardial infarction or death from coronary causes","primary_result":"A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent); the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006)","ldl_effect":"LDL cholesterol levels did not differ significantly between the groups","key_secondary_or_mortality":"There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001).","safety":"There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer.","result":"Benefit","bottom_line":"In men with coronary heart disease and low HDL cholesterol but not high LDL, gemfibrozil reduced the risk of major cardiovascular events despite not lowering LDL cholesterol.","us_status":"US-approved","evidence_quote":"A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006).","quote_verified":true,"slug":"va-hit","family":"fibrates-omega-3-niacin","outcome":"benefit"},{"trial":"HPS","drug_class":"Statin","drug":"Simvastatin","study_type":"Cardiovascular outcome trial","year":2002,"first_author":"Heart Protection Study Collaborative Group","journal":"Lancet","title":"MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.","pmid":"12114036","doi":"10.1016/S0140-6736(02)09327-3","design":"randomized, placebo-controlled","population":"20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes","n":20536,"intervention":"40 mg simvastatin daily (average compliance: 85%)","comparator":"matching placebo (average non-study statin use: 17%)","follow_up":"scheduled 5-year treatment period","primary_endpoint":"Mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses)","primary_result":"All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003)","ldl_effect":"average difference in LDL cholesterol of 1.0 mmol/L","key_secondary_or_mortality":"Highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005); for the first occurrence of any major vascular event, a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001)","safety":"The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause.","result":"Benefit","bottom_line":"Adding simvastatin 40 mg daily to existing treatment in high-risk patients safely reduced all-cause mortality and major vascular events, regardless of baseline cholesterol level.","us_status":"US-approved","evidence_quote":"All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005)","quote_verified":true,"slug":"hps","family":"statins","outcome":"benefit"},{"trial":"PROSPER","drug_class":"Statin","drug":"Pravastatin","study_type":"Cardiovascular outcome trial","year":2002,"first_author":"Shepherd","journal":"Lancet","title":"Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.","pmid":"12457784","doi":"10.1016/s0140-6736(02)11600-x","design":"randomised controlled trial","population":"Men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease; baseline cholesterol 4.0-9.0 mmol/L","n":5804,"intervention":"Pravastatin 40 mg per day (n=2891)","comparator":"Placebo (n=2913)","follow_up":"3.2 years on average","primary_endpoint":"Composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke","primary_result":"Reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014)","ldl_effect":"Pravastatin lowered LDL cholesterol concentrations by 34%","key_secondary_or_mortality":"Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006); Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8); hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051); Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group","safety":"New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020); however, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk; Pravastatin had no significant effect on cognitive function or disability","result":"Benefit","bottom_line":"In elderly people at risk of vascular disease, pravastatin reduced coronary heart disease events and coronary death but did not reduce stroke risk.","us_status":"US-approved","evidence_quote":"Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014).","quote_verified":true,"slug":"prosper","family":"statins","outcome":"benefit"},{"trial":"ASCOT-LLA","drug_class":"Statin","drug":"Atorvastatin","study_type":"Cardiovascular outcome trial","year":2003,"first_author":"Sever","journal":"Lancet","title":"Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.","pmid":"12686036","doi":"10.1016/S0140-6736(03)12948-0","design":"randomised controlled trial","population":"Hypertensive patients aged 40-79 years with at least three other cardiovascular risk factors and non-fasting total cholesterol concentrations 6.5 mmol/L or less (lipid-lowering arm of ASCOT)","n":10305,"intervention":"Atorvastatin 10 mg","comparator":"Placebo","follow_up":"median follow-up of 3.3 years (planned average 5 years)","primary_endpoint":"Non-fatal myocardial infarction and fatal CHD","primary_result":"100 primary events in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005)","ldl_effect":"Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up.","key_secondary_or_mortality":"There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered.","safety":"","result":"Benefit","bottom_line":"In hypertensive patients with average or below-average cholesterol, adding atorvastatin 10 mg to antihypertensive therapy substantially reduced coronary events, stroke, and total cardiovascular events, though it did not significantly reduce all-cause mortality.","us_status":"US-approved","evidence_quote":"By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005).","quote_verified":true,"slug":"ascot-lla","family":"statins","outcome":"benefit"},{"trial":"CARDS","drug_class":"Statin","drug":"Atorvastatin","study_type":"Cardiovascular outcome trial","year":2004,"first_author":"Colhoun","journal":"Lancet","title":"Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.","pmid":"15325833","doi":"10.1016/S0140-6736(04)16895-5","design":"Multicentre randomised placebo-controlled trial","population":"2838 patients aged 40-75 years with type 2 diabetes, no documented previous history of cardiovascular disease, LDL-cholesterol concentration of 4.14 mmol/L or lower, fasting triglyceride amount of 6.78 mmol/L or less, and at least one of: retinopathy, albuminuria, current smoking, or hypertension","n":2838,"intervention":"Atorvastatin 10 mg daily","comparator":"Placebo","follow_up":"Median duration of follow-up was 3.9 years (IQR 3.0-4.7)","primary_endpoint":"Time to first occurrence of acute coronary heart disease events, coronary revascularisation, or stroke","primary_result":"127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001).","ldl_effect":"''","key_secondary_or_mortality":"Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059).","safety":"No excess of adverse events was noted in the atorvastatin group.","result":"Benefit","bottom_line":"In people with type 2 diabetes but no prior cardiovascular disease and no high LDL-cholesterol, taking atorvastatin 10 mg daily substantially lowered the risk of heart attacks, revascularization, and stroke, with no increase in adverse events.","us_status":"US-approved","evidence_quote":"127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001).","quote_verified":true,"slug":"cards","family":"statins","outcome":"benefit"},{"trial":"PROVE IT-TIMI 22","drug_class":"Statin","drug":"Atorvastatin vs pravastatin","study_type":"Cardiovascular outcome trial","year":2004,"first_author":"Cannon","journal":"N Engl J Med","title":"Intensive versus moderate lipid lowering with statins after acute coronary syndromes.","pmid":"15007110","doi":"10.1056/NEJMoa040583","design":"Randomized, designed as a noninferiority trial comparing pravastatin with atorvastatin","population":"Patients hospitalized for an acute coronary syndrome within the preceding 10 days","n":4162,"intervention":"Atorvastatin 80 mg daily (intensive therapy)","comparator":"Pravastatin 40 mg daily (standard therapy)","follow_up":"18 to 36 months (mean, 24)","primary_endpoint":"Composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke","primary_result":"26.3% (pravastatin) vs 22.4% (atorvastatin) at two years; 16 percent reduction in hazard ratio favoring atorvastatin (P=0.005; 95% CI, 5 to 26 percent)","ldl_effect":"Median LDL cholesterol achieved: 95 mg/dL (2.46 mmol/L) with pravastatin vs 62 mg/dL (1.60 mmol/L) with atorvastatin (P<0.001)","key_secondary_or_mortality":"Primary composite endpoint included death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (≥30 days post-randomization), and stroke; not broken down separately for mortality alone in the abstract.","safety":"Not reported in the abstract","result":"Benefit","bottom_line":"In patients recently hospitalized for acute coronary syndrome, intensive lipid lowering with high-dose atorvastatin (80 mg) reduced death and major cardiovascular events more than standard-dose pravastatin (40 mg).","us_status":"US-approved","evidence_quote":"Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent).","quote_verified":true,"slug":"prove-it-timi-22","family":"statins","outcome":"benefit"},{"trial":"FIELD","drug_class":"Fibrate","drug":"Fenofibrate","study_type":"Cardiovascular outcome trial","year":2005,"first_author":"Keech","journal":"Lancet","title":"Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.","pmid":"16310551","doi":"10.1016/S0140-6736(05)67667-2","design":"multinational, randomised controlled trial","population":"9795 participants aged 50-75 years, with type 2 diabetes mellitus, not taking statin therapy at study entry; 2131 with previous cardiovascular disease and 7664 without; total-cholesterol 3.0-6.5 mmol/L and total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L","n":9795,"intervention":"micronised fenofibrate 200 mg daily (n=4895)","comparator":"matching placebo (n=4900)","follow_up":"5 years","primary_endpoint":"Coronary events (coronary heart disease death or non-fatal myocardial infarction)","primary_result":"5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16)","ldl_effect":"''","key_secondary_or_mortality":"Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035), including a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003); non-fatal MI reduced 24% (0.76, 0.62-0.94; p=0.010); CHD mortality non-significantly increased (1.19, 0.90-1.57; p=0.22); total mortality 6.6% placebo vs 7.3% fenofibrate (p=0.18)","safety":"Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2% vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5% vs 0.8%, p=0.031) and pulmonary embolism (0.7% vs 1.1%, p=0.022), but no other significant adverse effects.","result":"No significant benefit","bottom_line":"In patients with type 2 diabetes not on statins, fenofibrate did not significantly reduce coronary events but did reduce total cardiovascular events, driven by fewer nonfatal heart attacks and revascularizations, with a small increase in pancreatitis and pulmonary embolism.","us_status":"US-approved","evidence_quote":"5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16).","quote_verified":true,"slug":"field","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"IDEAL","drug_class":"Statin","drug":"Atorvastatin vs simvastatin","study_type":"Cardiovascular outcome trial","year":2005,"first_author":"Pedersen","journal":"JAMA","title":"High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.","pmid":"16287954","doi":"10.1001/jama.294.19.2437","design":"prospective, randomized, open-label, blinded end-point evaluation trial","population":"Patients aged 80 years or younger with a history of acute myocardial infarction","n":8888,"intervention":"High-dose atorvastatin (80 mg/d; n=4439)","comparator":"Usual-dose simvastatin (20 mg/d; n=4449)","follow_up":"median follow-up of 4.8 years","primary_endpoint":"Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation","primary_result":"A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07)","ldl_effect":"During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group","key_secondary_or_mortality":"Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02).","safety":"Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups.","result":"No significant benefit","bottom_line":"High-dose atorvastatin lowered LDL-C more than usual-dose simvastatin and reduced some secondary cardiovascular endpoints and nonfatal MI, but did not significantly reduce the primary composite of major coronary events or all-cause mortality after prior MI.","us_status":"US-approved","evidence_quote":"A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07).","quote_verified":true,"slug":"ideal","family":"statins","outcome":"no-benefit"},{"trial":"TNT","drug_class":"Statin","drug":"Atorvastatin 80 vs 10","study_type":"Cardiovascular outcome trial","year":2005,"first_author":"LaRosa","journal":"N Engl J Med","title":"Intensive lipid lowering with atorvastatin in patients with stable coronary disease.","pmid":"15755765","doi":"10.1056/NEJMoa050461","design":"Randomized, double-blind","population":"Patients with clinically evident coronary heart disease (CHD) and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter)","n":10001,"intervention":"Atorvastatin 80 mg per day","comparator":"Atorvastatin 10 mg per day","follow_up":"median of 4.9 years","primary_endpoint":"First major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke","primary_result":"A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001).","ldl_effect":"Mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin.","key_secondary_or_mortality":"There was no difference between the two treatment groups in overall mortality.","safety":"The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001).","result":"Benefit","bottom_line":"In patients with stable coronary disease, treating to a much lower LDL target with high-dose atorvastatin (80 mg) further reduced major cardiovascular events compared with the standard 10 mg dose, though with more liver enzyme elevations and no difference in overall mortality.","us_status":"US-approved","evidence_quote":"A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001).","quote_verified":true,"slug":"tnt","family":"statins","outcome":"benefit"},{"trial":"Cohen 2006","drug_class":"Genetics","drug":"PCSK9 variants","study_type":"Genetic study","year":2006,"first_author":"Cohen","journal":"N Engl J Med","title":"Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.","pmid":"16554528","doi":"10.1056/NEJMoa054013","design":"Observational genetic association study (cohort analysis within the Atherosclerosis Risk in Communities study)","population":"Participants in the Atherosclerosis Risk in Communities study: 3363 black subjects and 9524 white subjects examined for PCSK9 sequence variations","n":12887,"intervention":"Presence of PCSK9 sequence variants (nonsense mutations in black subjects; a specific sequence variation in white subjects) associated with lifelong reduced LDL-C","comparator":"Subjects without the respective PCSK9 sequence variants (nonsense mutations in black subjects; the specific sequence variation in white subjects)","follow_up":"15-year interval","primary_endpoint":"Incidence of coronary heart disease (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval","primary_result":"Black subjects with PCSK9 nonsense mutations: 88 percent reduction in risk of CHD (hazard ratio, 0.11; 95 percent CI, 0.02 to 0.81; P=0.03). White subjects with the PCSK9 sequence variation: 47 percent reduction in risk of CHD (hazard ratio, 0.50; 95 percent CI, 0.32 to 0.79; P=0.003).","ldl_effect":"28 percent reduction in mean LDL cholesterol (black subjects with nonsense mutations); 15 percent reduction in LDL cholesterol (white subjects with the sequence variation)","key_secondary_or_mortality":"''","safety":"''","result":"Supports LDL causality","bottom_line":"People who naturally carry LDL-lowering PCSK9 gene variants from birth have a dramatically lower lifetime risk of coronary heart disease, supporting that lowering LDL-C, even modestly, over a lifetime substantially cuts cardiovascular risk.","us_status":"Not applicable","evidence_quote":"Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).","quote_verified":true,"slug":"cohen-2006","family":"genetics","outcome":"safety"},{"trial":"SPARCL","drug_class":"Statin","drug":"Atorvastatin","study_type":"Cardiovascular outcome trial","year":2006,"first_author":"Amarenco","journal":"N Engl J Med","title":"High-dose atorvastatin after stroke or transient ischemic attack.","pmid":"16899775","doi":"10.1056/NEJMoa061894","design":"randomized, double-blind, placebo-controlled","population":"Patients who had had a stroke or TIA within one to six months before study entry, had LDL cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease","n":4731,"intervention":"80 mg of atorvastatin per day","comparator":"Placebo","follow_up":"median follow-up of 4.9 years","primary_endpoint":"First nonfatal or fatal stroke","primary_result":"265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05)","ldl_effect":"The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo","key_secondary_or_mortality":"The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98)","safety":"The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. Rates of serious adverse events were similar between groups. Elevated liver enzyme values were more common in patients taking atorvastatin.","result":"Benefit","bottom_line":"In patients with a recent stroke or TIA but no known coronary disease, high-dose atorvastatin modestly reduced recurrent stroke and cardiovascular events, though it slightly increased hemorrhagic stroke risk and did not improve overall mortality.","us_status":"US-approved","evidence_quote":"During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05).","quote_verified":true,"slug":"sparcl","family":"statins","outcome":"benefit"},{"trial":"CORONA","drug_class":"Statin","drug":"Rosuvastatin","study_type":"Cardiovascular outcome trial","year":2007,"first_author":"Kjekshus","journal":"N Engl J Med","title":"Rosuvastatin in older patients with systolic heart failure.","pmid":"17984166","doi":"10.1056/NEJMoa0706201","design":"randomized, placebo-controlled","population":"Patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure","n":5011,"intervention":"Rosuvastatin 10 mg per day","comparator":"Placebo","follow_up":"Median follow-up of 32.8 months","primary_endpoint":"Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (composite)","primary_result":"the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12)","ldl_effect":"decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001)","key_secondary_or_mortality":"728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31); fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001)","safety":"No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group.","result":"No significant benefit","bottom_line":"In older patients with ischemic systolic heart failure, rosuvastatin lowered LDL cholesterol but did not reduce cardiovascular events or death, though it was safe and reduced cardiovascular hospitalizations.","us_status":"US-approved","evidence_quote":"Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems.","quote_verified":true,"slug":"corona","family":"statins","outcome":"no-benefit"},{"trial":"ILLUMINATE","drug_class":"CETP inhibitor","drug":"Torcetrapib","study_type":"Cardiovascular outcome trial","year":2007,"first_author":"Barter","journal":"N Engl J Med","title":"Effects of torcetrapib in patients at high risk for coronary events.","pmid":"17984165","doi":"10.1056/NEJMoa0706628","design":"Randomized, double-blind study (terminated prematurely)","population":"Patients at high risk for coronary events","n":15067,"intervention":"Torcetrapib plus atorvastatin","comparator":"Atorvastatin alone","follow_up":"12 months (lipid/safety measures reported at 12 months; trial terminated prematurely)","primary_endpoint":"Time to first major cardiovascular event, defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina","primary_result":"Increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001)","ldl_effect":"Decrease of 24.9% in LDL cholesterol compared with baseline (P<0.001)","key_secondary_or_mortality":"Death from any cause: hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006","safety":"5.4 mm Hg increase in systolic blood pressure, decrease in serum potassium, increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons); post hoc analyses showed increased risk of death in patients whose reduction in potassium or increase in bicarbonate was greater than the median change.","result":"Harm","bottom_line":"Adding torcetrapib to atorvastatin raised HDL and lowered LDL but increased cardiovascular events and overall death, so the trial was stopped early and the drug should not be used.","us_status":"Discontinued","evidence_quote":"There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006).","quote_verified":true,"slug":"illuminate","family":"cetp","outcome":"no-benefit"},{"trial":"JELIS","drug_class":"Omega-3","drug":"EPA","study_type":"Cardiovascular outcome trial","year":2007,"first_author":"Yokoyama","journal":"Lancet","title":"Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.","pmid":"17398308","doi":"10.1016/S0140-6736(07)60527-3","design":"randomised open-label, blinded endpoint analysis","population":"Japanese patients with total cholesterol of 6.5 mmol/L or greater (hypercholesterolaemic), recruited 1996-1999","n":18645,"intervention":"1800 mg of EPA daily with statin (EPA group; n=9326)","comparator":"statin only (controls; n=9319)","follow_up":"mean follow-up of 4.6 years (5-year follow-up planned)","primary_endpoint":"Any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting","primary_result":"262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011)","ldl_effect":"Post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups","key_secondary_or_mortality":"Sudden cardiac death and coronary death did not differ between groups; unstable angina and non-fatal coronary events were significantly reduced in the EPA group; secondary prevention subgroup: 158 [8.7%] EPA vs 197 [10.7%] control, p=0.048; primary prevention subgroup: 104 [1.4%] EPA vs 127 [1.7%] control, p=0.132","safety":"''","result":"Benefit","bottom_line":"Adding EPA to statin therapy modestly reduced major coronary events, mainly non-fatal events, in hypercholesterolaemic Japanese patients, without a significant effect on sudden cardiac or coronary death.","us_status":"Not US-approved (Japan)","evidence_quote":"At mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011).","quote_verified":true,"slug":"jelis","family":"fibrates-omega-3-niacin","outcome":"benefit"},{"trial":"JUPITER","drug_class":"Statin","drug":"Rosuvastatin","study_type":"Cardiovascular outcome trial","year":2008,"first_author":"Ridker","journal":"N Engl J Med","title":"Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.","pmid":"18997196","doi":"10.1056/NEJMoa0807646","design":"randomized, double-blind, placebo-controlled","population":"Apparently healthy men and women with LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher","n":17802,"intervention":"Rosuvastatin, 20 mg daily","comparator":"Placebo","follow_up":"median follow-up of 1.9 years (maximum, 5.0)","primary_endpoint":"Combined end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes","primary_result":"The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001)","ldl_effect":"Rosuvastatin reduced LDL cholesterol levels by 50%","key_secondary_or_mortality":"1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02)","safety":"The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.","result":"Benefit","bottom_line":"In apparently healthy people with normal LDL but elevated CRP, rosuvastatin significantly reduced major cardiovascular events and all-cause death, though with a higher rate of reported diabetes.","us_status":"US-approved","evidence_quote":"The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001)","quote_verified":true,"slug":"jupiter","family":"statins","outcome":"benefit"},{"trial":"SEAS","drug_class":"Ezetimibe","drug":"Simvastatin + ezetimibe","study_type":"Cardiovascular outcome trial","year":2008,"first_author":"Rossebø","journal":"N Engl J Med","title":"Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.","pmid":"18765433","doi":"10.1056/NEJMoa0804602","design":"randomized, double-blind trial","population":"1873 patients with mild-to-moderate, asymptomatic aortic stenosis","n":1873,"intervention":"40 mg of simvastatin plus 10 mg of ezetimibe daily","comparator":"placebo","follow_up":"median follow-up of 52.2 months","primary_endpoint":"Composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke","primary_result":"the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59)","ldl_effect":"","key_secondary_or_mortality":"Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97).","safety":"Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01).","result":"No significant benefit","bottom_line":"In patients with mild-to-moderate asymptomatic aortic stenosis, simvastatin plus ezetimibe did not reduce the composite of aortic-valve and ischemic cardiovascular events, though it reduced ischemic events alone and was associated with more cancer cases.","us_status":"US-approved","evidence_quote":"During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59).","quote_verified":true,"slug":"seas","family":"ezetimibe","outcome":"no-benefit"},{"trial":"AURORA","drug_class":"Statin","drug":"Rosuvastatin","study_type":"Cardiovascular outcome trial","year":2009,"first_author":"Fellström","journal":"N Engl J Med","title":"Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.","pmid":"19332456","doi":"10.1056/NEJMoa0810177","design":"randomized, double-blind, prospective trial","population":"Patients 50 to 80 years of age undergoing maintenance hemodialysis","n":2776,"intervention":"Rosuvastatin, 10 mg daily","comparator":"Placebo","follow_up":"median follow-up period of 3.8 years","primary_endpoint":"Combined end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke","primary_result":"396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59)","ldl_effect":"After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter)","key_secondary_or_mortality":"There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51)","safety":"","result":"No significant benefit","bottom_line":"In patients on hemodialysis, rosuvastatin lowered LDL cholesterol but did not reduce cardiovascular events or all-cause mortality compared with placebo.","us_status":"US-approved","evidence_quote":"During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59).","quote_verified":true,"slug":"aurora","family":"statins","outcome":"no-benefit"},{"trial":"ACCORD Lipid","drug_class":"Fibrate","drug":"Fenofibrate + simvastatin","study_type":"Cardiovascular outcome trial","year":2010,"first_author":"ACCORD Study Group","journal":"N Engl J Med","title":"Effects of combination lipid therapy in type 2 diabetes mellitus.","pmid":"20228404","doi":"10.1056/NEJMoa1001282","design":"randomized, open-label simvastatin background with masked fenofibrate vs placebo","population":"Patients with type 2 diabetes mellitus at high risk for cardiovascular disease, treated with open-label simvastatin","n":5518,"intervention":"Fenofibrate (masked) added to open-label simvastatin","comparator":"Placebo added to open-label simvastatin","follow_up":"mean 4.7 years","primary_endpoint":"First occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes","primary_result":"The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32)","ldl_effect":"","key_secondary_or_mortality":"Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33)","safety":"","result":"No significant benefit","bottom_line":"Adding fenofibrate to simvastatin did not reduce cardiovascular events or death compared with simvastatin alone in high-risk patients with type 2 diabetes, so routine combination therapy is not supported.","us_status":"US-approved","evidence_quote":"The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32).","quote_verified":true,"slug":"accord-lipid","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"CTT 2010","drug_class":"Meta-analysis","drug":"Statins","study_type":"Meta-analysis","year":2010,"first_author":"Cholesterol Treatment Trialists’ (CTT) Collaboration","journal":"Lancet","title":"Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.","pmid":"21067804","doi":"10.1016/S0140-6736(10)61350-5","design":"Meta-analysis of individual participant data from randomised trials (more vs less intensive statin regimens, and statin vs control)","population":"Individuals in randomised trials of statin therapy (at least 1000 participants, at least 2 years' treatment duration), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen","n":170000,"intervention":"More intensive statin therapy (and statin therapy vs control)","comparator":"Less intensive statin regimens (more vs less intensive trials) and control/placebo (statin vs control trials)","follow_up":"Median follow-up 5·1 years (more vs less intensive trials) and 4·8 years (statin vs control trials)","primary_endpoint":"Major vascular events (and major vascular events per 1·0 mmol/L LDL cholesterol reduction)","primary_result":"More intensive statin regimens produced a 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events compared with less intensive regimens; combining both trial types, major vascular events were reduced by RR 0·78 (95% CI 0·76-0·80; p<0·0001) per 1·0 mmol/L LDL cholesterol reduction.","ldl_effect":"Weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L in the more vs less intensive trials; effects expressed per 1·0 mmol/L LDL cholesterol reduction","key_secondary_or_mortality":"All-cause mortality reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely due to reductions in coronary heart disease deaths (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac deaths (RR 0·89, 99% CI 0·81-0·98; p=0·002); no significant effect on stroke deaths or other vascular deaths.","safety":"No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations.","result":"Benefit","bottom_line":"More intensive LDL-lowering with statins produces further, dose-dependent reductions in major vascular events and all-cause mortality, with no evidence of harm from very low LDL levels.","us_status":"Not applicable","evidence_quote":"Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8).","quote_verified":true,"slug":"ctt-2010","family":"meta-analyses","outcome":"benefit"},{"trial":"AIM-HIGH","drug_class":"Niacin","drug":"Extended-release niacin","study_type":"Cardiovascular outcome trial","year":2011,"first_author":"AIM-HIGH Investigators","journal":"N Engl J Med","title":"Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.","pmid":"22085343","doi":"10.1056/NEJMoa1107579","design":"randomized, placebo-controlled (stopped early for lack of efficacy)","population":"Patients with established cardiovascular disease and low HDL cholesterol levels receiving intensive statin therapy, with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter","n":3414,"intervention":"Extended-release niacin, 1500 to 2000 mg per day, plus simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed","comparator":"Matching placebo plus simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed","follow_up":"mean follow-up period of 3 years (36-month follow-up period)","primary_endpoint":"First event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization","primary_result":"The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test).","ldl_effect":"Lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter); also increased median HDL cholesterol from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter) and lowered triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter)","key_secondary_or_mortality":"No incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.","safety":"''","result":"No significant benefit","bottom_line":"In statin-treated patients with established cardiovascular disease and already-low LDL, adding extended-release niacin raised HDL and lowered triglycerides but did not reduce cardiovascular events compared with placebo.","us_status":"US-approved","evidence_quote":"The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test).","quote_verified":true,"slug":"aim-high","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"SHARP","drug_class":"Ezetimibe","drug":"Simvastatin + ezetimibe","study_type":"Cardiovascular outcome trial","year":2011,"first_author":"Baigent","journal":"Lancet","title":"The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.","pmid":"21663949","doi":"10.1016/S0140-6736(11)60739-3","design":"randomised double-blind placebo-controlled trial","population":"9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation","n":9270,"intervention":"Simvastatin 20 mg plus ezetimibe 10 mg daily","comparator":"Matching placebo","follow_up":"median follow-up of 4·9 years","primary_endpoint":"First major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure)","primary_result":"526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74-0·94; log-rank p=0·0021","ldl_effect":"average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance)","key_secondary_or_mortality":"Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76-1·11; p=0·37); significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60-0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68-0·93; p=0·0036); no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13)","safety":"Excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]); no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89)","result":"Benefit","bottom_line":"In patients with moderate-to-severe chronic kidney disease, lowering LDL cholesterol with simvastatin plus ezetimibe safely reduced major atherosclerotic events compared with placebo.","us_status":"US-approved","evidence_quote":"Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74-0·94; log-rank p=0·0021).","quote_verified":true,"slug":"sharp","family":"ezetimibe","outcome":"benefit"},{"trial":"CTT 2012 low risk","drug_class":"Meta-analysis","drug":"Statins","study_type":"Meta-analysis","year":2012,"first_author":"Cholesterol Treatment Trialists' (CTT) Collaborators","journal":"Lancet","title":"The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.","pmid":"22607822","doi":"10.1016/S0140-6736(12)60367-5","design":"Meta-analysis of individual participant data from 27 randomised trials","population":"Participants from 27 randomised statin trials, stratified into five categories of baseline 5-year major vascular event risk on control therapy (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%)","n":174149,"intervention":"Statin therapy (lowering LDL cholesterol)","comparator":"Statin vs control (22 trials); more statin vs less statin (5 trials)","follow_up":"4·8 years (statin vs control trials, median); 5·1 years (more vs less statin trials)","primary_endpoint":"Major vascular events (major coronary events [non-fatal myocardial infarction or coronary death], strokes, or coronary revascularisations) per 1·0 mmol/L LDL cholesterol reduction","primary_result":"RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L LDL cholesterol reduction; proportional reduction at least as big in the two lowest risk categories as higher risk categories (RR from lowest to highest risk: 0·62 [99% CI 0·47-0·81], 0·69 [99% CI 0·60-0·79], 0·79 [99% CI 0·74-0·85], 0·81 [99% CI 0·77-0·86], and 0·79 [99% CI 0·74-0·84]; trend p=0·04)","ldl_effect":"Mean LDL cholesterol difference 1·08 mmol/L (statin vs control trials); 0·51 mmol/L (more vs less statin trials)","key_secondary_or_mortality":"In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77-0·95) and all-cause mortality (RR 0·91, 95% CI 0·85-0·97), and the proportional reductions were similar by baseline risk.","safety":"There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96-1·04), cancer mortality (RR 0·99, 95% CI 0·93-1·06), or other non-vascular mortality.","result":"Benefit","bottom_line":"Even in people at low baseline cardiovascular risk, lowering LDL cholesterol with statin therapy reduces major vascular events and all-cause mortality without increasing cancer risk, suggesting current risk-threshold guidelines for statin use may need reconsideration.","us_status":"Not applicable","evidence_quote":"Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality.","quote_verified":true,"slug":"ctt-2012-low-risk","family":"meta-analyses","outcome":"benefit"},{"trial":"dal-OUTCOMES","drug_class":"CETP inhibitor","drug":"Dalcetrapib","study_type":"Cardiovascular outcome trial","year":2012,"first_author":"Schwartz","journal":"N Engl J Med","title":"Effects of dalcetrapib in patients with a recent acute coronary syndrome.","pmid":"23126252","doi":"10.1056/NEJMoa1206797","design":"randomized","population":"Patients who had had a recent acute coronary syndrome","n":15871,"intervention":"Dalcetrapib 600 mg daily, in addition to best available evidence-based care","comparator":"Placebo, in addition to best available evidence-based care","follow_up":"median of 31 months","primary_endpoint":"Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation","primary_result":"Cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52","ldl_effect":"Dalcetrapib had a minimal effect on LDL cholesterol levels; HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group","key_secondary_or_mortality":"Did not have a significant effect on any component of the primary end point or total mortality","safety":"The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons)","result":"No significant benefit","bottom_line":"In patients with a recent acute coronary syndrome, dalcetrapib raised HDL cholesterol but did not reduce cardiovascular events or mortality compared with placebo.","us_status":"Not approved","evidence_quote":"As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality.","quote_verified":true,"slug":"dal-outcomes","family":"cetp","outcome":"no-benefit"},{"trial":"Lomitapide phase 3 HoFH","drug_class":"MTP inhibitor","drug":"Lomitapide","study_type":"Lipid-efficacy RCT","year":2013,"first_author":"Cuchel","journal":"Lancet","title":"Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.","pmid":"23122768","doi":"10.1016/S0140-6736(12)61731-0","design":"single-arm, open-label, phase 3 study","population":"Men and women aged 18 years or older with homozygous familial hypercholesterolaemia, recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy)","n":29,"intervention":"Lomitapide, dose escalated from 5 mg to a maximum of 60 mg a day (median dose 40 mg a day), with current lipid lowering therapy maintained","comparator":"None (single-arm, baseline comparison)","follow_up":"26 weeks (efficacy phase); 78 weeks (full study, safety assessment)","primary_endpoint":"Mean percent change in levels of LDL cholesterol from baseline to week 26","primary_result":"LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]); p<0·0001","ldl_effect":"Reduced by 50% (95% CI -62 to -39) at week 26; remained reduced by 44% (95% CI -57 to -31) at week 56 and 38% (-52 to -24) at week 78","key_secondary_or_mortality":"Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks","safety":"Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.","result":"Primary lipid endpoint met","bottom_line":"In patients with homozygous familial hypercholesterolaemia, lomitapide added to existing lipid-lowering therapy substantially lowered LDL cholesterol with durable effect through 78 weeks, though gastrointestinal side effects and reversible liver enzyme elevations were common.","us_status":"US-approved","evidence_quote":"LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]); p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78.","quote_verified":true,"slug":"lomitapide-phase-3-hofh","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"DESCARTES","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2014,"first_author":"Blom","journal":"N Engl J Med","title":"A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.","pmid":"24678979","doi":"10.1056/NEJMoa1316222","design":"Randomized, placebo-controlled, phase 3 trial (2:1 randomization) with background lipid-lowering therapy stratified by risk category","population":"Patients with hyperlipidemia stratified by Adult Treatment Panel III risk categories, with LDL cholesterol ≥75 mg/dL (1.9 mmol/L) after a 4- to 12-week run-in on background lipid-lowering therapy","n":901,"intervention":"Evolocumab 420 mg every 4 weeks, added to background therapy (diet alone, atorvastatin 10 mg, atorvastatin 80 mg, or atorvastatin 80 mg plus ezetimibe 10 mg)","comparator":"Placebo (added to same background lipid-lowering therapy)","follow_up":"52 weeks","primary_endpoint":"Percent change from baseline in LDL cholesterol (measured by ultracentrifugation) at week 52","primary_result":"Overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001)","ldl_effect":"Overall LDL-C reduction vs placebo of 57.0±2.1% (P<0.001); by background therapy: 55.7±4.2% (diet alone), 61.6±2.6% (atorvastatin 10 mg), 56.8±5.3% (atorvastatin 80 mg), 48.5±5.2% (atorvastatin 80 mg + ezetimibe 10 mg) (P<0.001 for all comparisons)","key_secondary_or_mortality":"Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides.","safety":"The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.","result":"Primary lipid endpoint met","bottom_line":"In patients with hyperlipidemia across a range of background lipid therapies, adding evolocumab for 52 weeks substantially lowered LDL cholesterol compared with placebo.","us_status":"US-approved","evidence_quote":"Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001).","quote_verified":true,"slug":"descartes","family":"pcsk9","outcome":"lipids"},{"trial":"HPS2-THRIVE","drug_class":"Niacin","drug":"Niacin/laropiprant","study_type":"Cardiovascular outcome trial","year":2014,"first_author":"HPS2-THRIVE Collaborative Group","journal":"N Engl J Med","title":"Effects of extended-release niacin with laropiprant in high-risk patients.","pmid":"25014686","doi":"10.1056/NEJMoa1300955","design":"randomized, placebo-controlled (with prerandomization run-in phase)","population":"25,673 adults with vascular disease, on background statin-based LDL cholesterol-lowering therapy","n":25673,"intervention":"2 g of extended-release niacin and 40 mg of laropiprant daily","comparator":"matching placebo","follow_up":"median follow-up period of 3.9 years","primary_endpoint":"First major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization)","primary_result":"13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29","ldl_effect":"LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower; HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher","key_secondary_or_mortality":"Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events","safety":"Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001)","result":"No significant benefit","bottom_line":"Adding extended-release niacin-laropiprant to statin therapy in patients with vascular disease did not reduce major vascular events and increased serious adverse effects, including new-onset diabetes, infection, and bleeding.","us_status":"Not available in US","evidence_quote":"Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29).","quote_verified":true,"slug":"hps2-thrive","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"MENDEL-2","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2014,"first_author":"Koren","journal":"J Am Coll Cardiol","title":"Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.","pmid":"24691094","doi":"10.1016/j.jacc.2014.03.018","design":"Randomized, controlled phase III trial (1:1:1:1:2:2 allocation)","population":"Patients 18 to 80 years of age with fasting LDL-C ≥100 and <190 mg/dl and Framingham risk scores ≤10% with hypercholesterolemia","n":614,"intervention":"Evolocumab 140 mg SC biweekly or 420 mg SC monthly (with oral placebo)","comparator":"Oral placebo and SC placebo (biweekly/monthly); ezetimibe and SC placebo (biweekly/monthly)","follow_up":"''","primary_endpoint":"LDL-C reduction from baseline compared with placebo and ezetimibe","primary_result":"Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons).","ldl_effect":"Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons).","key_secondary_or_mortality":"Evolocumab treatment also favorably altered other lipoprotein levels.","safety":"Treatment-emergent adverse events (AEs), muscle-related AEs, and laboratory abnormalities were comparable across treatment groups.","result":"Primary lipid endpoint met","bottom_line":"In people with moderate hypercholesterolemia and low cardiovascular risk, evolocumab monotherapy (biweekly or monthly) lowered LDL-C far more than placebo or ezetimibe and had a similar rate of side effects as placebo/ezetimibe.","us_status":"US-approved","evidence_quote":"Evolocumab treatment reduced LDL-C from baseline, on average, by 55% to 57% more than placebo and 38% to 40% more than ezetimibe (p < 0.001 for all comparisons).","quote_verified":true,"slug":"mendel-2","family":"pcsk9","outcome":"lipids"},{"trial":"IMPROVE-IT","drug_class":"Ezetimibe","drug":"Ezetimibe + simvastatin","study_type":"Cardiovascular outcome trial","year":2015,"first_author":"Cannon","journal":"N Engl J Med","title":"Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.","pmid":"26039521","doi":"10.1056/NEJMoa1410489","design":"double-blind, randomized trial","population":"Patients hospitalized for an acute coronary syndrome within the preceding 10 days with LDL cholesterol levels of 50 to 100 mg per deciliter (if receiving lipid-lowering therapy) or 50 to 125 mg per deciliter (if not receiving lipid-lowering therapy)","n":18144,"intervention":"Simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe)","comparator":"Simvastatin (40 mg) and placebo (simvastatin monotherapy)","follow_up":"median follow-up was 6 years","primary_endpoint":"A composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke","primary_result":"Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016)","ldl_effect":"The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001).","key_secondary_or_mortality":"","safety":"Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.","result":"Benefit","bottom_line":"Adding ezetimibe to statin therapy after acute coronary syndrome modestly reduces cardiovascular events beyond statin alone, with similar safety.","us_status":"US-approved","evidence_quote":"The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016).","quote_verified":true,"slug":"improve-it","family":"ezetimibe","outcome":"benefit"},{"trial":"ODYSSEY ALTERNATIVE","drug_class":"PCSK9 antibody","drug":"Alirocumab","study_type":"Lipid-efficacy RCT","year":2015,"first_author":"Moriarty","journal":"J Clin Lipidol","title":"Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial.","pmid":"26687696","doi":"10.1016/j.jacl.2015.08.006","design":"Randomized, single-blind placebo run-in followed by double-blind, active-comparator, 2:2:1 randomized trial with statin rechallenge arm","population":"Patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms","n":361,"intervention":"Alirocumab 75 mg SC every 2 weeks (plus oral placebo), with dose increase to 150 mg Q2W at week 12 depending on week 8 LDL-C values","comparator":"Ezetimibe 10 mg/d (plus SC placebo Q2W); atorvastatin 20 mg/d rechallenge arm (plus SC placebo Q2W)","follow_up":"24 weeks","primary_endpoint":"Percent change in LDL-C from baseline to week 24 (intent-to-treat), alirocumab vs ezetimibe","primary_result":"Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001)","ldl_effect":"Baseline mean (SD) LDL-C 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L); alirocumab -45.0% (2.2%) vs ezetimibe -14.6% (2.2%), mean difference 30.4% (3.1%), P<.0001","key_secondary_or_mortality":"Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042)","safety":"Skeletal muscle-related events less frequent with alirocumab vs atorvastatin rechallenge (HR 0.61, 95% CI 0.38-0.99, P=.042)","result":"Primary lipid endpoint met","bottom_line":"In statin-intolerant patients, alirocumab lowered LDL-C far more than ezetimibe and caused fewer muscle-related adverse events than statin rechallenge with atorvastatin.","us_status":"US-approved","evidence_quote":"Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042).","quote_verified":true,"slug":"odyssey-alternative","family":"pcsk9","outcome":"lipids"},{"trial":"ODYSSEY FH I and II","drug_class":"PCSK9 antibody","drug":"Alirocumab","study_type":"Lipid-efficacy RCT","year":2015,"first_author":"Kastelein","journal":"Eur Heart J","title":"ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.","pmid":"26330422","doi":"10.1093/eurheartj/ehv370","design":"Two randomized, double-blind, placebo-controlled studies; 2:1 randomization to alirocumab or placebo","population":"Patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT)","n":735,"intervention":"Alirocumab 75 mg Q2W (up-titrated to 150 mg Q2W at Week 12 if Week 8 LDL-C ≥1.8 mmol/L [70 mg/dL])","comparator":"Placebo (added to maximally tolerated lipid-lowering therapy), every 2 weeks","follow_up":"78 weeks","primary_endpoint":"Percentage change in calculated LDL-C from baseline to Week 24","primary_result":"-57.9% vs. placebo (FH I) and -51.4% vs. placebo (FH II) at Week 24 (P < 0.0001)","ldl_effect":"-57.9% vs. placebo (FH I) and -51.4% vs. placebo (FH II) at Week 24, maintained through Week 78","key_secondary_or_mortality":"LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively.","safety":"Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo).","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolemia inadequately controlled on maximally tolerated lipid-lowering therapy, adding alirocumab produced large, durable LDL-C reductions through 78 weeks and was generally well tolerated.","us_status":"US-approved","evidence_quote":"Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; -57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; -51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78.","quote_verified":true,"slug":"odyssey-fh-i-and-ii","family":"pcsk9","outcome":"lipids"},{"trial":"ODYSSEY LONG TERM","drug_class":"PCSK9 antibody","drug":"Alirocumab","study_type":"Lipid-efficacy RCT","year":2015,"first_author":"Robinson","journal":"N Engl J Med","title":"Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.","pmid":"25773378","doi":"10.1056/NEJMoa1501031","design":"randomized, 2:1 allocation, placebo-controlled (double-blind not specified)","population":"Patients at high risk for cardiovascular events with LDL cholesterol levels of 70 mg/dL (1.8 mmol/L) or more, receiving statins at the maximum tolerated dose, with or without other lipid-lowering therapy","n":2341,"intervention":"Alirocumab 150 mg as a 1-ml subcutaneous injection every 2 weeks","comparator":"Placebo","follow_up":"78 weeks","primary_endpoint":"Percentage change in calculated LDL cholesterol level from baseline to week 24","primary_result":"At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks.","ldl_effect":"-62 percentage points difference vs placebo at week 24 (P<0.001), consistent over 78 weeks","key_secondary_or_mortality":"In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).","safety":"The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).","result":"Primary lipid endpoint met","bottom_line":"Adding alirocumab to maximally tolerated statin therapy markedly lowered LDL cholesterol and was associated with a post hoc reduction in cardiovascular events, though with somewhat higher rates of injection-site reactions, myalgia, neurocognitive, and ophthalmologic events.","us_status":"US-approved","evidence_quote":"At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks.","quote_verified":true,"slug":"odyssey-long-term","family":"pcsk9","outcome":"lipids"},{"trial":"RUTHERFORD-2","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2015,"first_author":"Raal","journal":"Lancet","title":"PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.","pmid":"25282519","doi":"10.1016/S0140-6736(14)61399-4","design":"multicentre, randomised, double-blind, placebo-controlled trial","population":"Patients 18-80 years of age meeting clinical criteria for heterozygous familial hypercholesterolaemia, on stable lipid-lowering therapy for at least 4 weeks, with fasting LDL cholesterol concentration of 2·6 mmol/L or higher","n":331,"intervention":"Evolocumab (AMG 145) 140 mg subcutaneous every 2 weeks (n=111) or 420 mg monthly (n=110)","comparator":"Subcutaneous placebo every 2 weeks (n=55) or monthly (n=55)","follow_up":"12 weeks","primary_endpoint":"Percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12","primary_result":"Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001)","ldl_effect":"59·2% reduction (every-2-weeks dose, week 12) and 61·3% reduction (monthly dose, week 12); 60·2% and 65·6% reduction at mean of weeks 10 and 12, respectively","key_secondary_or_mortality":"","safety":"Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]).","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolaemia on stable lipid-lowering therapy, adding evolocumab produced rapid, large LDL cholesterol reductions of about 60% compared with placebo with a tolerability profile similar to placebo.","us_status":"US-approved","evidence_quote":"Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001).","quote_verified":true,"slug":"rutherford-2","family":"pcsk9","outcome":"lipids"},{"trial":"TESLA Part B","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2015,"first_author":"Raal","journal":"Lancet","title":"Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.","pmid":"25282520","doi":"10.1016/S0140-6736(14)61374-X","design":"randomised, double-blind, placebo-controlled phase 3 trial","population":"Patients (aged ≥12 years) with homozygous familial hypercholesterolaemia, on stable lipid-regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis","n":50,"intervention":"Subcutaneous evolocumab 420 mg every 4 weeks for 12 weeks","comparator":"Placebo","follow_up":"12 weeks","primary_endpoint":"Percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo","primary_result":"Evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI -43·9% to -18·0%; p<0·0001)","ldl_effect":"30.9% reduction in ultracentrifugation LDL cholesterol vs placebo (95% CI -43.9% to -18.0%; p<0.0001)","key_secondary_or_mortality":"","safety":"Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study.","result":"Primary lipid endpoint met","bottom_line":"In patients with homozygous familial hypercholesterolaemia on stable background therapy, adding evolocumab 420 mg every 4 weeks significantly lowered LDL cholesterol compared with placebo and was well tolerated over 12 weeks.","us_status":"US-approved","evidence_quote":"Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI -43·9% to -18·0%; p<0·0001).","quote_verified":true,"slug":"tesla-part-b","family":"pcsk9","outcome":"lipids"},{"trial":"Ference 2016","drug_class":"Genetics","drug":"PCSK9/HMGCR variants","study_type":"Genetic study","year":2016,"first_author":"Ference","journal":"N Engl J Med","title":"Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.","pmid":"27959767","doi":"10.1056/NEJMoa1604304","design":"Mendelian randomization using genetic scores of independently inherited PCSK9 and HMGCR variants to randomly assign participants according to number of LDL-lowering alleles inherited, across 14 studies","population":"112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, grouped by number of LDL cholesterol-lowering alleles inherited in PCSK9 and HMGCR genes","n":112772,"intervention":"Genetic score of LDL-lowering alleles in PCSK9 (and HMGCR) used as proxy for pharmacologic PCSK9 inhibition (and statin therapy)","comparator":"PCSK9 variants vs HMGCR variants (Mendelian randomization comparison); also combined vs individual gene scores","follow_up":"","primary_endpoint":"Risk of cardiovascular events (and risk of diabetes) associated with LDL cholesterol-lowering genetic variants in PCSK9 and HMGCR","primary_result":"Odds ratio for cardiovascular events per 10 mg/dl decrease in LDL cholesterol: 0.81 (95% CI, 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR","ldl_effect":"Analyzed per 10 mg/dl (0.26 mmol/liter) decrease in LDL cholesterol level","key_secondary_or_mortality":"Diabetes risk: odds ratio per 10 mg/dl decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR; increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events; when present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes.","safety":"","result":"Supports LDL causality","bottom_line":"Genetic mimicry shows that lowering LDL cholesterol via PCSK9 variants protects against cardiovascular events about as much as HMGCR (statin-target) variants, but both are linked to a smaller, additive increase in diabetes risk.","us_status":"Not applicable","evidence_quote":"Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR.","quote_verified":true,"slug":"ference-2016","family":"genetics","outcome":"safety"},{"trial":"GAUSS-3","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2016,"first_author":"Nissen","journal":"JAMA","title":"Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.","pmid":"27039291","doi":"10.1001/jama.2016.3608","design":"Two-stage randomized clinical trial; Phase A: crossover with atorvastatin vs placebo; Phase B: randomized (2:1) to evolocumab or ezetimibe","population":"Adult patients with uncontrolled LDL-C levels and history of intolerance to 2 or more statins, with muscle symptoms confirmed by statin rechallenge (or elevated creatine kinase)","n":218,"intervention":"Subcutaneous evolocumab 420 mg monthly (n=145)","comparator":"Oral ezetimibe 10 mg daily (n=73)","follow_up":"24 weeks","primary_endpoint":"Mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels, and from baseline to week 24 levels","primary_result":"For the mean of weeks 22 and 24, mean percent LDL-C change was -16.7% (95% CI, -20.5% to -12.9%) with ezetimibe vs -54.5% (95% CI, -57.2% to -51.8%) with evolocumab (P < .001); between-group difference -37.8%. At week 24, mean percent change was -16.7% (95% CI, -20.8% to -12.5%) with ezetimibe vs -52.8% (95% CI, -55.8% to -49.8%) with evolocumab (P < .001); between-group difference -36.1%.","ldl_effect":"Ezetimibe: LDL-C 183.0 mg/dL at mean of weeks 22/24 (absolute change -31.0 mg/dL), 181.5 mg/dL at week 24 (absolute change -31.2 mg/dL). Evolocumab: LDL-C 103.6 mg/dL at mean of weeks 22/24 (absolute change -106.8 mg/dL), 104.1 mg/dL at week 24 (absolute change -102.9 mg/dL). Between-group absolute difference -75.8 mg/dL (mean of weeks 22/24) and -71.7 mg/dL (week 24).","key_secondary_or_mortality":"Not reported","safety":"Muscle symptoms reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).","result":"Primary lipid endpoint met","bottom_line":"In statin-intolerant patients, evolocumab produced substantially greater LDL-C lowering than ezetimibe over 24 weeks, with fewer treatment discontinuations for muscle symptoms.","us_status":"US-approved","evidence_quote":"For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001).","quote_verified":true,"slug":"gauss-3","family":"pcsk9","outcome":"lipids"},{"trial":"GLAGOV","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Imaging RCT","year":2016,"first_author":"Nicholls","journal":"JAMA","title":"Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial.","pmid":"27846344","doi":"10.1001/jama.2016.16951","design":"double-blind, placebo-controlled, randomized clinical trial","population":"Patients with angiographic coronary disease presenting for coronary angiography, on background statin therapy (mean age 59.8 years [SD 9.2]; 27.8% women; mean LDL-C 92.5 mg/dL [SD 27.2])","n":968,"intervention":"Monthly evolocumab 420 mg subcutaneous injection plus statin (n=484)","comparator":"Placebo subcutaneous injection plus statin (n=484)","follow_up":"76 weeks of treatment (imaging at week 78)","primary_endpoint":"Nominal change in percent atheroma volume (PAV) from baseline to week 78 by serial IVUS imaging","primary_result":"PAV increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001)","ldl_effect":"Evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001)","key_secondary_or_mortality":"Normalized TAV decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV)","safety":"Safety and tolerability were also evaluated (no specific safety data reported in abstract)","result":"Plaque regression / favourable change","bottom_line":"Adding evolocumab to statin therapy in patients with coronary artery disease caused regression of coronary atherosclerosis on IVUS imaging compared with placebo, though its effect on clinical cardiovascular outcomes was not assessed in this trial.","us_status":"US-approved","evidence_quote":"The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001).","quote_verified":true,"slug":"glagov","family":"pcsk9","outcome":"lipids"},{"trial":"HOPE-3","drug_class":"Statin","drug":"Rosuvastatin","study_type":"Cardiovascular outcome trial","year":2016,"first_author":"Yusuf","journal":"N Engl J Med","title":"Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease.","pmid":"27040132","doi":"10.1056/NEJMoa1600176","design":"randomized, 2-by-2 factorial trial (this comparison placebo-controlled)","population":"12,705 participants in 21 countries without cardiovascular disease, at intermediate risk, ethnically diverse","n":12705,"intervention":"Rosuvastatin 10 mg per day","comparator":"Placebo","follow_up":"median follow-up of 5.6 years","primary_endpoint":"First coprimary outcome: composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; Second coprimary outcome: additionally included revascularization, heart failure, and resuscitated cardiac arrest","primary_result":"The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001).","ldl_effect":"The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group.","key_secondary_or_mortality":"The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group.","safety":"In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005).","result":"Benefit","bottom_line":"In an intermediate-risk, ethnically diverse population without cardiovascular disease, rosuvastatin 10 mg daily significantly lowered the risk of major cardiovascular events compared with placebo, though with a modest increase in cataract surgery and muscle symptoms.","us_status":"US-approved","evidence_quote":"The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002).","quote_verified":true,"slug":"hope-3","family":"statins","outcome":"benefit"},{"trial":"ACCELERATE","drug_class":"CETP inhibitor","drug":"Evacetrapib","study_type":"Cardiovascular outcome trial","year":2017,"first_author":"Lincoff","journal":"N Engl J Med","title":"Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease.","pmid":"28514624","doi":"10.1056/NEJMoa1609581","design":"multicenter, randomized, double-blind, placebo-controlled phase 3 trial","population":"patients with high-risk vascular disease: acute coronary syndrome within previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease","n":12092,"intervention":"Evacetrapib 130 mg daily plus standard medical therapy","comparator":"Matching placebo plus standard medical therapy","follow_up":"median of 26 months","primary_endpoint":"First occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina","primary_result":"a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91)","ldl_effect":"At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo.","key_secondary_or_mortality":"","safety":"Trial terminated early after 1363 of the planned 1670 primary end-point events because of a lack of efficacy.","result":"No significant benefit","bottom_line":"Despite markedly improving LDL and HDL cholesterol levels, evacetrapib did not reduce cardiovascular events compared with placebo in high-risk vascular disease patients, and the trial was stopped early for futility.","us_status":"Discontinued","evidence_quote":"After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).","quote_verified":true,"slug":"accelerate","family":"cetp","outcome":"no-benefit"},{"trial":"EBBINGHAUS","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Safety/tolerability RCT","year":2017,"first_author":"Giugliano","journal":"N Engl J Med","title":"Cognitive Function in a Randomized Trial of Evolocumab.","pmid":"28813214","doi":"10.1056/NEJMoa1701131","design":"randomized, placebo-controlled trial (noninferiority analysis for primary endpoint)","population":"Subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, with prospective cognitive function assessment","n":1204,"intervention":"Evolocumab added to statin therapy","comparator":"Placebo added to statin therapy","follow_up":"median of 19 months","primary_endpoint":"Mean change from baseline in score on the spatial working memory strategy index of executive function (noninferiority comparison)","primary_result":"the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was -0.21±2.62 in the evolocumab group and -0.29±2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority)","ldl_effect":"In an exploratory analysis, there were no associations between LDL cholesterol levels and cognitive changes.","key_secondary_or_mortality":"There were no significant between-group differences in the secondary end points of scores for working memory (change in raw score, -0.52 in the evolocumab group and -0.93 in the placebo group), episodic memory (change in raw score, -1.53 and -1.53, respectively), or psychomotor speed (change in raw score, 5.2 msec and 0.9 msec, respectively).","safety":"No significant between-group differences in cognitive secondary endpoints reported; no other safety data provided in abstract.","result":"No excess harm vs placebo","bottom_line":"Adding evolocumab to statin therapy did not worsen cognitive function compared with placebo over a median follow-up of 19 months.","us_status":"US-approved","evidence_quote":"the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was -0.21±2.62 in the evolocumab group and -0.29±2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority).","quote_verified":true,"slug":"ebbinghaus","family":"pcsk9","outcome":"safety"},{"trial":"FOURIER","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Cardiovascular outcome trial","year":2017,"first_author":"Sabatine","journal":"N Engl J Med","title":"Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.","pmid":"28304224","doi":"10.1056/NEJMoa1615664","design":"randomized, double-blind, placebo-controlled trial","population":"patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy","n":27564,"intervention":"evolocumab (either 140 mg every 2 weeks or 420 mg monthly)","comparator":"matching placebo","follow_up":"median duration of follow-up was 2.2 years","primary_endpoint":"composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization","primary_result":"1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001","ldl_effect":"least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001)","key_secondary_or_mortality":"key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke): 816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001","safety":"There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%)","result":"Benefit","bottom_line":"Adding evolocumab to statin therapy substantially lowers LDL cholesterol and reduces cardiovascular events in patients with atherosclerotic cardiovascular disease, with injection-site reactions being the main added safety concern.","us_status":"US-approved","evidence_quote":"Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001).","quote_verified":true,"slug":"fourier","family":"pcsk9","outcome":"benefit"},{"trial":"ORION-1","drug_class":"PCSK9 siRNA","drug":"Inclisiran","study_type":"Lipid-efficacy RCT","year":2017,"first_author":"Ray","journal":"N Engl J Med","title":"Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.","pmid":"28306389","doi":"10.1056/NEJMoa1615758","design":"Phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial","population":"Patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels","n":501,"intervention":"Single dose of 200, 300, or 500 mg inclisiran, or two doses (days 1 and 90) of 100, 200, or 300 mg inclisiran, subcutaneous injection","comparator":"Placebo (single dose or two doses)","follow_up":"Safety data through day 210; LDL cholesterol and PCSK9 data through day 240","primary_endpoint":"Change from baseline in LDL cholesterol level at 180 days","primary_result":"At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo).","ldl_effect":"Least-squares mean LDL-C reductions at day 180: 27.9-41.9% after a single dose; 35.5-52.6% after two doses; two-dose 300-mg regimen produced greatest reduction, with 48% of patients achieving LDL-C below 50 mg/dL (1.3 mmol/L) at day 180; at day 240, PCSK9 and LDL-C remained significantly lower than baseline with all regimens.","key_secondary_or_mortality":"Not reported","safety":"Serious adverse events occurred in 11% of patients who received inclisiran and in 8% of patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.","result":"Primary lipid endpoint met","bottom_line":"In this phase 2 trial, inclisiran produced substantial, dose-dependent, and durable reductions in LDL cholesterol and PCSK9 levels in high cardiovascular risk patients, with an acceptable safety profile, but the trial was not designed to assess cardiovascular outcomes.","us_status":"US-approved","evidence_quote":"At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo).","quote_verified":true,"slug":"orion-1","family":"pcsk9","outcome":"lipids"},{"trial":"REVEAL","drug_class":"CETP inhibitor","drug":"Anacetrapib","study_type":"Cardiovascular outcome trial","year":2017,"first_author":"HPS3/TIMI55–REVEAL Collaborative Group","journal":"N Engl J Med","title":"Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease.","pmid":"28847206","doi":"10.1056/NEJMoa1706444","design":"Randomized, double-blind, placebo-controlled trial","population":"Adults with atherosclerotic vascular disease receiving intensive atorvastatin therapy, mean LDL cholesterol 61 mg/dL, mean non-HDL cholesterol 92 mg/dL, mean HDL cholesterol 40 mg/dL","n":30449,"intervention":"100 mg of anacetrapib once daily (15,225 patients), added to intensive atorvastatin therapy","comparator":"Matching placebo (plus intensive atorvastatin therapy)","follow_up":"median follow-up period of 4.1 years","primary_endpoint":"First major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization","primary_result":"1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004","ldl_effect":"Mean LDL cholesterol level at baseline was 61 mg per deciliter (1.58 mmol per liter); mean non-HDL cholesterol level was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%, in the anacetrapib group at the trial midpoint.","key_secondary_or_mortality":"There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.","safety":"There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.","result":"Benefit","bottom_line":"Adding the CETP inhibitor anacetrapib to intensive statin therapy modestly reduced major coronary events in patients with atherosclerotic vascular disease, without significant safety concerns.","us_status":"Not marketed","evidence_quote":"During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004).","quote_verified":true,"slug":"reveal","family":"cetp","outcome":"benefit"},{"trial":"SPIRE-1/2","drug_class":"PCSK9 antibody","drug":"Bococizumab","study_type":"Cardiovascular outcome trial","year":2017,"first_author":"Ridker","journal":"N Engl J Med","title":"Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.","pmid":"28304242","doi":"10.1056/NEJMoa1701488","design":"randomized, placebo-controlled (two parallel multinational trials, SPIRE-1 and SPIRE-2), stopped early","population":"High cardiovascular risk patients; SPIRE-1 (lower-risk) baseline LDL ≥70 mg/dl; SPIRE-2 (higher-risk) baseline LDL ≥100 mg/dl; 93% on statin therapy at baseline","n":27438,"intervention":"Bococizumab 150 mg subcutaneously every 2 weeks","comparator":"Placebo","follow_up":"Median follow-up 10 months (combined); 7 months (SPIRE-1); 12 months (SPIRE-2)","primary_endpoint":"Nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death","primary_result":"Combined trials hazard ratio 0.88 (95% CI, 0.76 to 1.02; P=0.08); SPIRE-1 (lower-risk): hazard ratio 0.99 (95% CI, 0.80 to 1.22; P=0.94); SPIRE-2 (higher-risk): hazard ratio 0.79 (95% CI, 0.65 to 0.97; P=0.02)","ldl_effect":"Mean change from baseline in LDL cholesterol at 14 weeks: -56.0% bococizumab vs +2.9% placebo, between-group difference -59.0 percentage points (P<0.001); median reduction from baseline of 64.2% (P<0.001)","key_secondary_or_mortality":"Major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group in SPIRE-1; major cardiovascular events occurred in 179 and 224 patients, respectively, in SPIRE-2","safety":"Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001); trials stopped early owing in part to development of high rates of antidrug antibodies","result":"No significant benefit (program stopped)","bottom_line":"Bococizumab substantially lowered LDL cholesterol but showed no significant reduction in major cardiovascular events overall, with benefit seen only in the higher-risk trial, and the drug's development was discontinued due to high rates of antidrug antibodies and injection-site reactions.","us_status":"Discontinued","evidence_quote":"The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001).","quote_verified":true,"slug":"spire-1-2","family":"pcsk9","outcome":"no-benefit"},{"trial":"ASCEND","drug_class":"Omega-3","drug":"Omega-3 (1 g)","study_type":"Cardiovascular outcome trial","year":2018,"first_author":"ASCEND Study Collaborative Group","journal":"N Engl J Med","title":"Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.","pmid":"30146932","doi":"10.1056/NEJMoa1804989","design":"Randomized, placebo-controlled trial","population":"Patients with diabetes mellitus but without evidence of atherosclerotic cardiovascular disease","n":15480,"intervention":"n-3 fatty acid 1-g capsules daily (fatty acid group)","comparator":"Placebo (olive oil)","follow_up":"mean follow-up of 7.4 years","primary_endpoint":"First serious vascular event (nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage)","primary_result":"A serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% CI, 0.87 to 1.08; P=0.55)","ldl_effect":"","key_secondary_or_mortality":"Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09).","safety":"There were no significant between-group differences in the rates of nonfatal serious adverse events.","result":"No significant benefit","bottom_line":"In diabetic patients without known cardiovascular disease, daily 1-g omega-3 fatty acid supplementation did not reduce serious vascular events compared with placebo.","us_status":"OTC supplement / Rx omega-3 ethyl esters","evidence_quote":"During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55).","quote_verified":true,"slug":"ascend","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"ODYSSEY OUTCOMES","drug_class":"PCSK9 antibody","drug":"Alirocumab","study_type":"Cardiovascular outcome trial","year":2018,"first_author":"Schwartz","journal":"N Engl J Med","title":"Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.","pmid":"30403574","doi":"10.1056/NEJMoa1801174","design":"multicenter, randomized, double-blind, placebo-controlled trial","population":"Patients who had an acute coronary syndrome 1 to 12 months earlier, with LDL cholesterol ≥70 mg/dl (1.8 mmol/liter), non-HDL cholesterol ≥100 mg/dl (2.6 mmol/liter), or apolipoprotein B ≥80 mg/dl, receiving statin therapy at a high-intensity dose or at the maximum tolerated dose","n":18924,"intervention":"Alirocumab 75 mg subcutaneously every 2 weeks (dose adjusted under blinded conditions to target LDL cholesterol 25 to 50 mg/deciliter), 9462 patients","comparator":"Matching placebo, 9462 patients","follow_up":"median duration of follow-up was 2.8 years","primary_endpoint":"Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization","primary_result":"A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001)","ldl_effect":"The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter)","key_secondary_or_mortality":"A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98)","safety":"The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group)","result":"Benefit","bottom_line":"In post-ACS patients already on high-intensity statins, adding alirocumab reduced recurrent cardiovascular events and all-cause death compared with placebo.","us_status":"US-approved","evidence_quote":"A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001).","quote_verified":true,"slug":"odyssey-outcomes","family":"pcsk9","outcome":"benefit"},{"trial":"APPROACH","drug_class":"APOC3","drug":"Volanesorsen","study_type":"Lipid-efficacy RCT","year":2019,"first_author":"Witztum","journal":"N Engl J Med","title":"Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.","pmid":"31390500","doi":"10.1056/NEJMoa1715944","design":"phase 3, double-blind, randomized 52-week trial","population":"Patients with familial chylomicronemia syndrome, a rare genetic disorder caused by loss of lipoprotein lipase activity characterized by chylomicronemia and recurrent episodes of pancreatitis","n":66,"intervention":"Volanesorsen (antisense-mediated inhibition of hepatic APOC3 mRNA)","comparator":"Placebo","follow_up":"52 weeks (primary endpoint assessed at 3 months)","primary_endpoint":"Percentage change in fasting triglyceride levels from baseline to 3 months","primary_result":"Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% CI, 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001)","ldl_effect":"Not reported for LDL; apolipoprotein C-III decreased from baseline by 25.7 mg per deciliter (84% decrease) at 3 months with volanesorsen vs. increase of 1.9 mg per deciliter (6.1% increase) with placebo (P<0.001)","key_secondary_or_mortality":"At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter)","safety":"A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began.","result":"Primary lipid endpoint met","bottom_line":"In patients with familial chylomicronemia syndrome, volanesorsen substantially lowered triglyceride and apolipoprotein C-III levels compared with placebo but caused frequent injection-site reactions and thrombocytopenia.","us_status":"Not US-approved (EU)","evidence_quote":"Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001).","quote_verified":true,"slug":"approach","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"CLEAR Harmony","drug_class":"Bempedoic acid","drug":"Bempedoic acid","study_type":"Lipid-efficacy RCT","year":2019,"first_author":"Ray","journal":"N Engl J Med","title":"Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol.","pmid":"30865796","doi":"10.1056/NEJMoa1803917","design":"Randomized, controlled trial (2:1 randomization), 52 weeks","population":"Patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both, with LDL cholesterol ≥70 mg/dL while receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy","n":2230,"intervention":"Bempedoic acid","comparator":"Placebo (added to maximally tolerated statin therapy)","follow_up":"52 weeks","primary_endpoint":"Safety (incidence of adverse events); principal secondary (efficacy) end point was percentage change in LDL cholesterol level at week 12","primary_result":"Incidence of adverse events: 1167 of 1487 patients (78.5%) in the bempedoic acid group and 584 of 742 (78.7%) in the placebo group; did not differ substantially between groups","ldl_effect":"Reduced mean LDL cholesterol by 19.2 mg/dL, a -16.5% change from baseline; difference vs. placebo -18.1 percentage points (95% CI, -20.0 to -16.1; P<0.001)","key_secondary_or_mortality":"Not reported in abstract (principal secondary/efficacy endpoint was percentage change in LDL cholesterol at week 12; no mortality data reported)","safety":"Serious adverse events: 216 patients (14.5%) bempedoic acid vs. 104 (14.0%) placebo; adverse events leading to discontinuation: 162 (10.9%) vs. 53 (7.1%); gout: 18 patients (1.2%) vs. 2 (0.3%)","result":"Primary safety endpoint met; LDL-C lowered","bottom_line":"In statin-treated patients with ASCVD or familial hypercholesterolemia, adding bempedoic acid significantly lowered LDL cholesterol compared with placebo over 52 weeks without increasing overall adverse events, though it was linked to more treatment discontinuations and gout.","us_status":"US-approved","evidence_quote":"At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001).","quote_verified":true,"slug":"clear-harmony","family":"bempedoic-acid","outcome":"lipids"},{"trial":"CLEAR Serenity","drug_class":"Bempedoic acid","drug":"Bempedoic acid","study_type":"Lipid-efficacy RCT","year":2019,"first_author":"Laufs","journal":"J Am Heart Assoc","title":"Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance.","pmid":"30922146","doi":"10.1161/JAHA.118.011662","design":"Phase 3, double-blind, placebo-controlled, randomized 2:1","population":"Patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose); mean age 65.2 years, mean baseline LDL-C 157.6 mg/dL, 93% with history of statin-associated muscle symptoms","n":345,"intervention":"Bempedoic acid 180 mg once daily","comparator":"Placebo once daily","follow_up":"24 weeks (primary endpoint assessed at week 12)","primary_endpoint":"Mean percent change from baseline to week 12 in low-density lipoprotein cholesterol","primary_result":"Placebo-corrected difference in LDL-C, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001","ldl_effect":"Placebo-corrected difference in LDL-C, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001","key_secondary_or_mortality":"Significant reductions vs placebo in non-HDL cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%); P<0.001 for all comparisons.","safety":"Bempedoic acid was safe and well tolerated. Myalgia (most common muscle-related adverse event) occurred in 4.7% of bempedoic acid patients vs 7.2% of placebo patients.","result":"Primary lipid endpoint met","bottom_line":"In statin-intolerant patients with high cholesterol, bempedoic acid 180 mg daily significantly lowered LDL cholesterol and other atherogenic lipids and inflammation markers compared with placebo, with a safety and muscle-symptom profile similar to or better than placebo.","us_status":"US-approved","evidence_quote":"Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively.","quote_verified":true,"slug":"clear-serenity","family":"bempedoic-acid","outcome":"lipids"},{"trial":"CLEAR Wisdom","drug_class":"Bempedoic acid","drug":"Bempedoic acid","study_type":"Lipid-efficacy RCT","year":2019,"first_author":"Goldberg","journal":"JAMA","title":"Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial.","pmid":"31714986","doi":"10.1001/jama.2019.16585","design":"Phase 3, randomized, double-blind, placebo-controlled clinical trial","population":"Patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both, with LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy","n":779,"intervention":"Bempedoic acid (180 mg) once daily (n=522)","comparator":"Placebo once daily (n=257)","follow_up":"52 weeks (primary endpoint assessed at week 12; final follow-up date September 22, 2018)","primary_endpoint":"Percent change from baseline in LDL-C level at week 12","primary_result":"Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001)","ldl_effect":"-15.1% vs 2.4%; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001","key_secondary_or_mortality":"Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04)","safety":"Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%)","result":"Primary lipid endpoint met","bottom_line":"Adding bempedoic acid to maximally tolerated statin therapy significantly lowered LDL-C and other atherogenic lipid markers compared with placebo over 12 weeks, though cardiovascular outcome benefit was not assessed in this trial.","us_status":"US-approved","evidence_quote":"Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001).","quote_verified":true,"slug":"clear-wisdom","family":"bempedoic-acid","outcome":"lipids"},{"trial":"CTT 2019 older people","drug_class":"Meta-analysis","drug":"Statins","study_type":"Meta-analysis","year":2019,"first_author":"Cholesterol Treatment Trialists' Collaboration","journal":"Lancet","title":"Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials.","pmid":"30712900","doi":"10.1016/S0140-6736(18)31942-1","design":"Meta-analysis of individual participant data from randomised controlled trials of statin therapy versus control and more intensive versus less intensive statin therapy","population":"Participants in 28 randomised statin trials, subdivided into six age groups (≤55, 56-60, 61-65, 66-70, 71-75, >75 years); 14 483 (8%) of 186 854 participants were older than 75 years at randomisation","n":186854,"intervention":"Statin therapy or more intensive statin regimen","comparator":"Control or less intensive statin therapy","follow_up":"median follow-up duration was 4·9 years","primary_endpoint":"Major vascular events (major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence, expressed as rate ratio per 1·0 mmol/L reduction in LDL cholesterol","primary_result":"Statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77-0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol; proportional reductions diminished slightly with age but trend was not statistically significant (ptrend=0·06)","ldl_effect":"Effects expressed per 1·0 mmol/L reduction in LDL cholesterol","key_secondary_or_mortality":"12% (RR 0·88, 95% CI 0·85-0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with trend towards smaller proportional reductions with older age (ptrend=0·004) that did not persist after exclusion of heart failure/dialysis trials (ptrend=0·2); statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence","safety":"Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence","result":"Benefit","bottom_line":"Statins reduce major vascular events across all age groups including older people, though the evidence for benefit beyond age 75 without pre-existing vascular disease is less direct and being addressed by further trials.","us_status":"Not applicable","evidence_quote":"Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77-0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06).","quote_verified":true,"slug":"ctt-2019-older-people","family":"meta-analyses","outcome":"benefit"},{"trial":"EWTOPIA 75","drug_class":"Ezetimibe","drug":"Ezetimibe","study_type":"Cardiovascular outcome trial","year":2019,"first_author":"Ouchi","journal":"Circulation","title":"Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.","pmid":"31434507","doi":"10.1161/CIRCULATIONAHA.118.039415","design":"multicenter, prospective, randomized, open-label, blinded end-point evaluation","population":"Patients aged ≥75 years with elevated LDL-C without history of coronary artery disease, in Japan","n":3796,"intervention":"Ezetimibe 10 mg once daily plus dietary counseling","comparator":"Usual care plus dietary counseling","follow_up":"Median follow-up was 4.1 years","primary_endpoint":"Composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke","primary_result":"Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002)","ldl_effect":"","key_secondary_or_mortality":"Composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group; no difference in incidence of stroke, all-cause mortality, or adverse events between trial groups","safety":"No difference in the incidence of ... adverse events between trial groups","result":"Benefit","bottom_line":"In patients aged 75 or older with elevated LDL-C and no history of coronary disease, adding ezetimibe to usual care reduced cardiovascular events, though open-label design, early termination, and follow-up issues warrant cautious interpretation of the benefit's magnitude.","us_status":"US-approved","evidence_quote":"Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002).","quote_verified":true,"slug":"ewtopia-75","family":"ezetimibe","outcome":"benefit"},{"trial":"REDUCE-IT","drug_class":"Omega-3","drug":"Icosapent ethyl","study_type":"Cardiovascular outcome trial","year":2019,"first_author":"Bhatt","journal":"N Engl J Med","title":"Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.","pmid":"30415628","doi":"10.1056/NEJMoa1812792","design":"multicenter, randomized, double-blind, placebo-controlled trial","population":"Patients with established cardiovascular disease or with diabetes and other risk factors, receiving statin therapy, with fasting triglyceride level of 135 to 499 mg per deciliter and LDL-C level of 41 to 100 mg per deciliter (70.7% enrolled for secondary prevention)","n":8179,"intervention":"2 g of icosapent ethyl twice daily (total daily dose, 4 g)","comparator":"Placebo","follow_up":"median of 4.9 years","primary_endpoint":"Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina","primary_result":"A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001)","ldl_effect":"''","key_secondary_or_mortality":"Key secondary end point (cardiovascular death, nonfatal MI, or nonfatal stroke) rates were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001); cardiovascular death rate was 4.3% vs. 5.2% (hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03)","safety":"A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06).","result":"Benefit","bottom_line":"In statin-treated patients with elevated triglycerides, icosapent ethyl significantly reduced cardiovascular events including cardiovascular death, though at the cost of more atrial fibrillation hospitalizations and a trend toward more serious bleeding.","us_status":"US-approved","evidence_quote":"A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001).","quote_verified":true,"slug":"reduce-it","family":"fibrates-omega-3-niacin","outcome":"benefit"},{"trial":"VITAL","drug_class":"Omega-3","drug":"Omega-3 (1 g)","study_type":"Cardiovascular outcome trial","year":2019,"first_author":"Manson","journal":"N Engl J Med","title":"Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer.","pmid":"30415637","doi":"10.1056/NEJMoa1811403","design":"randomized, placebo-controlled trial, with a two-by-two factorial design","population":"Men 50 years of age or older and women 55 years of age or older in the United States, primary prevention population, including 5106 black participants","n":25871,"intervention":"Marine n-3 fatty acids at a dose of 1 g per day","comparator":"Placebo","follow_up":"median follow-up of 5.3 years","primary_endpoint":"Major cardiovascular events (composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type","primary_result":"Major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% CI, 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56).","ldl_effect":"","key_secondary_or_mortality":"For death from cardiovascular causes, hazard ratio 0.96 (95% CI, 0.76 to 1.21); for death from cancer (341 deaths from cancer), hazard ratio 0.97 (95% CI, 0.79 to 1.20); death from any cause (978 deaths overall), hazard ratio 1.02 (95% CI, 0.90 to 1.15). Key secondary: expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); total stroke, 1.04 (95% CI, 0.83 to 1.31).","safety":"No excess risks of bleeding or other serious adverse events were observed.","result":"No significant benefit","bottom_line":"Daily supplementation with 1 g marine omega-3 fatty acids did not reduce the incidence of major cardiovascular events or invasive cancer compared with placebo, though it was safe and reduced total myocardial infarction as a secondary finding.","us_status":"OTC supplement / Rx omega-3 ethyl esters","evidence_quote":"During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n-3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n-3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56).","quote_verified":true,"slug":"vital","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"ELIPSE HoFH","drug_class":"ANGPTL3","drug":"Evinacumab","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Raal","journal":"N Engl J Med","title":"Evinacumab for Homozygous Familial Hypercholesterolemia.","pmid":"32813947","doi":"10.1056/NEJMoa2004215","design":"Double-blind, placebo-controlled, phase 3 trial, randomized 2:1","population":"Patients with homozygous familial hypercholesterolemia receiving stable lipid-lowering therapy; mean baseline LDL cholesterol 255.1 mg per deciliter despite maximum doses of background lipid-lowering therapy","n":65,"intervention":"Evinacumab 15 mg per kilogram intravenous infusion every 4 weeks","comparator":"Placebo (intravenous infusion every 4 weeks)","follow_up":"24 weeks","primary_endpoint":"Percent change from baseline in LDL cholesterol level at week 24","primary_result":"Between-group least-squares mean difference in percent change in LDL cholesterol of -49.0 percentage points (95% CI, -65.0 to -33.1; P<0.001)","ldl_effect":"Relative reduction from baseline in LDL cholesterol of 47.1% with evinacumab vs. increase of 1.9% with placebo; between-group least-squares mean difference -49.0 percentage points (95% CI, -65.0 to -33.1; P<0.001); absolute difference -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001)","key_secondary_or_mortality":"LDL cholesterol was lower with evinacumab than placebo in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%)","safety":"Adverse events were similar in the two groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with homozygous familial hypercholesterolemia already on maximal lipid-lowering therapy, adding evinacumab markedly lowered LDL cholesterol compared with placebo, with similar adverse event rates.","us_status":"US-approved","evidence_quote":"At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001).","quote_verified":true,"slug":"elipse-hofh","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"Evinacumab refractory HC","drug_class":"ANGPTL3","drug":"Evinacumab","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Rosenson","journal":"N Engl J Med","title":"Evinacumab in Patients with Refractory Hypercholesterolemia.","pmid":"33196153","doi":"10.1056/NEJMoa2031049","design":"double-blind, placebo-controlled, phase 2 trial","population":"Patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis","n":272,"intervention":"Subcutaneous evinacumab (450 mg weekly, 300 mg weekly, or 300 mg every 2 weeks) or intravenous evinacumab (15 mg/kg every 4 weeks or 5 mg/kg every 4 weeks)","comparator":"Placebo (subcutaneous or intravenous)","follow_up":"16 weeks","primary_endpoint":"Percent change from baseline in LDL cholesterol level at week 16 with evinacumab as compared with placebo","primary_result":"At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively.","ldl_effect":"Reduced LDL cholesterol by more than 50% at the maximum dose; differences vs placebo ranged from -24.2 to -56.0 percentage points across dose groups","key_secondary_or_mortality":"","safety":"The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with refractory hypercholesterolemia despite maximal lipid-lowering therapy, evinacumab substantially and significantly lowered LDL cholesterol compared with placebo, with serious adverse events occurring at variable rates across dose groups.","us_status":"US-approved","evidence_quote":"At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons).","quote_verified":true,"slug":"evinacumab-refractory-hc","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"HAUSER-RCT","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Santos","journal":"N Engl J Med","title":"Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia.","pmid":"32865373","doi":"10.1056/NEJMoa2019910","design":"24-week, randomized, double-blind, placebo-controlled trial, 2:1 randomization","population":"Patients 10 to 17 years of age with heterozygous familial hypercholesterolemia, on stable lipid-lowering treatment for at least 4 weeks before screening, with LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less","n":157,"intervention":"Evolocumab 420 mg monthly subcutaneous injections (104 patients)","comparator":"Placebo monthly subcutaneous injections (53 patients)","follow_up":"24 weeks","primary_endpoint":"Percent change in LDL cholesterol level from baseline to week 24","primary_result":"At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001)","ldl_effect":"Mean percent change from baseline: -44.5% (evolocumab) vs -6.2% (placebo), difference -38.3 percentage points (P<0.001); absolute change -77.5 mg per deciliter (-2.0 mmol per liter) vs -9.0 mg per deciliter (-0.2 mmol per liter), difference -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001)","key_secondary_or_mortality":"Results for all secondary lipid variables were significantly better with evolocumab than with placebo.","safety":"The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups.","result":"Primary lipid endpoint met","bottom_line":"In pediatric patients with heterozygous familial hypercholesterolemia already on lipid-lowering therapy, adding monthly evolocumab substantially lowered LDL cholesterol compared with placebo with a similar adverse event rate.","us_status":"US-approved","evidence_quote":"At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001).","quote_verified":true,"slug":"hauser-rct","family":"pcsk9","outcome":"lipids"},{"trial":"ORION-10/11","drug_class":"PCSK9 siRNA","drug":"Inclisiran","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Ray","journal":"N Engl J Med","title":"Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.","pmid":"32187462","doi":"10.1056/NEJMoa1912387","design":"Two Phase 3, randomized trials (1:1 randomization to inclisiran or placebo); placebo-controlled","population":"Patients with atherosclerotic cardiovascular disease (ORION-10) or atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11) with elevated LDL cholesterol despite maximum tolerated statin therapy","n":3178,"intervention":"Inclisiran 284 mg subcutaneous injection on day 1, day 90, and every 6 months thereafter","comparator":"Placebo (subcutaneous injection on same schedule)","follow_up":"540 days","primary_endpoint":"Coprimary end points: placebo-corrected percentage change in LDL cholesterol from baseline to day 510, and time-adjusted percentage change in LDL cholesterol from baseline after day 90 up to day 540","primary_result":"Inclisiran reduced LDL cholesterol levels by 52.3% (95% CI, 48.8 to 55.7) in ORION-10 and 49.9% (95% CI, 46.6 to 53.1) in ORION-11 at day 510, with time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo)","ldl_effect":"Placebo-corrected LDL-C reduction of 52.3% (95% CI, 48.8 to 55.7) at day 510 in ORION-10 and 49.9% (95% CI, 46.6 to 53.1) in ORION-11; time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6), respectively (P<0.001 for all comparisons vs. placebo)","key_secondary_or_mortality":"Not reported in this abstract","safety":"Adverse events were generally similar between inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in ORION-10 and 4.7% vs. 0.5% in ORION-11); such reactions were generally mild, and none were severe or persistent","result":"Primary lipid endpoint met","bottom_line":"Twice-yearly inclisiran injections lowered LDL cholesterol by about 50% compared with placebo in statin-treated patients with atherosclerotic cardiovascular disease, with mostly mild injection-site reactions as the main safety difference.","us_status":"US-approved","evidence_quote":"At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo).","quote_verified":true,"slug":"orion-10-11","family":"pcsk9","outcome":"lipids"},{"trial":"ORION-9","drug_class":"PCSK9 siRNA","drug":"Inclisiran","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Raal","journal":"N Engl J Med","title":"Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.","pmid":"32197277","doi":"10.1056/NEJMoa1913805","design":"phase 3, double-blind, randomized, placebo-controlled trial (1:1)","population":"Adults with heterozygous familial hypercholesterolemia; median age 56 years, 47% men, mean baseline LDL cholesterol 153 mg/dl","n":482,"intervention":"Inclisiran sodium 300 mg subcutaneous injection on days 1, 90, 270, and 450","comparator":"Matching placebo","follow_up":"Through day 540","primary_endpoint":"Percent change from baseline in LDL cholesterol level on day 510, and time-adjusted percent change from baseline in LDL cholesterol level between day 90 and day 540","primary_result":"At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% CI, -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001).","ldl_effect":"Reduction of 39.7% at day 510 and time-averaged reduction of 38.1% (day 90-540) with inclisiran vs increases of 8.2% and 6.2% respectively with placebo; between-group differences of -47.9 and -44.3 percentage points","key_secondary_or_mortality":"There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia.","safety":"Adverse events and serious adverse events were similar in the two groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolemia, twice-yearly inclisiran injections significantly lowered LDL cholesterol compared with placebo, with a similar safety profile and a convenient infrequent dosing schedule.","us_status":"US-approved","evidence_quote":"At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001).","quote_verified":true,"slug":"orion-9","family":"pcsk9","outcome":"lipids"},{"trial":"PCSK9/ezetimibe diabetes meta-analysis","drug_class":"Meta-analysis","drug":"PCSK9 inhibitors, ezetimibe","study_type":"Meta-analysis","year":2020,"first_author":"Chiu","journal":"J Cardiovasc Pharmacol Ther","title":"Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials.","pmid":"32419478","doi":"10.1177/1074248420924983","design":"Systematic review and meta-analysis of double-blinded randomized controlled trials, random effects model","population":"Patients without previously diagnosed diabetes from large, double-blinded RCTs of PCSK9 inhibitors (8 trials) or ezetimibe (3 trials), with at least 100 patients per treatment arm and follow-up of at least 52 weeks","n":72298,"intervention":"PCSK9 inhibitors (PCSK9i) or ezetimibe","comparator":"Placebo/control added to guideline-directed medical therapy","follow_up":"At least 52 weeks","primary_endpoint":"Number of incident (new-onset) diabetes cases","primary_result":"PCSK9i: risk ratio [RR] = 0.99, P = .87, 95% CI = 0.92-1.07; Ezetimibe: RR = 1.05, P = .37, 95% CI = 0.95-1.15","ldl_effect":"","key_secondary_or_mortality":"","safety":"","result":"No excess risk","bottom_line":"Neither PCSK9 inhibitors nor ezetimibe increase the risk of new-onset diabetes when added to guideline-directed medical therapy.","us_status":"Not applicable","evidence_quote":"Participants randomized to PCSK9i did not differ from the control patients in diabetes incidence (risk ratio [RR] = 0.99, P = .87, 95% CI = 0.92-1.07). Participants randomized to ezetimibe did not differ from the control patients in diabetes incidence (RR = 1.05, P = .37, 95% CI = 0.95-1.15).","quote_verified":true,"slug":"pcsk9-ezetimibe-diabetes-meta-analysis","family":"meta-analyses","outcome":"safety"},{"trial":"Pelacarsen phase 2","drug_class":"Lp(a)","drug":"Pelacarsen","study_type":"Lipid-efficacy RCT","year":2020,"first_author":"Tsimikas","journal":"N Engl J Med","title":"Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.","pmid":"31893580","doi":"10.1056/NEJMoa1905239","design":"randomized, double-blind, placebo-controlled, dose-ranging trial","population":"Patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter)","n":286,"intervention":"Hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx (pelacarsen) at 20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week, subcutaneously","comparator":"Saline placebo subcutaneously","follow_up":"6 to 12 months","primary_endpoint":"Percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in monthly-dose groups and week 27 in more frequent dose groups)","primary_result":"Mean percent decreases in lipoprotein(a) of 35% at 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001)","ldl_effect":"''","key_secondary_or_mortality":"''","safety":"There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.","result":"Primary lipid endpoint met","bottom_line":"In patients with cardiovascular disease and elevated Lp(a), the antisense drug APO(a)-LRx (pelacarsen) lowered Lp(a) levels in a dose-dependent manner, with no significant safety signals versus placebo, though cardiovascular outcomes were not assessed in this trial.","us_status":"Investigational","evidence_quote":"Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001).","quote_verified":true,"slug":"pelacarsen-phase-2","family":"lpa","outcome":"lipids"},{"trial":"STRENGTH","drug_class":"Omega-3","drug":"Omega-3 carboxylic acids","study_type":"Cardiovascular outcome trial","year":2020,"first_author":"Nicholls","journal":"JAMA","title":"Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.","pmid":"33190147","doi":"10.1001/jama.2020.22258","design":"double-blind, randomized, multicenter trial","population":"Statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low HDL-C (mean age 62.5 years; 35% women; 70% with diabetes; median LDL 75.0 mg/dL; median triglycerides 240 mg/dL; median HDL-C 36 mg/dL; median hs-CRP 2.1 mg/L)","n":13078,"intervention":"4 g/d omega-3 carboxylic acids (EPA and DHA formulation) (n=6539)","comparator":"Corn oil, intended as inert comparator (n=6539)","follow_up":"Enrollment October 30, 2014, to June 14, 2017; trial terminated January 8, 2020; last patient visit May 14, 2020","primary_endpoint":"Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization","primary_result":"The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84)","ldl_effect":"''","key_secondary_or_mortality":"''","safety":"A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%).","result":"No significant benefit","bottom_line":"In statin-treated high-risk patients, adding high-dose omega-3 carboxylic acids to usual therapy did not reduce major adverse cardiovascular events compared with corn oil and caused more GI side effects.","us_status":"FDA-approved for TG (not marketed)","evidence_quote":"The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84).","quote_verified":true,"slug":"strength","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"SAMSON","drug_class":"Statin","drug":"Atorvastatin","study_type":"Safety/tolerability RCT","year":2021,"first_author":"Howard","journal":"J Am Coll Cardiol","title":"Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.","pmid":"34531021","doi":"10.1016/j.jacc.2021.07.022","design":"randomized crossover trial of statin, placebo, and no treatment (blinded, N-of-1 style design using 12 monthly bottles: 4 atorvastatin, 4 placebo, 4 empty)","population":"Participants who had previously abandoned statin therapy due to side effects","n":60,"intervention":"Atorvastatin 20 mg (4 months)","comparator":"Placebo (4 months) and no treatment/empty bottle (4 months)","follow_up":"12-month protocol; 6 months post-trial follow-up","primary_endpoint":"Daily symptom intensity score (scale 1-100) during statin, placebo, and no-treatment months","primary_result":"Mean symptom score 8.0 (95% CI: 4.7-11.3) in no-tablet months; 16.3 (95% CI: 13.0-19.6; P < 0.001) in statin months; 15.4 (95% CI: 12.1-18.7; P < 0.001) in placebo months; no difference between statin and placebo (P = 0.388); nocebo ratio 0.90","ldl_effect":"","key_secondary_or_mortality":"Neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo; stopping was no more frequent for statin than placebo (P = 0.173); subsequent symptom relief was similar between statin and placebo; at 6 months after the trial, 30 of 60 (50%) participants were back taking statins","safety":"","result":"Symptoms largely nocebo","bottom_line":"In patients who had previously stopped statins due to side effects, symptom scores were equally elevated on statin and placebo compared with no treatment, indicating most statin-associated symptoms are a nocebo effect rather than a pharmacological effect of the drug.","us_status":"US-approved","evidence_quote":"Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90.","quote_verified":true,"slug":"samson","family":"statins","outcome":"safety"},{"trial":"StatinWISE","drug_class":"Statin","drug":"Atorvastatin","study_type":"Safety/tolerability RCT","year":2021,"first_author":"Herrett","journal":"BMJ","title":"Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials.","pmid":"33627334","doi":"10.1136/bmj.n135","design":"Series of randomised, placebo controlled n-of-1 trials, double blinded","population":"200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms; primary care across 50 sites in the United Kingdom, December 2016 to April 2018","n":200,"intervention":"Atorvastatin 20 mg daily","comparator":"Placebo","follow_up":"Six double blinded treatment periods of two months each","primary_endpoint":"Comparison of muscle symptom scores (0-10 visual analogue scale) between statin and placebo periods","primary_result":"mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40","ldl_effect":"","key_secondary_or_mortality":"Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins.","safety":"Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period.","result":"No excess harm vs placebo","bottom_line":"In patients with prior statin-associated muscle symptoms, atorvastatin 20 mg did not cause more muscle symptoms than placebo when tested in a blinded n-of-1 design, and most participants intended to resume statin therapy.","us_status":"US-approved","evidence_quote":"Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period.","quote_verified":true,"slug":"statinwise","family":"statins","outcome":"safety"},{"trial":"CTT 2022 muscle","drug_class":"Meta-analysis","drug":"Statins","study_type":"Meta-analysis","year":2022,"first_author":"Cholesterol Treatment Trialists' Collaboration","journal":"Lancet","title":"Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials.","pmid":"36049498","doi":"10.1016/S0140-6736(22)01545-8","design":"Individual participant data meta-analysis of randomised, double-blind trials","population":"Participants in large-scale, long-term, randomised, double-blind trials of statin therapy; 19 placebo-controlled trials (mean age 63 years [SD 8], 27.9% women, 48.1% with previous vascular disease, 18.5% with diabetes) and 4 trials of more vs less intensive statin regimens","n":154664,"intervention":"Statin therapy (various statins; also more intensive regimens such as 40-80 mg atorvastatin or 20-40 mg rosuvastatin once per day)","comparator":"Placebo (19 trials, n=123 940) or less intensive statin regimen (4 trials, n=30 724)","follow_up":"Weighted average median follow-up of 4.3 years","primary_endpoint":"Muscle pain or weakness reported by participants","primary_result":"16 835 (27.1%) allocated statin versus 16 446 (26.6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1.03; 95% CI 1.01-1.06); during year 1, RR 1.07 (1.04-1.10); after year 1, RR 0.99 (0.96-1.02)","ldl_effect":"''","key_secondary_or_mortality":"For all years combined, more intensive statin regimens yielded a higher RR than less intensive or moderate-intensity regimens (1.08 [1.04-1.13] vs 1.03 [1.00-1.05]) compared with placebo, with a small excess (1.05 [0.99-1.12]) for more intensive regimens after year 1","safety":"Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0.02 times the upper limit of normal; an absolute excess rate of 11 (6-16) events per 1000 person-years in year 1","result":"Adverse-effect signal (small)","bottom_line":"Statins cause a small, mostly mild excess of muscle pain primarily in the first year of treatment, with over 90% of muscle symptom reports in statin users not actually due to the statin, and this risk is far outweighed by cardiovascular benefits.","us_status":"Not applicable","evidence_quote":"During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04-1·10), corresponding to an absolute excess rate of 11 (6-16) events per 1000 person-years, which indicates that only one in 15 ([1·07-1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96-1·02).","quote_verified":true,"slug":"ctt-2022-muscle","family":"meta-analyses","outcome":"safety"},{"trial":"FOURIER-OLE","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Open-label extension","year":2022,"first_author":"O'Donoghue","journal":"Circulation","title":"Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.","pmid":"36031810","doi":"10.1161/CIRCULATIONAHA.122.061620","design":"Open-label extension (pooled analysis of two open-label extension studies) following randomized, parent trial (FOURIER)","population":"Patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin who completed the parent FOURIER trial at participating sites","n":6635,"intervention":"Open-label evolocumab (patients originally randomized to evolocumab or placebo in parent trial continued/initiated evolocumab)","comparator":"Original parent-trial randomization group (evolocumab vs placebo during parent FOURIER study, before open-label evolocumab initiation)","follow_up":"Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years","primary_endpoint":"Incidence of adverse events","primary_result":"Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time","ldl_effect":"At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab","key_secondary_or_mortality":"A 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04); also 15% lower risk of CV death/MI/stroke/hospitalization for unstable angina or coronary revascularization (HR 0.85 [0.75-0.96]; P=0.008) and 20% lower risk of CV death, MI, or stroke (HR 0.80 [0.68-0.93]; P=0.003)","safety":"Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time","result":"Long-term safety; benefit sustained","bottom_line":"Long-term evolocumab treatment after FOURIER maintained very low LDL-C with a persistently favorable safety profile over more than 8 years, and earlier initiation of evolocumab was associated with fewer cardiovascular events, including cardiovascular death, compared with delayed treatment start.","us_status":"US-approved","evidence_quote":"During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68-0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04).","quote_verified":true,"slug":"fourier-ole","family":"pcsk9","outcome":"safety"},{"trial":"HUYGENS","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Imaging RCT","year":2022,"first_author":"Nicholls","journal":"JACC Cardiovasc Imaging","title":"Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction.","pmid":"35431172","doi":"10.1016/j.jcmg.2022.03.002","design":"Randomized, (implied double-blind), placebo-controlled imaging trial","population":"Patients with non-ST-segment elevation myocardial infarction, on statin therapy; age 60.5 ± 9.6 years; 28.6% women; baseline LDL-C 141.3 ± 33.1 mg/dL","n":161,"intervention":"Monthly evolocumab 420 mg plus statin","comparator":"Placebo (on background statin)","follow_up":"52 weeks","primary_endpoint":"Change in minimum fibrous cap thickness and maximum lipid arc throughout the imaged arterial segment (OCT)","primary_result":"Evolocumab vs placebo: minimum fibrous cap thickness +42.7 vs +21.5 μm (P = 0.015); maximum lipid arc -57.5° vs -31.4° (P = 0.04)","ldl_effect":"Evolocumab group achieved LDL-C 28.1 mg/dL vs 87.2 mg/dL with placebo; P < 0.001","key_secondary_or_mortality":"Greater regression of percent atheroma volume was observed with evolocumab compared with placebo (-2.29% ± 0.47% vs -0.61% ± 0.46%; P = 0.009). Groups did not differ regarding changes in microchannels or calcium.","safety":"Safety and tolerability were evaluated (no specific adverse event data reported in abstract).","result":"Plaque regression / favourable change","bottom_line":"Adding evolocumab to statin therapy after NSTEMI led to greater regression and stabilization of coronary plaque on imaging (thicker fibrous caps, smaller lipid cores, less plaque burden) compared with placebo.","us_status":"US-approved","evidence_quote":"The evolocumab group demonstrated a greater increase in minimum fibrous cap thickness (+42.7 vs +21.5 μm; P = 0.015) and decrease in maximum lipid arc (-57.5o vs. -31.4o; P = 0.04) and macrophage index (-3.17 vs -1.45 mm; P = 0.04) throughout the arterial segment.","quote_verified":true,"slug":"huygens","family":"pcsk9","outcome":"lipids"},{"trial":"OCEAN(a)-DOSE","drug_class":"Lp(a)","drug":"Olpasiran","study_type":"Lipid-efficacy RCT","year":2022,"first_author":"O'Donoghue","journal":"N Engl J Med","title":"Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.","pmid":"36342163","doi":"10.1056/NEJMoa2211023","design":"randomized, double-blind, placebo-controlled, dose-finding trial","population":"Patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter","n":281,"intervention":"Olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks, subcutaneous)","comparator":"Matching placebo","follow_up":"36 weeks","primary_endpoint":"Percent change in lipoprotein(a) concentration from baseline to week 36 (placebo-adjusted mean percent change)","primary_result":"Placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline)","ldl_effect":"Median LDL-C at baseline was 67.5 mg per deciliter; no post-treatment LDL-C change reported","key_secondary_or_mortality":"Not reported; longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease","safety":"The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain.","result":"Primary lipid endpoint met","bottom_line":"Olpasiran markedly and dose-dependently lowered lipoprotein(a) levels in patients with established atherosclerotic cardiovascular disease and elevated Lp(a), with similar overall adverse event rates to placebo, but whether this translates into reduced cardiovascular events remains to be determined.","us_status":"Investigational","evidence_quote":"At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline).","quote_verified":true,"slug":"ocean-a-dose","family":"lpa","outcome":"lipids"},{"trial":"PACMAN-AMI","drug_class":"PCSK9 antibody","drug":"Alirocumab","study_type":"Imaging RCT","year":2022,"first_author":"Räber","journal":"JAMA","title":"Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial.","pmid":"35368058","doi":"10.1001/jama.2022.5218","design":"double-blind, placebo-controlled, randomized clinical trial","population":"Patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] LDL-C level, 152.4 [33.8] mg/dL)","n":300,"intervention":"Biweekly subcutaneous alirocumab (150 mg; n=148) added to high-intensity statin therapy (rosuvastatin, 20 mg), initiated less than 24 hours after urgent PCI of the culprit lesion, for 52 weeks","comparator":"Placebo (n=152) added to high-intensity statin therapy (rosuvastatin, 20 mg)","follow_up":"52 weeks","primary_endpoint":"Change in IVUS-derived percent atheroma volume from baseline to week 52","primary_result":"Mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001)","ldl_effect":"''","key_secondary_or_mortality":"Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001)","safety":"Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo","result":"Plaque regression / favourable change","bottom_line":"Adding alirocumab to high-intensity statin therapy after acute MI led to significantly greater regression of coronary plaque burden, lipid content, and thickening of fibrous caps over 52 weeks, with similar adverse event rates to placebo.","us_status":"US-approved","evidence_quote":"At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001).","quote_verified":true,"slug":"pacman-ami","family":"pcsk9","outcome":"lipids"},{"trial":"PROMINENT","drug_class":"Fibrate","drug":"Pemafibrate","study_type":"Cardiovascular outcome trial","year":2022,"first_author":"Das Pradhan","journal":"N Engl J Med","title":"Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.","pmid":"36342113","doi":"10.1056/NEJMoa2210645","design":"multinational, double-blind, randomized, controlled trial","population":"Patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and HDL cholesterol levels of 40 mg per deciliter or lower, receiving guideline-directed lipid-lowering therapy or unable to receive statins, with LDL cholesterol levels of 100 mg per deciliter or lower (66.9% with previous cardiovascular disease)","n":10497,"intervention":"Pemafibrate (0.2-mg tablets twice daily)","comparator":"Matching placebo","follow_up":"Median follow-up was 3.4 years","primary_endpoint":"Composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes","primary_result":"A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15)","ldl_effect":"4.8% for apolipoprotein B (no direct LDL percent change reported; triglycerides -26.2%, VLDL cholesterol -25.8%, remnant cholesterol -25.6%, apolipoprotein C-III -27.6%)","key_secondary_or_mortality":"No apparent effect modification in any prespecified subgroup","safety":"The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.","result":"No significant benefit","bottom_line":"In patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL/LDL cholesterol, pemafibrate lowered triglycerides and related lipid markers but did not reduce cardiovascular events compared with placebo and increased risks of renal events and venous thromboembolism.","us_status":"Not US-approved","evidence_quote":"A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup.","quote_verified":true,"slug":"prominent","family":"fibrates-omega-3-niacin","outcome":"no-benefit"},{"trial":"RACING","drug_class":"Ezetimibe","drug":"Rosuvastatin + ezetimibe","study_type":"Cardiovascular outcome trial","year":2022,"first_author":"Kim","journal":"Lancet","title":"Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial.","pmid":"35863366","doi":"10.1016/S0140-6736(22)00916-3","design":"randomised, open-label, non-inferiority trial","population":"Patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea","n":3780,"intervention":"Moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg)","comparator":"High-intensity statin monotherapy (rosuvastatin 20 mg)","follow_up":"3 years","primary_endpoint":"3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%","primary_result":"The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83).","ldl_effect":"LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001).","key_secondary_or_mortality":"","safety":"Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001).","result":"No significant benefit","bottom_line":"In patients with atherosclerotic cardiovascular disease, moderate-intensity rosuvastatin plus ezetimibe was non-inferior to high-intensity rosuvastatin alone for 3-year cardiovascular outcomes, achieved more patients with LDL under 70 mg/dL, and caused less drug intolerance-related discontinuation or dose reduction.","us_status":"US-approved","evidence_quote":"The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83).","quote_verified":true,"slug":"racing","family":"ezetimibe","outcome":"no-benefit"},{"trial":"CLEAR Outcomes","drug_class":"Bempedoic acid","drug":"Bempedoic acid","study_type":"Cardiovascular outcome trial","year":2023,"first_author":"Nissen","journal":"N Engl J Med","title":"Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.","pmid":"36876740","doi":"10.1056/NEJMoa2215024","design":"double-blind, randomized, placebo-controlled trial","population":"statin-intolerant patients with, or at high risk for, cardiovascular disease","n":13970,"intervention":"oral bempedoic acid, 180 mg daily","comparator":"placebo","follow_up":"median 40.6 months","primary_endpoint":"four-component composite of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization)","primary_result":"819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004","ldl_effect":"reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid","key_secondary_or_mortality":"Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. Composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction: 575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006; fatal or nonfatal myocardial infarction: 261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002; coronary revascularization: 435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001","safety":"The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.","result":"Benefit","bottom_line":"In statin-intolerant patients, bempedoic acid significantly lowered LDL cholesterol and reduced major adverse cardiovascular events compared with placebo, though it did not significantly reduce stroke or death, and was associated with more gout, gallstones, and modest increases in creatinine, uric acid, and liver enzymes.","us_status":"US-approved","evidence_quote":"The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004)","quote_verified":true,"slug":"clear-outcomes","family":"bempedoic-acid","outcome":"benefit"},{"trial":"LIBerate-HeFH","drug_class":"PCSK9 binder","drug":"Lerodalcibep","study_type":"Lipid-efficacy RCT","year":2023,"first_author":"Raal","journal":"Eur Heart J","title":"Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.","pmid":"37639462","doi":"10.1093/eurheartj/ehad596","design":"Randomized, placebo-controlled, Phase 3 trial (2:1 randomization)","population":"Heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering; mean age (range) 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L","n":478,"intervention":"","comparator":"Placebo subcutaneous injection monthly","follow_up":"24 weeks","primary_endpoint":"Per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24","primary_result":"Lerodalcibep reduced LDL-C vs placebo by -58.61 (3.25)% at Week 24 and -65.0 (2.87)% at mean of Weeks 22 and 24 (P < .0001 for all)","ldl_effect":"Absolute reduction vs placebo of 2.08 (0.11) mmol/L (95% CI -2.30 to -1.87), percentage difference -58.61 (3.25)% at Week 24; and 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09), percentage difference -65.0 (2.87)% at mean of Weeks 22 and 24 (P < .0001 for all)</ldl_effect>\n<parameter name=\"mortality_or_key_secondary\">With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study.","key_secondary_or_mortality":"","safety":"Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo.","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolaemia needing more LDL-C lowering, adding monthly subcutaneous lerodalcibep to therapy produced a large, highly significant LDL-C reduction versus placebo over 24 weeks with a safety profile similar to placebo aside from mild injection site reactions.","us_status":"US-approved","evidence_quote":"In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < .0001 for all).","quote_verified":true,"slug":"liberate-hefh","family":"pcsk9","outcome":"lipids"},{"trial":"LODESTAR","drug_class":"Statin","drug":"Rosuvastatin vs atorvastatin","study_type":"Cardiovascular outcome trial","year":2023,"first_author":"Lee","journal":"BMJ","title":"Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial.","pmid":"37852649","doi":"10.1136/bmj-2023-075837","design":"Randomised, open label, multicentre trial (2x2 factorial randomisation)","population":"4400 adults (age ≥19 years) with coronary artery disease, enrolled at 12 hospitals in South Korea, September 2016 to November 2019","n":4400,"intervention":"Rosuvastatin (n=2204; mean daily dose 17.1 mg (SD 5.2 mg) at three years)","comparator":"Atorvastatin (n=2196; mean daily dose 36.0 (12.8) mg at three years)","follow_up":"Three years","primary_endpoint":"Three year composite of all cause death, myocardial infarction, stroke, or any coronary revascularisation","primary_result":"The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58)","ldl_effect":"The mean low density lipoprotein (LDL) cholesterol level during treatment was 1.8 mmol/L (SD 0.5 mmol/L) in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin group (P<0.001)","key_secondary_or_mortality":"Composite primary outcome (including all-cause death) did not differ significantly between groups; no separate all-cause mortality figure reported","safety":"Rosuvastatin group had higher incidence of new onset diabetes mellitus requiring antidiabetics (7.2% v 5.3%; hazard ratio 1.39, 95% CI 1.03 to 1.87; P=0.03) and cataract surgery (2.5% v 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between groups.","result":"No significant benefit","bottom_line":"In patients with coronary artery disease, rosuvastatin and atorvastatin provide similar long-term cardiovascular protection, but rosuvastatin carries a higher risk of new-onset diabetes requiring medication and cataract surgery.","us_status":"US-approved","evidence_quote":"The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58).","quote_verified":true,"slug":"lodestar","family":"statins","outcome":"no-benefit"},{"trial":"MK-0616 phase 2b","drug_class":"Oral PCSK9 inhibitor","drug":"Enlicitide (MK-0616)","study_type":"Lipid-efficacy RCT","year":2023,"first_author":"Ballantyne","journal":"J Am Coll Cardiol","title":"Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.","pmid":"36889610","doi":"10.1016/j.jacc.2023.02.018","design":"Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial","population":"Adult participants with hypercholesterolemia and a wide range of atherosclerotic cardiovascular disease risk; 49% female, median age 62 years","n":381,"intervention":"MK-0616 (enlicitide), oral PCSK9 inhibitor, 6, 12, 18, or 30 mg once daily","comparator":"Matching placebo","follow_up":"8 weeks of treatment plus an additional 8 weeks of follow-up","primary_endpoint":"Percentage change from baseline in LDL-C at Week 8; proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs","primary_result":"All doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg)","ldl_effect":"Least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg), P < 0.001 for all doses","key_secondary_or_mortality":"''","safety":"AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.","result":"Primary lipid endpoint met","bottom_line":"In this phase 2b trial, the oral PCSK9 inhibitor MK-0616 produced large, dose-dependent LDL-C reductions compared with placebo and was well tolerated over 8 weeks of treatment plus 8 weeks of follow-up.","us_status":"US-approved 2026 (as enlicitide)","evidence_quote":"Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.","quote_verified":true,"slug":"mk-0616-phase-2b","family":"pcsk9","outcome":"lipids"},{"trial":"ORION-3","drug_class":"PCSK9 siRNA","drug":"Inclisiran","study_type":"Open-label extension","year":2023,"first_author":"Ray","journal":"Lancet Diabetes Endocrinol","title":"Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial.","pmid":"36620965","doi":"10.1016/S2213-8587(22)00353-9","design":"4-year open-label extension of placebo-controlled phase 2 trial, inclisiran-only arm and switching arm (evolocumab then inclisiran)","population":"Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial","n":497,"intervention":"Twice-yearly 300 mg subcutaneous inclisiran sodium (inclisiran-only arm); placebo arm from ORION-1 received evolocumab 140 mg every 2 weeks until day 360 then transitioned to twice-yearly inclisiran (switching arm)","comparator":"Within-patient comparison from ORION-1 baseline; switching arm initially evolocumab","follow_up":"approximately 570 days of total inclisiran exposure for primary endpoint; up to 1440 days (4 years) for secondary/exploratory endpoints","primary_endpoint":"Percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm","primary_result":"LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days","ldl_effect":"4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%","key_secondary_or_mortality":"Changes in LDL-C cholesterol and PCSK9 concentrations up to day 1440 (4 years) in each arm; secondary/exploratory, not a mortality endpoint","safety":"Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm.","result":"Sustained effect","bottom_line":"Twice-yearly inclisiran produced durable, substantial LDL cholesterol and PCSK9 lowering over 4 years of repeated hepatic dosing and was well tolerated with low rates of serious drug-related adverse events.","us_status":"US-approved","evidence_quote":"In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%.","quote_verified":true,"slug":"orion-3","family":"pcsk9","outcome":"lipids"},{"trial":"REPRIEVE","drug_class":"Statin","drug":"Pitavastatin","study_type":"Cardiovascular outcome trial","year":2023,"first_author":"Grinspoon","journal":"N Engl J Med","title":"Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.","pmid":"37486775","doi":"10.1056/NEJMoa2304146","design":"randomized, double-blind, placebo-controlled","population":"Persons with HIV infection receiving antiretroviral therapy, with low-to-moderate cardiovascular risk; median age 50 years, median CD4 count 621 cells/mm3","n":7769,"intervention":"Pitavastatin calcium 4 mg daily","comparator":"Placebo","follow_up":"median follow-up of 5.1 years (interquartile range, 4.3 to 5.9)","primary_endpoint":"Major adverse cardiovascular event: composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause","primary_result":"The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002).","ldl_effect":"","key_secondary_or_mortality":"","safety":"Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively.","result":"Benefit","bottom_line":"In people with HIV at low-to-moderate cardiovascular risk, daily pitavastatin significantly reduced major adverse cardiovascular events compared with placebo, though with modestly more muscle symptoms and diabetes.","us_status":"US-approved","evidence_quote":"The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002).","quote_verified":true,"slug":"reprieve","family":"statins","outcome":"benefit"},{"trial":"SPORT","drug_class":"Statin","drug":"Rosuvastatin vs supplements","study_type":"Lipid-efficacy RCT","year":2023,"first_author":"Laffin","journal":"J Am Coll Cardiol","title":"Comparative Effects of Low-Dose Rosuvastatin, Placebo, and Dietary Supplements on Lipids and Inflammatory Biomarkers.","pmid":"36351465","doi":"10.1016/j.jacc.2022.10.013","design":"single-center, prospective, randomized, single-blind clinical trial","population":"Adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD","n":190,"intervention":"Rosuvastatin 5 mg daily","comparator":"Placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, red yeast rice","follow_up":"28 days","primary_endpoint":"Percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days","primary_result":"The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P < 0.001).","ldl_effect":"Difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P < 0.001); none of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo.","key_secondary_or_mortality":"","safety":"Adverse event rates were similar across study groups.","result":"Primary lipid endpoint met","bottom_line":"In people with elevated ASCVD risk but no prior ASCVD, low-dose rosuvastatin (5 mg) lowered LDL-C far more than placebo or any of six common dietary supplements, which showed no significant LDL-C benefit over placebo.","us_status":"US-approved","evidence_quote":"The difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo.","quote_verified":true,"slug":"sport","family":"statins","outcome":"lipids"},{"trial":"ALPACA (zerlasiran phase 2)","drug_class":"Lp(a)","drug":"Zerlasiran","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Nissen","journal":"JAMA","title":"Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial.","pmid":"39556769","doi":"10.1001/jama.2024.21957","design":"Multicenter, randomized, placebo-controlled, phase 2 trial","population":"Patients with stable atherosclerotic cardiovascular disease (ASCVD) and serum lipoprotein(a) concentrations ≥125 nmol/L, enrolled at 26 sites in Europe and South Africa; mean age 63.7 years, 25.8% female, median baseline Lp(a) 213 (177-282) nmol/L","n":178,"intervention":"Zerlasiran (siRNA targeting hepatic apolipoprotein(a) synthesis): 450 mg every 24 weeks for 2 doses (n=45), 300 mg every 16 weeks for 3 doses (n=42), or 300 mg every 24 weeks for 2 doses (n=44)","comparator":"Placebo (pooled: subcutaneous placebo every 16 weeks for 3 doses, n=23, or every 24 weeks for 2 doses, n=24)","follow_up":"Primary outcome at 36 weeks; follow-up to 60 weeks","primary_endpoint":"Time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks","primary_result":"Least-squares mean time-averaged percent change in Lp(a) vs pooled placebo: -85.6% (95% CI, -90.9% to -80.3%) for 450 mg q24wk, -82.8% (95% CI, -88.2% to -77.4%) for 300 mg q16wk, and -81.3% (95% CI, -86.7% to -76.0%) for 300 mg q24wk","ldl_effect":"Not reported (trial measured lipoprotein(a), not LDL-C)","key_secondary_or_mortality":"Median (IQR) percent change in lipoprotein(a) concentration at week 36 was -94.5% (-97.3% to -84.2%) for the 450 mg every 24 weeks group, -96.4% (-97.7% to -92.3%) for the 300 mg every 16 weeks group, and -90.0% (-93.7% to -81.3%) for the 300 mg every 24 weeks group.","safety":"The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.","result":"Primary lipid endpoint met","bottom_line":"In patients with established atherosclerotic cardiovascular disease and very high Lp(a), zerlasiran safely lowered Lp(a) levels by more than 80% on average over 36 weeks compared with placebo.","us_status":"Investigational","evidence_quote":"Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was -85.6% (95% CI, -90.9% to -80.3%), -82.8% (95% CI, -88.2% to -77.4%), and -81.3% (95% CI, -86.7% to -76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively.","quote_verified":true,"slug":"alpaca-zerlasiran-phase-2","family":"lpa","outcome":"lipids"},{"trial":"ARCHES-2","drug_class":"ANGPTL3","drug":"Zodasiran","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Rosenson","journal":"N Engl J Med","title":"Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.","pmid":"38809174","doi":"10.1056/NEJMoa2404147","design":"Double-blind, placebo-controlled, dose-ranging phase 2b trial, randomized 3:1","population":"Adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter)","n":204,"intervention":"Zodasiran (subcutaneous injections of 50, 100, or 200 mg on day 1 and week 12)","comparator":"Placebo","follow_up":"Followed through week 36; primary endpoint at week 24","primary_endpoint":"Percent change in triglyceride level from baseline to week 24","primary_result":"Significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons)","ldl_effect":"for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively (50, 100, 200 mg vs placebo)","key_secondary_or_mortality":"for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively","safety":"We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.","result":"Primary lipid endpoint met","bottom_line":"In adults with mixed hyperlipidemia, zodasiran (an RNAi therapy against ANGPTL3) produced significant, dose-dependent reductions in triglycerides and improvements in non-HDL-C, ApoB, and LDL-C compared with placebo, with a signal of transient HbA1c elevation in diabetic patients at the highest dose.","us_status":"Investigational","evidence_quote":"At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons).","quote_verified":true,"slug":"arches-2","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"Balance","drug_class":"APOC3","drug":"Olezarsen","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Stroes","journal":"N Engl J Med","title":"Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.","pmid":"38587247","doi":"10.1056/NEJMoa2400201","design":"phase 3, double-blind, placebo-controlled trial","population":"Patients with genetically identified familial chylomicronemia syndrome; baseline mean triglyceride 2630±1315 mg/dl; 71% had history of acute pancreatitis within previous 10 years","n":66,"intervention":"Olezarsen 80 mg or 50 mg subcutaneously every 4 weeks for 49 weeks","comparator":"Placebo","follow_up":"49 weeks treatment; assessed through 53 weeks","primary_endpoint":"Percent change in fasting triglyceride level from baseline to 6 months, 80-mg olezarsen vs placebo (and, if significant, 50-mg olezarsen vs placebo)","primary_result":"Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% CI, -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08)","ldl_effect":"Not reported (triglyceride-focused trial); apolipoprotein C-III level change: -73.7 percentage points (95% CI, -94.6 to -52.8) for 80-mg vs placebo and -65.5 percentage points (95% CI, -82.6 to -48.3) for 50-mg vs placebo","key_secondary_or_mortality":"By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66)","safety":"Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group","result":"Primary lipid endpoint met","bottom_line":"In patients with familial chylomicronemia syndrome, olezarsen 80 mg significantly lowered triglycerides and markedly reduced acute pancreatitis episodes compared with placebo, with the 50-mg dose not reaching significance for the triglyceride endpoint.","us_status":"US-approved","evidence_quote":"Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08).","quote_verified":true,"slug":"balance","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"Bridge-TIMI 73a","drug_class":"APOC3","drug":"Olezarsen","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Bergmark","journal":"N Engl J Med","title":"Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.","pmid":"38587249","doi":"10.1056/NEJMoa2402309","design":"Phase 2b, randomized, controlled trial (1:1 to 50-mg or 80-mg cohort, then 3:1 olezarsen vs placebo within each cohort)","population":"Adults with moderate hypertriglyceridemia (triglyceride level 150-499 mg/dL) and elevated cardiovascular risk, or severe hypertriglyceridemia (triglyceride level ≥500 mg/dL); median age 62 years, median triglyceride level 241.5 mg/dL; 24 sites in North America","n":154,"intervention":"Monthly subcutaneous olezarsen (50-mg or 80-mg cohort)","comparator":"Matching placebo","follow_up":"6 months","primary_endpoint":"Percent change in triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo","primary_result":"The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons).","ldl_effect":"No significant change in the LDL cholesterol level","key_secondary_or_mortality":"Each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, as compared with placebo","safety":"The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with moderate-to-severe hypertriglyceridemia and elevated cardiovascular risk, monthly olezarsen substantially lowered triglycerides, APOC3, apolipoprotein B, and non-HDL cholesterol compared with placebo, without major safety concerns.","us_status":"US-approved","evidence_quote":"The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons).","quote_verified":true,"slug":"bridge-timi-73a","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"CTT 2024 diabetes","drug_class":"Meta-analysis","drug":"Statins","study_type":"Meta-analysis","year":2024,"first_author":"Cholesterol Treatment Trialists’ (CTT) Collaboration. Electronic address: ctt@ndph.ox.ac.uk","journal":"Lancet Diabetes Endocrinol","title":"Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis.","pmid":"38554713","doi":"10.1016/S2213-8587(24)00040-8","design":"Individual participant data meta-analysis of double-blind randomised controlled trials of statin therapy (CTT Collaboration)","population":"Participants in large, long-term, double-blind statin trials of at least 2 years' scheduled duration and at least 1000 participants; 19 trials statin vs placebo (123 940 participants, 25 701 [21%] with diabetes) and 4 trials more vs less intensive statin therapy (30 724 participants, 5340 [17%] with diabetes)","n":154664,"intervention":"Statin therapy (low-intensity/moderate-intensity or high-intensity)","comparator":"Placebo (19 trials) or less intensive statin therapy (4 trials)","follow_up":"Median follow-up of 4·3 years (placebo-controlled trials) and 4·9 years (more vs less intensive trials)","primary_endpoint":"New-onset diabetes (defined by diabetes-related adverse events, use of new glucose-lowering medications, glucose concentrations, or HbA1c values) and worsening glycaemia in people with diabetes (defined by complications of glucose control, increased use of glucose-lowering medication, or HbA1c increase of ≥0·5%)","primary_result":"Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48)","ldl_effect":"Not reported in abstract; glucose increased by 0·04 mmol/L with both low-intensity or moderate-intensity (95% CI 0·03-0·05) and high-intensity statins (0·02-0·06); mean HbA1c increased by 0·06% (0·00-0·12) with low-intensity or moderate-intensity statins and 0·08% (0·07-0·09) with high-intensity statins","key_secondary_or_mortality":"Among participants with baseline diabetes, the RRs for worsening glycaemia were 1·10 (1·06-1·14) for low-intensity or moderate-intensity statin therapy and 1·24 (1·06-1·44) for high-intensity statin therapy compared with placebo","safety":"Statins cause a moderate dose-dependent increase in new diagnoses of diabetes that is consistent with a small upwards shift in glycaemia, with the majority of new diagnoses of diabetes occurring in people with baseline glycaemic markers that are close to the diagnostic threshold for diabetes; any theoretical adverse effects of statins on cardiovascular risk that might arise from these small increases in glycaemia are already accounted for in the overall reduction in cardiovascular risk seen with statin therapy","result":"Adverse-effect signal (small)","bottom_line":"Statins cause a modest, dose-dependent increase in new-onset diabetes and worsening glycaemia, driven by small upward shifts in glucose/HbA1c, but this risk is already outweighed by the overall cardiovascular benefit of statin therapy.","us_status":"Not applicable","evidence_quote":"Compared with placebo, allocation to low-intensity or moderate-intensity statin therapy resulted in a 10% proportional increase in new-onset diabetes (2420 of 39 179 participants assigned to receive a statin [1·3% per year] vs 2214 of 39 266 participants assigned to receive placebo [1·2% per year]; rate ratio [RR] 1·10, 95% CI 1·04-1·16), and allocation to high-intensity statin therapy resulted in a 36% proportional increase (1221 of 9935 participants assigned to receive a statin [4·8% per year] vs 905 of 9859 participants assigned to receive placebo [3·5% per year]; 1·36, 1·25-1·48).","quote_verified":true,"slug":"ctt-2024-diabetes","family":"meta-analyses","outcome":"safety"},{"trial":"LIBerate-HR","drug_class":"PCSK9 binder","drug":"Lerodalcibep","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Klug","journal":"JAMA Cardiol","title":"Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial.","pmid":"38958989","doi":"10.1001/jamacardio.2024.1659","design":"randomized, double-blind, placebo-controlled phase 3 trial","population":"Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD","n":922,"intervention":"Monthly 1.2-mL subcutaneous lerodalcibep, 300 mg","comparator":"Placebo","follow_up":"52 weeks","primary_endpoint":"Percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52 (co-primary end points)","primary_result":"The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all).","ldl_effect":"Placebo-adjusted reduction in LDL-C: 56.2% (2.2%) at week 52 and 62.7% (1.9%) for mean of weeks 50 and 52 by mITT analysis (P < .001 for all)","key_secondary_or_mortality":"With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study.","safety":"Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions, which occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy.","result":"Primary lipid endpoint met","bottom_line":"Monthly lerodalcibep added to maximally tolerated statins substantially lowers LDL-C and helps most high-risk patients reach guideline LDL-C targets, with a safety profile similar to placebo aside from mild/moderate injection site reactions.","us_status":"US-approved","evidence_quote":"The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all).","quote_verified":true,"slug":"liberate-hr","family":"pcsk9","outcome":"lipids"},{"trial":"SHASTA-2","drug_class":"APOC3","drug":"Plozasiran","study_type":"Lipid-efficacy RCT","year":2024,"first_author":"Gaudet","journal":"JAMA Cardiol","title":"Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial.","pmid":"38583092","doi":"10.1001/jamacardio.2024.0959","design":"placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial","population":"Adults with severe hypertriglyceridemia (fasting triglyceride levels 500 to 4000 mg/dL) while receiving stable lipid-lowering treatment","n":226,"intervention":"Plozasiran (ARO-APOC3), 2 subcutaneous doses (10, 25, or 50 mg) on day 1 and week 12","comparator":"Matched placebo","follow_up":"Followed up through week 48","primary_endpoint":"Placebo-subtracted difference in means of percentage triglyceride change at week 24","primary_result":"Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001) at the highest dose","ldl_effect":"Dose-dependent increases in LDL-C level, significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001); ApoB levels did not increase; non-HDL-C decreased significantly at all doses, placebo-adjusted change of -20% at the highest dose","key_secondary_or_mortality":"Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL; driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose; significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48","safety":"Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death.","result":"Primary lipid endpoint met","bottom_line":"Plozasiran markedly and durably lowered triglycerides (with most patients falling below the acute pancreatitis risk threshold) and APOC3 in severe hypertriglyceridemia, with a favorable safety profile, though it raised LDL-C without increasing ApoB and its effect on clinical complications remains unproven.","us_status":"US-approved","evidence_quote":"Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)-mean reductions in triglyceride levels (primary end point) of -57% (95% CI, -71.9% to -42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of -77% (95% CI, -89.1% to -65.8%; P < .001) at week 24 with the highest dose.","quote_verified":true,"slug":"shasta-2","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"ALPACA","drug_class":"Lp(a)","drug":"Lepodisiran","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Nissen","journal":"N Engl J Med","title":"Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a).","pmid":"40162643","doi":"10.1056/NEJMoa2415818","design":"randomized (1:2:2:2:2), placebo-controlled","population":"Participants with elevated lipoprotein(a); median baseline Lp(a) concentration 253.9 nmol per liter","n":320,"intervention":"Lepodisiran at 16 mg, 96 mg, or 400 mg at baseline and again at day 180, or 400 mg at baseline and placebo at day 180, administered by subcutaneous injection","comparator":"Placebo at baseline and at day 180","follow_up":"360 days","primary_endpoint":"Time-averaged percent change from baseline in serum lipoprotein(a) concentration (placebo-adjusted) from day 60 to day 180","primary_result":"Placebo-adjusted time-averaged percent change from baseline in serum Lp(a) from day 60 to day 180 was -40.8 percentage points (95% CI, -55.8 to -20.6) in the 16-mg group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups","ldl_effect":"''","key_secondary_or_mortality":"The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively","safety":"Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group.","result":"Primary lipid endpoint met","bottom_line":"Lepodisiran produced large, dose-dependent and durable reductions in serum lipoprotein(a) with generally mild injection-site reactions, but this trial did not assess cardiovascular outcomes.","us_status":"Investigational","evidence_quote":"The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups.","quote_verified":true,"slug":"alpaca","family":"lpa","outcome":"lipids"},{"trial":"BROADWAY","drug_class":"CETP inhibitor","drug":"Obicetrapib","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Nicholls","journal":"N Engl J Med","title":"Safety and Efficacy of Obicetrapib in Patients at High Cardiovascular Risk.","pmid":"40337982","doi":"10.1056/NEJMoa2415820","design":"multinational, randomized, placebo-controlled trial, 2:1 randomization","population":"Patients with heterozygous familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease, receiving maximum tolerated doses of lipid-lowering therapy, with LDL cholesterol ≥100 mg/dl or non-HDL ≥130 mg/dl, or LDL 55-100 mg/dl or non-HDL 85-130 mg/dl plus at least one additional cardiovascular risk factor","n":2530,"intervention":"Obicetrapib 10 mg once daily (n=1686)","comparator":"Matching placebo (n=844)","follow_up":"365 days","primary_endpoint":"Percent change in LDL cholesterol level from baseline to day 84","primary_result":"Least-squares mean percent change from baseline to day 84 in LDL cholesterol: -29.9% (95% CI, -32.1 to -27.8) with obicetrapib vs 2.7% (95% CI, -0.4 to 5.8) with placebo, between-group difference -32.6 percentage points (95% CI, -35.8 to -29.5; P<0.001)","ldl_effect":"-29.9% (95% CI, -32.1 to -27.8) vs 2.7% (95% CI, -0.4 to 5.8) with placebo; between-group difference -32.6 percentage points (95% CI, -35.8 to -29.5; P<0.001)","key_secondary_or_mortality":"''","safety":"The incidence of adverse events appeared to be similar in the two groups.","result":"Primary lipid endpoint met","bottom_line":"In high-risk patients already on maximum tolerated lipid-lowering therapy, adding obicetrapib 10 mg daily lowered LDL cholesterol by about 30% more than placebo with a similar rate of adverse events.","us_status":"Investigational","evidence_quote":"The least-squares mean percent change from baseline to day 84 in the LDL cholesterol level was -29.9% (95% confidence interval [CI], -32.1 to -27.8) in the obicetrapib group, as compared with 2.7% (95% CI, -0.4 to 5.8) in the placebo group, for a between-group difference of -32.6 percentage points (95% CI, -35.8 to -29.5; P<0.001).","quote_verified":true,"slug":"broadway","family":"cetp","outcome":"lipids"},{"trial":"CTX310 phase 1","drug_class":"ANGPTL3","drug":"CTX310","study_type":"Phase 1/2 trial","year":2025,"first_author":"Laffin","journal":"N Engl J Med","title":"Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3.","pmid":"41211945","doi":"10.1056/NEJMoa2511778","design":"ascending-dose phase 1 trial","population":"Adults who had uncontrolled hypercholesterolemia, hypertriglyceridemia, or mixed dyslipidemia and were receiving maximally tolerated lipid-lowering therapy","n":15,"intervention":"Single intravenous dose of CTX310 (lipid-nanoparticle-encapsulated CRISPR-Cas9 mRNA and guide RNA targeting hepatic ANGPTL3) at 0.1, 0.3, 0.6, 0.7, or 0.8 mg per kilogram","comparator":"None (single-arm, ascending dose)","follow_up":"at least 60 days","primary_endpoint":"Adverse events, including dose-limiting toxic effects","primary_result":"No dose-limiting toxic effects related to CTX310 occurred.","ldl_effect":"Not reported in abstract (ANGPTL3 level changes reported instead)","key_secondary_or_mortality":"one participant died suddenly 179 days after treatment with the 0.1-mg-per-kilogram dose","safety":"Serious adverse events occurred in two participants (13%): one participant had a spinal disk herniation, and the other died suddenly 179 days after treatment with the 0.1-mg-per-kilogram dose. Infusion-related reactions were reported in three participants (20%), and one participant (7%) who had elevated levels of aminotransferases at baseline had a transient elevation in aminotransferases to between three times and five times as high as those at baseline, peaking on day 4 and returning to baseline by day 14.","result":"Early safety/biomarker data","bottom_line":"A single dose of the CRISPR-Cas9 gene-editing therapy CTX310 was generally well tolerated and produced dose-dependent reductions in ANGPTL3 levels, supporting further clinical development for dyslipidemia.","us_status":"Investigational","evidence_quote":"The mean percent change in ANGPTL3 level was 9.6% (range, -21.8 to 71.2) with the dose of 0.1 mg per kilogram, 9.4% (range, -25.0 to 63.9) with 0.3 mg per kilogram, -32.7% (range, -51.4 to -19.4) with 0.6 mg per kilogram, -79.7% (range, -86.8 to -72.5) with 0.7 mg per kilogram, and -73.2% (range, -89.0 to -66.9) with 0.8 mg per kilogram.","quote_verified":true,"slug":"ctx310-phase-1","family":"apoc3-angptl3","outcome":"safety"},{"trial":"ESSENCE-TIMI 73b","drug_class":"APOC3","drug":"Olezarsen","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Bergmark","journal":"N Engl J Med","title":"Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia.","pmid":"40888739","doi":"10.1056/NEJMoa2507227","design":"phase 3, international, double-blind, randomized, placebo-controlled trial","population":"Patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter); median age 64 years, 40% women, median baseline triglyceride level 238.5 mg per deciliter (IQR 190.5 to 307.5)","n":1349,"intervention":"Olezarsen (N-acetylgalactosamine-conjugated antisense oligonucleotide targeting APOC3 mRNA), monthly subcutaneous, 50-mg or 80-mg dose cohorts","comparator":"Matching placebo","follow_up":"6 months","primary_endpoint":"Least-squares mean percent change in triglyceride level from baseline to 6 months among patients with moderate hypertriglyceridemia, reported as the placebo-adjusted change for each olezarsen dose group","primary_result":"At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% CI, -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group","ldl_effect":"","key_secondary_or_mortality":"","safety":"The incidence of serious adverse events appeared to be similar across the trial groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with moderate hypertriglyceridemia and elevated cardiovascular risk, olezarsen significantly lowered triglyceride levels at 6 months compared with placebo, with similar rates of serious adverse events.","us_status":"US-approved","evidence_quote":"At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group.","quote_verified":true,"slug":"essence-timi-73b","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"KRAKEN","drug_class":"Lp(a)","drug":"Muvalaplin","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Nicholls","journal":"JAMA","title":"Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial.","pmid":"39556768","doi":"10.1001/jama.2024.24017","design":"Phase 2, placebo-controlled, randomized, double-blind trial","population":"233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States","n":233,"intervention":"Muvalaplin orally administered at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68)","comparator":"Placebo (n = 67)","follow_up":"12 weeks","primary_endpoint":"Placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay","primary_result":"Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay.","ldl_effect":"Not reported (lipoprotein(a) and apolipoprotein B reported; dose-dependent reductions in apolipoprotein B observed at 8.9% (95% CI, -2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively)","key_secondary_or_mortality":"Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein; no change in high-sensitivity C-reactive protein was observed","safety":"No safety or tolerability concerns were observed at any dosage.","result":"Primary lipid endpoint met","bottom_line":"Oral muvalaplin produced large, dose-dependent reductions in lipoprotein(a) over 12 weeks with no safety or tolerability concerns, though whether this translates into fewer cardiovascular events is still unknown.","us_status":"Investigational","evidence_quote":"Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay.","quote_verified":true,"slug":"kraken","family":"lpa","outcome":"lipids"},{"trial":"PALISADE","drug_class":"APOC3","drug":"Plozasiran","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Watts","journal":"N Engl J Med","title":"Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.","pmid":"39225259","doi":"10.1056/NEJMoa2409368","design":"Randomized, placebo-controlled, phase 3 trial (dose groups: 25 mg, 50 mg, and placebo)","population":"Patients with persistent chylomicronemia (with or without a genetic diagnosis), classically caused by familial chylomicronemia syndrome (FCS); baseline median triglyceride level 2044 mg per deciliter","n":75,"intervention":"Subcutaneous plozasiran (25 mg or 50 mg) every 3 months","comparator":"Placebo (subcutaneous, every 3 months for 12 months)","follow_up":"12 months","primary_endpoint":"Median percent change from baseline in the fasting triglyceride level at 10 months","primary_result":"Median change from baseline in fasting triglyceride level at 10 months was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001)","ldl_effect":"''","key_secondary_or_mortality":"Incidence of acute pancreatitis: odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03. Also key secondary end points included percent change in fasting triglyceride level from baseline to mean of values at 10 and 12 months, and changes in fasting apolipoprotein C-III level from baseline to 10 and 12 months, all better with plozasiran than placebo.","safety":"The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline.","result":"Primary lipid endpoint met","bottom_line":"In patients with persistent chylomicronemia, plozasiran (siRNA against APOC3) sharply lowered triglycerides and reduced acute pancreatitis episodes compared with placebo, with a similar overall adverse event rate but a signal for hyperglycemia in those with prediabetes/diabetes.","us_status":"US-approved","evidence_quote":"At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03).","quote_verified":true,"slug":"palisade","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"PROLONG-ANG3","drug_class":"ANGPTL3","drug":"Solbinsiran","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Ray","journal":"Lancet","title":"Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial.","pmid":"40179932","doi":"10.1016/S0140-6736(25)00507-0","design":"double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial","population":"Adults (aged ≥18 years) with mixed dyslipidaemia, receiving moderate-intensity or high-intensity statins, with fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L","n":205,"intervention":"Solbinsiran (GalNAc-conjugated siRNA targeting ANGPTL3) 100 mg, 400 mg, or 800 mg subcutaneous injection on days 0 and 90","comparator":"Placebo","follow_up":"Followed up for at least 270 days","primary_endpoint":"Percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand","primary_result":"The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg.","ldl_effect":"Baseline median LDL-C was 3·16 mmol/L (2·57-3·82); specific placebo-adjusted percent change in LDL-C not reported in abstract","key_secondary_or_mortality":"Not reported in abstract","safety":"Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group.","result":"Primary lipid endpoint met (400 mg only)","bottom_line":"In adults with mixed dyslipidaemia on background statin therapy, solbinsiran 400 mg significantly reduced apoB levels compared with placebo and was generally well tolerated, though its effect on cardiovascular outcomes is still unknown.","us_status":"Investigational","evidence_quote":"The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg.","quote_verified":true,"slug":"prolong-ang3","family":"apoc3-angptl3","outcome":"safety"},{"trial":"PURSUIT","drug_class":"Oral PCSK9 inhibitor","drug":"AZD0780","study_type":"Lipid-efficacy RCT","year":2025,"first_author":"Koren","journal":"J Am Coll Cardiol","title":"An Oral PCSK9 Inhibitor for Treatment of Hypercholesterolemia: The PURSUIT Randomized Trial.","pmid":"40167413","doi":"10.1016/j.jacc.2025.03.499","design":"randomized, double-blind, placebo-controlled, multicenter, phase 2","population":"Patients with hypercholesterolemia on background moderate-to-high-intensity statin treatment, fasting LDL-C ≥70 mg/dL (1.8 mmol/L) and <190 mg/dL (4.9 mmol/L), triglycerides <400 mg/dL, with or without ezetimibe at baseline; 52.1% male, average age 62.4 ± 7.6 years","n":428,"intervention":"AZD0780 oral once daily at 1, 3, 10, or 30 mg doses","comparator":"Matching placebo, oral once daily","follow_up":"12 weeks","primary_endpoint":"Percent change of LDL-C from baseline to week 12","primary_result":"Placebo-corrected difference in least squares mean percent change of LDL-C for AZD0780 1, 3, 10, and 30 mg vs placebo was -35.3% (95% CI: -43.6% to -26.9%), -37.9% (95% CI:-46.3% to -29.5%), -45.2% (95% CI: -53.5% to -36.9%), and -50.7% (95% CI: -59.0% to -42.4%), respectively","ldl_effect":"Placebo-corrected LDL-C reduction of -35.3% to -50.7% across the 1-30 mg dose range at week 12","key_secondary_or_mortality":"The proportion of patients reaching the ACC/AHA guideline LDL-C goal for high-risk patients increased in a dose-proportional manner","safety":"Adverse events compared similarly between the total AZD0780 treatment group (38.2%) and placebo (32.6%)","result":"Primary lipid endpoint met","bottom_line":"In statin-treated patients with hypercholesterolemia, the oral PCSK9 inhibitor AZD0780 produced robust, dose-dependent LDL-C reductions over 12 weeks with an adverse event rate similar to placebo.","us_status":"Investigational","evidence_quote":"At week 12, compared with baseline, the placebo-corrected difference in least squares mean percent change of LDL-C for AZD0780 1, 3, 10, and 30 mg vs placebo was -35.3% (95% CI: -43.6% to -26.9%), -37.9% (95% CI:-46.3% to -29.5%), -45.2% (95% CI: -53.5% to -36.9%), and -50.7% (95% CI: -59.0% to -42.4%), respectively.","quote_verified":true,"slug":"pursuit","family":"pcsk9","outcome":"lipids"},{"trial":"BROOKLYN","drug_class":"CETP inhibitor","drug":"Obicetrapib","study_type":"Lipid-efficacy RCT","year":2026,"first_author":"Nicholls","journal":"Nat Med","title":"Obicetrapib in patients with heterozygous familial hypercholesterolemia: the BROOKLYN randomized clinical trial.","pmid":"41760952","doi":"10.1038/s41591-025-04179-4","design":"Randomized (2:1), presumably double-blind, placebo-controlled trial","population":"Patients with heterozygous familial hypercholesterolemia and LDL cholesterol ≥70 mg dl-1 on maximally tolerated lipid-lowering therapy (mean LDL cholesterol 122 mg dl-1, 87% on statins; 190 women, 164 men)","n":354,"intervention":"Obicetrapib 10 mg daily","comparator":"Placebo","follow_up":"365 days","primary_endpoint":"Change in LDL cholesterol from baseline to day 84","primary_result":"Placebo-adjusted change in LDL cholesterol of -36.3% (95% confidence interval -42.2% to -30.4%, P < 0.0001)","ldl_effect":"Placebo-adjusted change in LDL cholesterol of -36.3% (95% CI -42.2% to -30.4%, P < 0.0001)","key_secondary_or_mortality":"At day 84, placebo-adjusted reductions in apolipoprotein B of -24.4%, non-HDL cholesterol of -34.5% and lipoprotein(a) of -45.9%, as well as a placebo-adjusted increase in high-density lipoprotein cholesterol of +138.7%.","safety":"Obicetrapib was well tolerated.","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolemia already on maximally tolerated lipid-lowering therapy, adding obicetrapib substantially lowered LDL cholesterol (and improved other lipid parameters) compared with placebo and was well tolerated.","us_status":"Investigational","evidence_quote":"For the primary endpoint, the change in LDL cholesterol from baseline to day 84, obicetrapib treatment resulted in a placebo-adjusted change in LDL cholesterol of -36.3% (95% confidence interval -42.2% to -30.4%, P < 0.0001).","quote_verified":true,"slug":"brooklyn","family":"cetp","outcome":"lipids"},{"trial":"CORALreef HeFH","drug_class":"Oral PCSK9 inhibitor","drug":"Enlicitide","study_type":"Lipid-efficacy RCT","year":2026,"first_author":"Ballantyne","journal":"JAMA","title":"Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.","pmid":"41206969","doi":"10.1001/jama.2025.20620","design":"Phase 3, randomized, double-blind, placebo-controlled","population":"Adults aged 18 years or older with heterozygous familial hypercholesterolemia on at least moderate- or high-intensity statin therapy, with LDL-C ≥55 mg/dL and history of major ASCVD or LDL-C ≥70 mg/dL without history of major ASCVD","n":303,"intervention":"Enlicitide decanoate 20 mg orally once daily (n=202)","comparator":"Placebo (n=101)","follow_up":"52 weeks","primary_endpoint":"Mean percentage change in LDL-C level at week 24","primary_result":"The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001).","ldl_effect":"-58.2% (enlicitide) vs 2.6% (placebo) at week 24; between-group difference -59.4% (95% CI, -65.6% to -53.2%), P<.001. At week 52: -55.3% vs 8.7%; between-group difference -61.5% (95% CI, -69.4% to -53.7%), P<.001.","key_secondary_or_mortality":"At week 24, mean percentage change in non-HDL-C was -52.3% vs 2.1% (difference -53.0% [95% CI, -58.5% to -47.4%]; P<.001); apolipoprotein B was -48.2% vs 1.8% (difference -49.1% [95% CI, -54.0% to -44.3%]; P<.001); median percentage change in lipoprotein(a) was -24.7% vs -1.6% (difference -27.5% [95% CI, -34.3% to -20.6%]; P<.001).","safety":"The incidence of adverse events, serious adverse events, and study discontinuation due to adverse events was similar between groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with heterozygous familial hypercholesterolemia already on statin therapy, adding oral enlicitide substantially and safely lowered LDL-C and other atherogenic lipid measures compared with placebo.","us_status":"US-approved","evidence_quote":"The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001).","quote_verified":true,"slug":"coralreef-hefh","family":"pcsk9","outcome":"lipids"},{"trial":"CORALreef Lipids","drug_class":"Oral PCSK9 inhibitor","drug":"Enlicitide","study_type":"Lipid-efficacy RCT","year":2026,"first_author":"Navar","journal":"N Engl J Med","title":"A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide.","pmid":"41879224","doi":"10.1056/NEJMoa2511002","design":"multinational, double-blind, randomized, placebo-controlled trial","population":"Adults with a history of a major atherosclerotic cardiovascular disease event with an LDL cholesterol level of 55 mg per deciliter or higher and those who were at risk for a first atherosclerotic cardiovascular disease event with an LDL cholesterol level of 70 mg per deciliter or higher","n":2909,"intervention":"Enlicitide decanoate (oral PCSK9 inhibitor), 20 mg daily for 52 weeks","comparator":"Placebo","follow_up":"52 weeks","primary_endpoint":"Mean percent change in LDL cholesterol level from baseline to week 24","primary_result":"The mean percent change in LDL cholesterol levels at week 24 was -57.1% (95% confidence interval [CI], -61.8 to -52.5) with enlicitide and 3.0% (95% CI, 0.9 to 5.1) with placebo, representing an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001)","ldl_effect":"-57.1% (95% CI, -61.8 to -52.5) with enlicitide vs 3.0% (95% CI, 0.9 to 5.1) with placebo; adjusted between-group difference -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001)","key_secondary_or_mortality":"The mean percent change in LDL cholesterol level at week 52, the mean percent changes in non-HDL cholesterol and apolipoprotein B levels at week 24, and the percent change in lipoprotein(a) levels at week 24 were significantly greater with enlicitide than with placebo (P<0.001 for all comparisons).","safety":"The incidence of adverse events did not appear to differ between the groups.","result":"Primary lipid endpoint met","bottom_line":"In patients with or at risk for atherosclerotic cardiovascular disease, the oral PCSK9 inhibitor enlicitide substantially lowered LDL cholesterol and other atherogenic lipid markers compared with placebo, with adverse event rates similar between groups.","us_status":"US-approved","evidence_quote":"The mean percent change in LDL cholesterol levels at week 24 was -57.1% (95% confidence interval [CI], -61.8 to -52.5) with enlicitide and 3.0% (95% CI, 0.9 to 5.1) with placebo, representing an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001).","quote_verified":true,"slug":"coralreef-lipids","family":"pcsk9","outcome":"lipids"},{"trial":"CORE/CORE2","drug_class":"APOC3","drug":"Olezarsen","study_type":"Lipid-efficacy RCT","year":2026,"first_author":"Marston","journal":"N Engl J Med","title":"Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.","pmid":"41211918","doi":"10.1056/NEJMoa2512761","design":"Two double-blind, randomized, placebo-controlled trials","population":"Patients with severe hypertriglyceridemia","n":1061,"intervention":"Olezarsen 50 mg or 80 mg monthly for 12 months","comparator":"Placebo","follow_up":"12 months","primary_endpoint":"Percent change in triglyceride level at 6 months (placebo-adjusted)","primary_result":"At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo).","ldl_effect":"Not specifically reported; decreases in triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons)","key_secondary_or_mortality":"The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001).","safety":"The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted.","result":"Primary lipid endpoint met","bottom_line":"In patients with severe hypertriglyceridemia, olezarsen substantially lowered triglycerides and reduced acute pancreatitis risk compared with placebo, though higher-dose treatment carried more liver enzyme and platelet-related side effects.","us_status":"US-approved","evidence_quote":"The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001).","quote_verified":true,"slug":"core-core2","family":"apoc3-angptl3","outcome":"lipids"},{"trial":"Heart-2","drug_class":"Gene editing","drug":"VERVE-102","study_type":"Phase 1/2 trial","year":2026,"first_author":"Vafai","journal":"N Engl J Med","title":"In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia.","pmid":"42187087","doi":"10.1056/NEJMoa2601283","design":"phase 1, open-label, single-ascending-dose study","population":"Adults with heterozygous familial hypercholesterolemia or premature coronary artery disease","n":35,"intervention":"VERVE-102 (mRNA encoding adenine base-editor protein plus guide RNA targeting PCSK9, encapsulated in a GalNAc-containing lipid nanoparticle), single IV infusion at one of six doses from 0.3 to 1.0 mg of total RNA per kilogram","comparator":"None (single-arm, dose-ascending; no placebo/active comparator)","follow_up":"at least 28 days for all participants; at least 1 year in 15 participants","primary_endpoint":"Safety and changes in blood PCSK9 protein and LDL cholesterol levels","primary_result":"No dose-limiting toxic effects occurred; dose-dependent mean reductions in PCSK9 ranged from 51% (0.3 mg/kg) to 88% (1.0 mg/kg), with corresponding LDL cholesterol reductions of 9% to 62% (78 mg/dL absolute reduction at the highest dose)","ldl_effect":"Reductions in LDL cholesterol ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose","key_secondary_or_mortality":"Not reported","safety":"No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease.","result":"Early safety/biomarker data","bottom_line":"A single intravenous dose of the base-editing drug VERVE-102 produced dose-dependent, durable reductions in PCSK9 and LDL cholesterol, with an acceptable early safety profile, in a small phase 1 trial.","us_status":"Investigational","evidence_quote":"Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose. Corresponding reductions in the LDL cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose. Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants.","quote_verified":true,"slug":"heart-2","family":"genetics","outcome":"safety"},{"trial":"PCSK9 vs statin monotherapy meta-analysis","drug_class":"Meta-analysis","drug":"PCSK9 inhibitors vs statins","study_type":"Meta-analysis","year":2026,"first_author":"Kyan","journal":"Front Cardiovasc Med","title":"The lipid lowering efficacy of PCSK9 inhibitors alone vs. statins alone: a meta-analysis.","pmid":"41783026","doi":"10.3389/fcvm.2026.1769430","design":"Meta-analysis of RCTs, PRISMA-adherent, comparing PCSK9i monotherapy subgroups vs. high-intensity statin monotherapy trials","population":"Patients in RCTs of PCSK9i monotherapy (predominantly due to total statin intolerance) vs. patients in RCTs of high-intensity statin monotherapy; 5 trials (766 patients) for PCSK9is and 49 trials (19,603 patients) for statins; mean age 57.5±5.1 (PCSK9i) vs 60.2±2.3 (statin) years, women 54.3% vs 39.9%","n":20369,"intervention":"PCSK9 inhibitor monotherapy (in statin-intolerant patient subgroups from PCSK9i vs. control RCTs)","comparator":"High-intensity statin monotherapy (atorvastatin 40 or 80 mg daily or rosuvastatin 20 or 40 mg daily) vs. control","follow_up":"''","primary_endpoint":"Mean percent change in serum LDL-C","primary_result":"PCSK9is showed significantly greater reductions in LDL-C compared to all high-intensity statin regimens combined (-52.4% vs. -46.6%, p = 0.03)","ldl_effect":"PCSK9i: -52.4% vs. statins: -46.6% (p = 0.03)","key_secondary_or_mortality":"Statin agent subgroup analysis found PCSK9is were superior to atorvastatin and comparable to rosuvastatin in increasing HDL-C and reducing LDL-C, ApoB, and TC, and inferior to atorvastatin and rosuvastatin in reducing TG.","safety":"''","result":"Primary lipid endpoint met","bottom_line":"In patients who cannot tolerate statins, PCSK9 inhibitor monotherapy lowers LDL-C, ApoB, and raises HDL-C more than high-intensity statin monotherapy, though it is less effective at lowering triglycerides.","us_status":"Not applicable","evidence_quote":"Compared to all high-intensity statin regimens combined, PCSK9is showed significantly greater reductions in LDL-C (-52.4% vs. -46.6%, p = 0.03), ApoB (-43.3% vs. -32.8%, p = 0.004), and increases in HDL-C (8.0% vs. 4.4%, p = 0.02).","quote_verified":true,"slug":"pcsk9-vs-statin-monotherapy-meta-analysis","family":"meta-analyses","outcome":"lipids"},{"trial":"VESALIUS-CV","drug_class":"PCSK9 antibody","drug":"Evolocumab","study_type":"Cardiovascular outcome trial","year":2026,"first_author":"Bohula","journal":"N Engl J Med","title":"Evolocumab in Patients without a Previous Myocardial Infarction or Stroke.","pmid":"41211925","doi":"10.1056/NEJMoa2514428","design":"international, double-blind, randomized, placebo-controlled trial","population":"Patients with atherosclerosis or diabetes and without a previous myocardial infarction or stroke who had an LDL-C level of at least 90 mg per deciliter","n":12257,"intervention":"Evolocumab 140 mg every 2 weeks","comparator":"Placebo","follow_up":"median follow-up was 4.6 years","primary_endpoint":"Co-primary end points: (1) 3-point MACE (composite of death from coronary heart disease, myocardial infarction, or ischemic stroke) and (2) 4-point MACE (3-point MACE or ischemia-driven arterial revascularization)","primary_result":"3-point MACE: hazard ratio, 0.75; 95% CI, 0.65 to 0.86; P<0.001. 4-point MACE: hazard ratio, 0.81; 95% CI, 0.73 to 0.89; P<0.001.","ldl_effect":"''","key_secondary_or_mortality":"''","safety":"No evidence of a between-group difference was seen in the incidence of safety events.","result":"Benefit","bottom_line":"In patients with atherosclerosis or diabetes but no prior MI or stroke, adding evolocumab to therapy significantly lowered the risk of major cardiovascular events compared with placebo, with no apparent safety concerns.","us_status":"US-approved","evidence_quote":"A 3-point MACE event occurred in 336 patients (5-year Kaplan-Meier estimate, 6.2%) in the evolocumab group, as compared with 443 (8.0%) in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). A 4-point MACE event occurred in 747 patients (5-year Kaplan-Meier estimate, 13.4%) in the evolocumab group, as compared with 907 (16.2%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.73 to 0.89; P<0.001).","quote_verified":true,"slug":"vesalius-cv","family":"pcsk9","outcome":"benefit"}]}