Metabolic & Cardiometabolic
bempedoic acid decreases major adverse cardiovascular events
In plain terms: Does bempedoic acid reduce major adverse cardiovascular events (MACE)?
Strong support Metabolic & Cardiometabolic 💰 Industry COI noted🔬 Includes disconfirming
Part of: 💊 bempedoic acid
RefutedContestedStrong support
consensus score 0.90
Yes — CLEAR Outcomes (the sole large CV outcomes RCT) showed a 13% relative reduction in 4-point MACE in statin-intolerant high-risk patients, confirmed by meta-analyses; driven by MI and revascularization, with no reduction in CV or all-cause death.
📅 Last reviewed: 2026-07-15 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: All trials, pooled (Meta-analysis)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
6 support 0 contradict 1 tested null 0 mixed · 7 sources, 6 independent groups
What the evidence shows
CLEAR Outcomes, the only large cardiovascular outcomes trial, found a 13 percent relative reduction in four-point major adverse cardiovascular events in 13,970 statin-intolerant high-risk patients, and pooled analyses across seven to eleven trials reproduce it with clearer effects on myocardial infarction and revascularisation. One outcome trial, one population.
The evidence (21)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, Thompson PD, Libby P, Cho L, Plutzky J, Bays HE, Moriarty PM, Menon V, Grobbee DE, Louie MJ, Chen CF, Li N, Bloedon L, Robinson P, Horner M, Sasiela WJ, McCluskey J, Davey D, Fajardo-Campos P, Petrovic P, Fedacko J, Zmuda W, Lukyanov Y, Nicholls SJ, CLEAR Outcomes Investigators 2023 · N Engl J Med | RCT | supports | high | CLEAR Outcomes (n=13,970): primary 4-pt MACE HR 0.87 (95% CI 0.79-0.96), 13% relative reduction over median 40.6 mo; MI -23%, coronary revasc -19%. |
| Rhabneh L, Ababneh R, Alnaser I, Aloqaily M, Alfarrajin I, Albadawi I, Amawi A 2026 · Pol Merkur Lekarski | observational | supports | low | Retrospective TriNetX cohort of adults with established coronary disease, propensity-matched into 6,549 on atorvastatin alone and 6,549 on atorvastatin plus bempedoic acid. Major adverse cardiovascular events occurred in 5.7% on atorvastatin alone versus 3.2% on the combination (hazard ratio 1.606, 95% CI 1.302-1.980, for the monotherapy group); cardiac arrest (1.628) and all-cause hospitalisation (1.418) were also higher without the drug, and myopathy did not differ (0.915, 0.741-1.129). Follow-up length is not reported, and the cardiac-arrest interval disagrees with its stated P<0.001. |
| Zhao X, Zheng S, Tang C, Chen J, Shi C, Yuan T, Liu X, Yang R, Zhi Y, Wang S 2026 · Cardiovascular drugs and therapy | meta-analysis | supports | low | Network meta-analysis of 18 randomised trials in 89,717 people with diabetes. Bempedoic acid reduced major adverse cardiovascular events by 16% against placebo (RR 0.84, 95% CI 0.74-0.95), and the estimate held across every sensitivity analysis (0.84, 0.72-0.96 once add-on-therapy trials were dropped). Its whole contribution comes from the diabetes subgroup of one trial, CLEAR Outcomes, and the paper reports no myocardial-infarction estimate for bempedoic acid at all. The authors rate their own certainty in this comparison as low, downgraded for heterogeneity. |
| Bays HE, Bloedon L, Brennan D, Lei L, Lincoff AM, Nicholls SJ, Plutzky J, Powell HA, Nissen SE 2025 · J Am Heart Assoc | RCT | supports | moderate | Prespecified obesity subgroup of the 13,970-patient CLEAR Outcomes trial: 6,179 statin-intolerant adults with BMI 30+, median 40.7 months. Bempedoic acid cut the 4-part cardiovascular composite from 14.8% to 11.6% (HR 0.77, 95% CI 0.67-0.89); LDL-C fell 22.5% and hs-CRP 23.2% at 6 months, while cardiovascular death (HR 0.95) and all-cause death (HR 1.02) were unchanged. In the trial's leaner patients the same endpoint showed no benefit (BMI under 25, HR 0.99; BMI 25-30, HR 0.96); the authors say the interaction test cannot establish that the effect differs by BMI. Esperion-funded. |
| Patel J, Shah S, Reddy A, Prajapati D, Pandya A, Sawhney S 2026 · J Clin Med Res | observational | supports | low | Narrative review of lipid-lowering options beyond statins and PCSK9 inhibitors; it runs no study of its own and restates the CLEAR Outcomes trial of bempedoic acid in 13,970 statin-intolerant patients. First major vascular event: 703 (10.1%) on bempedoic acid vs 816 (11.7%) on placebo, HR 0.85 (95% CI 0.77-0.94), and HR 0.75 (0.63-0.90) per 1.0 mmol/L of LDL-C lowered. Total-events analysis: MACE-4 HR 0.80 (0.72-0.89), heart attack HR 0.69 (0.58-0.83), stroke alone not significant HR 0.80 (0.63-1.03). |
| Myerson M, Warden BA, Saseen JJ, Paparodis R 2025 · J Am Heart Assoc | observational | supports | low | Clinical review of nonstatin LDL-lowering drugs; it summarizes other trials rather than reporting new data. On bempedoic acid it recounts CLEAR Outcomes, which randomized 6992 statin-intolerant patients to bempedoic acid and 6978 to placebo: LDL-C fell 29.2 mg/dL more than placebo at 6 months, and over a median 40.6 months cardiovascular death, heart attack, stroke or revascularization occurred in 11.7% vs 13.3% (HR 0.87, 95% CI 0.79-0.96). No significant benefit on stroke, cardiovascular death or all-cause death singly. Esperion, which makes the drug, convened and funded the article. |
| Lincoff AM, Ray KK, Sasiela WJ, Haddad T, Nicholls SJ, Li N, Cho L, Mason D, Libby P, Goodman SG, Nissen SE 2024 · J Am Coll Cardiol | RCT | supports | high | The same 13,970 patients from the CLEAR Outcomes trial, re-scored under the endpoint definitions used by the Cholesterol Treatment Trialists' Collaboration so the drug could be compared with statins. A first major vascular event occurred in 703 (10.1%) on bempedoic acid versus 816 (11.7%) on placebo, a hazard ratio of 0.85 (95% CI 0.77-0.94). Scaled to a 1 mmol/L fall in LDL cholesterol the hazard ratio was 0.75 (0.63-0.90), close to the 0.78 statins achieve. No new patients and no new events: the trial's own results counted again under a different composite. |
| Nissen SE, Menon V, Nicholls SJ, Brennan D, Laffin L, Ridker P, Ray KK, Mason D, Kastelein JJP, Cho L, Libby P, Li N, Foody J, Louie MJ, Lincoff AM 2023 · JAMA | RCT | supports | high | Among the 4,206 CLEAR Outcomes participants who were statin-intolerant and had no prior cardiovascular event, bempedoic acid 180 mg daily cut LDL cholesterol by 30.2 mg/dL (21.3%) from a mean of 142.2 mg/dL. Over a median 39.9 months the composite of cardiovascular death, heart attack, stroke or revascularisation occurred in 5.3% on the drug versus 7.6% on placebo (hazard ratio 0.70, 95% CI 0.55-0.89). Stroke and revascularisation individually showed no significant effect. These 4,206 are a subgroup of the 13,970 in the main trial, not a separate study. |
| Menon V, Bloedon L, Li N, Lincoff AM, Nicholls SJ, Powell HA, Nissen SE 2026 · J Clin Lipidol | RCT | supports | moderate | A post hoc look at the same 13,970 statin-intolerant patients in CLEAR Outcomes, asking whether extra cholesterol drugs started after randomisation explained its result. Only 1,749 (12.5%) started one, and most first cardiovascular events (92.9% on bempedoic acid, 90.9% on placebo) came before that. Censoring patients when they started add-on therapy, the four-part composite still favoured bempedoic acid: hazard ratio 0.86 (95% CI 0.77-0.94), essentially the trial's own 0.87 (0.79-0.96). No new patients: the parent trial counted again. Three authors work for the maker, Esperion. |
| Uddin N, Syed AA, Ismail SM, Ashraf MT, Khan MK, Sohail A 2023 · Curr Probl Cardiol | meta-analysis | supports | high | 7 RCTs (n=17,816): MACE RR 0.87 (0.80-0.94); nonfatal MI RR 0.73; unstable-angina hospitalization RR 0.69; revascularization RR 0.82. |
| Abdullah M, Khalid N, Frishman WH, Aronow WS 2025 · Cardiol Rev | observational | supports | low | Review of the indications for bempedoic acid, an oral ATP-citrate lyase inhibitor that lowers LDL cholesterol in the liver with less risk of muscle toxicity. Summarizing other people's trials, it reports randomized trials cutting LDL-C by 15-20% with the drug alone and up to 40% combined with ezetimibe, 'alongside cardiovascular event reduction in statin-intolerant patients.' It presents no patients of its own and gives no figure for the size of that event reduction. US, EU and UK approvals cover people who cannot tolerate statins or are inadequately controlled on standard therapy. |
| Cho L, Plutzky J, Brennan D, Louie MJ, Lei L, Robinson P, Powell HA, Nicholls SJ, Lincoff AM, Nissen SE 2024 · Circulation | RCT | supports | moderate | CLEAR Outcomes (13,970 patients) reported its results split by sex. Four-component major cardiovascular events occurred in 8.4% of women on bempedoic acid vs 9.7% on placebo (HR 0.89, 95% CI 0.75-1.04) and 14.8% of men vs 16.6% (0.86, 0.77-0.97); three-component events 6.1% vs 7.2% in women (0.88, 0.73-1.06) and 10.2% vs 11.6% in men (0.84, 0.73-0.97). Tests for a sex difference were not significant (P=0.82, P=0.84). The women-only estimates did not reach significance alone. These are the same patients as the main trial report. |
| Mancini GBJ, Lincoff AM, Goldberg AC, Broestl C, Li N, Duell PB, Laufs U, Catapano AL, Leiter LA, Banach M, Herout PM, Nicholls SJ, Bloedon L, Powell HA, Nissen SE, Mukherjee D 2026 · J Am Heart Assoc. 2026 Jul 7;15(13):e047897 | RCT | supports | moderate | Post hoc age analysis of bempedoic acid's phase 3 programme: 3,009 patients on maximal statins and the 13,970 statin-intolerant patients of the CLEAR Outcomes trial - the same people the parent reports already cover. What it measured was lipids and hs-CRP, not events: LDL cholesterol fell 18.3-18.6% across age bands on top of a statin and 21.9-24.5% in the statin-intolerant pool. For cardiovascular events it gives no counts, rates or hazard ratios, only that event reduction was statistically comparable across all ages. Adverse events were more frequent in patients aged 75 and over. |
| Sayed A, Shazly O, Slipczuk L, Krittanawong C, Baloch F, Virani SS 2023 · Cardiovasc Drugs Ther | meta-analysis | supports | high | Meta-analysis of 11 randomized trials, 18,496 adults at elevated cardiovascular risk, weighted median follow-up 40.6 months; the single CLEAR Outcomes trial supplied 13,970 of those patients. Bempedoic acid cut major adverse cardiovascular events, a five-part composite, by 13% (RR 0.87, 95% CI 0.80-0.95; 1.63 percentage points absolute, 62 treated to prevent one event), with myocardial infarction 0.76 (0.66-0.89), unstable-angina hospitalization 0.70 (0.55-0.89) and revascularization 0.81 (0.72-0.91). Stroke, cardiovascular death and death from any cause showed no significant difference. |
| Yarrarapu SNS, Goyal A, Venkata VS, Panchal V, Sivasubramanian BP, Du DT, Jakulla RS, Pamulapati H, Afaq MA, Owens S, Dalia T 2024 · J Cardiol | observational | supports | moderate | This review reports that the CLEAR Outcomes trial established significant cardiovascular benefits with bempedoic acid, given at 180 mg/day. On the separate question of mortality, the authors state that current evidence does not demonstrate a reduction in deaths from cardiovascular causes. The abstract gives no number for the size of the benefit on events. |
| Colivicchi F, Arca M, Di Fusco SA, Pirillo A, Alonzo A, Nardi F, Catapano AL 2025 · G Ital Cardiol (Rome) | observational | supports | low | Italian-language review article on the CLEAR Outcomes trial and its subgroup analyses, reporting that the LDL-cholesterol reduction achieved with bempedoic acid 'translates into a significant decrease in major adverse cardiovascular events', consistently in primary prevention and in patients with recurrent events. The article presents no patients of its own and reports no effect sizes or event counts. |
| Wang X, Zhang Y, Tan H, Wang P, Zha X, Chong W, Zhou L, Fang F 2020 · Cardiovasc Diabetol | meta-analysis | supports | moderate | Meta-analysis of 11 randomized trials of bempedoic acid in 4,391 adults with high cholesterol, most either statin-intolerant or already on the highest statin dose they could take. Only 2 of those trials (3,008 patients) followed cardiovascular events: they occurred in 5.6% on bempedoic acid versus 7.4% on placebo, a risk ratio of 0.75 (95% CI 0.56-0.99), with no heterogeneity, and the finding held in every sensitivity analysis. Taken one at a time, cardiovascular death, heart attack, stroke, unstable angina and revascularization each showed no significant difference. |
| Lin Y, Parco C, Karathanos A, Krieger T, Schulze V, Chernyak N, Icks A, Kelm M, Brockmeyer M, Wolff G 2022 · BMJ Open | meta-analysis | tested-null | low | Pooled 6 placebo-controlled trials of bempedoic acid (3,956 patients, follow-up 4 to 52 weeks). MACE was reported by only 4 of them (3,413 patients): 4.7% on the drug vs 5.5% on placebo, OR 0.84 (95% CI 0.61 to 1.15; p=0.27; I2 11%) - an underpowered trend toward fewer events, interval includes no effect. Authors rated certainty for MACE low and call the endpoints secondary/exploratory; protocol unregistered. Non-fatal MI OR 0.57 (0.32 to 1.00); LDL-C fell 19.9%. Too few events over too short a follow-up to settle whether the drug prevents cardiovascular events. |
| Nicholls SJ, Nelson AJ, Lincoff AM, Brennan D, Ray KK, Cho L, Menon V, Li N, Bloedon L, Nissen SE 2024 · JAMA Cardiol | RCT | supports | high | A reanalysis of the same 13,970 statin-intolerant CLEAR Outcomes patients, counting repeat events rather than only the first. Over a median 3.4 years there were 1,746 first major cardiovascular events plus 915 further events in 612 patients. Bempedoic acid cut total events: hazard ratio 0.80 (95% CI 0.72-0.89) for the four-part composite, 0.69 for heart attack and 0.78 for coronary revascularization, with no clear effect on stroke (0.80, 0.63-1.03). Coronary revascularization made up 69% of the repeat events. |
| Katzmann JL, Laufs U 2026 · Curr Atheroscler Rep | observational | supports | low | A narrative review on sequencing non-statin lipid-lowering drugs. It places bempedoic acid, with statins, ezetimibe and PCSK9 antibodies, among the LDL-lowering options with proven cardiovascular benefit, citing CLEAR Outcomes: 13,970 statin-intolerant patients on bempedoic acid or placebo, median 41 months, LDL cholesterol cut 21% from 3.6 mmol/L, and a primary endpoint of cardiovascular death, non-fatal heart attack, non-fatal stroke or revascularisation cut 13% relative. That 13% comes with no hazard ratio or confidence interval, and the review generated no data of its own. |
| Colivicchi F, Di Fusco SA, Arca M, Averna M, Scicchitano P, Nardi F, Catapano AL 2026 · Nutr Metab Cardiovasc Dis. 2026 Apr 30:104777. Online ahead of print. | observational | supports | low | Viewpoint/narrative discussion (not a systematic review) stating RCTs 'have shown bempedoic acid efficacy in...reducing...major cardiovascular adverse events,' citing this as basis for ESC guideline inclusion. |
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