Metabolic & Cardiometabolic
bempedoic acid decreases LDL cholesterol (~20-25%)
In plain terms: Does bempedoic acid lower LDL cholesterol, and by how much?
Strong support Metabolic & Cardiometabolic 💰 Industry COI noted
Part of: 💊 bempedoic acid
RefutedContestedStrong support
consensus score 1.00
Yes — consistently ~15-25% LDL-C reduction (≈17-18% on a statin background, ~21-28% as monotherapy/statin-intolerant; ~38% with ezetimibe), proven across the CLEAR phase 3 program and multiple meta-analyses.
📅 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
12 support 0 contradict 0 tested null 0 mixed · 12 sources, 11 independent groups · 4 superseded — pooled inside a review, counted once
What the evidence shows
Bempedoic acid lowers LDL cholesterol consistently: about 17 to 18 percent added to a statin, 21 to 28 percent as monotherapy or in statin-intolerant patients, and roughly 38 percent combined with ezetimibe. CLEAR Outcomes, in 13,970 statin-intolerant patients, found a durable 21 percent reduction against placebo, and a Japanese phase 3 trial replicated it.
The evidence (19)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Giammanco A, Gambacurta R, Gouni-Berthold I, Jukema JW, Roeters van Lennep JE, Ray K, Koskinas K, Stulnig T, Vanassche T, Lamparter M, Wenz-Pöschl K, Chhabra R, De Muniategui Climente M, Pintó X, Parhofer KG, Averna M, a nome del Gruppo di Studio MILOS 2026 · Giornale italiano di cardiologia | observational | supports | moderate | MILOS (NCT04579367), 'a European prospective observational study' — Italian subset, 8-week interim: 'Of the 1310 patients enrolled, 855 (BA, n = 445; BA+EZE FDC, n = 410)' had paired LDL-C, and after a mean 59.3 days 'mean LDL-C reduction of 22.6 ± 32.3% was observed, with a median reduction of' '25.4% (interquartile range 8.1-43.2), from 2.9 ± 1.2 mmol/l (110.7 ± 44.8 mg/dl)' to 2.1 ± 0.8 mmol/l (79.2 ± 32.2 mg/dl). Supports the ~20-25% LDL-lowering claim, but held at moderate quality, not high: single-arm and uncontrolled, six authors are Daiichi Sankyo employees, the SD (32.3%) exceeds the mean effect, 410/855 (48%) took the bempedoic acid+ezetimibe fixed-dose combination so the pooled figure is not a monotherapy effect (no per-arm split in the abstract), and 'Before starting BA or BA+EZE FDC, 33.1% of patients were not receiving' lipid-lowering therapy at all. |
| Zhao X, Ma X, Luo X, Shi Z, Deng Z, Jin Y, Xiao Z, Tan L, Liu P, Jiang S, Shu Y, Tang B, Qiu C 2020 · BMC Pharmacol Toxicol 2020;21(1):86 | meta-analysis | supports | moderate | Zhao 2020 (BMC Pharmacol Toxicol 21:86), random-effects meta-analysis of 13 double-blind RCTs / 4858 hypercholesterolemic adults (mean age 61, baseline LDL-C ≥70 mg/dL, 72% high CVD risk). Primary endpoint is the net LSM percentage change in LDL-C, so the claim's outcome IS the paper's outcome. Monotherapy vs placebo: −25.01% (95% CI −30.66 to −19.35, I² = 86%) — the top of the claim's ~20–25% object. The increment on top of background therapy is smaller: bempedoic acid + statin vs statin −18.37% (−20.16 to −16.57, I² = 0); + ezetimibe vs ezetimibe −18.89% (−29.66 to −8.13, I² = 87%); + ezetimibe vs placebo −37.82% (−41.85 to −33.79, I² = 0). Two gradients temper the headline: effect decays with duration (−22% at wk 8 → −19.13% wk 12 → −18.65% wk 24 → −16.10% wk 52) and with background statin intensity (−28.49% none, −20.02% low/moderate, −17.64% high, p<0.001) — yet it stays large even on high-intensity statin. Head-to-head, 'difference in the magnitude of LDL-C reduction between bempedoic acid and ezetimibe was not obvious.' Secondary lipids move too: TC −11.40%, non-HDL-C −13.57%, ApoB −12.73%, hsCRP −20.72% vs statin alone. Non-industry synthesis of industry trials — Hunan provincial grants, 'The authors declare that they have no competing interests.' Quality held at MODERATE, not high: trial-level (not IPD) pooling, I² = 86% in the monotherapy pool, 'allocation concealment in 7 trials and completeness of outcome data in 3 trials were classified as 'unclear risk of bias'', publication bias judged by funnel-plot eyeball alone with no Egger test, and no PROSPERO protocol. Scope limit stated by the authors: 'this study failed to identify the cardiovascular risk reduction by bempedoic acid' — LDL only, CLEAR Outcomes was still ongoing. |
| Yamashita S, Kiyosue A, Fujita H, Yokota D, Nakamura Y, Yasuda S 2025 · Circ J | RCT | supports | moderate | CLEAR-J (Japanese phase 3): bempedoic acid significantly lowered LDL-C vs placebo, replicating Western trials in a distinct population. |
| Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM, CLEAR Harmony Trial 2019 · N Engl J Med | RCT | supports | high | CLEAR Harmony (n=2230, on max-tolerated statin): LDL-C -16.5% from baseline, placebo-corrected -18.1 percentage points at wk 12. ↩ SUPERSEDED — pooled in the review above, counted once |
| Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S, Stroes ESG 2019 · J Am Heart Assoc. 2019 Apr 2;8(7):e011662 (e-pub 29 Mar 2019) | RCT | supports | high | CLEAR Serenity (NCT02988115, n=345 statin-intolerant, 2:1, 24 wk): LDL-C placebo-corrected -21.4% at wk 12 (95% CI -25.1 to -17.7), attenuating to -18.9% at wk 24 (95% CI -23.0 to -14.9); on-treatment (adherent) estimate -23.9% (95% CI -27.5 to -20.2). apoB fell less than LDL-C (-15.0%). [FT-verified 2026-08-19 from PMC6509724] ↩ SUPERSEDED — pooled in the review above, counted once |
| Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, Leiter LA 2018 · Atherosclerosis 2018 Oct;277:195-203 | RCT | supports | moderate | CLEAR Tranquility (NCT03001076), phase 3 double-blind placebo-controlled RCT, n=269 statin-intolerant patients (181 bempedoic acid, 88 placebo) already on ezetimibe after a 4-week run-in; primary endpoint percent change in LDL-C at 12 weeks. 'Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo).' Placebo-corrected effect is therefore 28.5%; -23.5% is the within-arm change from an already-ezetimibe-treated baseline (the prior extract had these two reversed, and its '~38% combo total' figure appears nowhere in the paper). Effect is incremental to ezetimibe, not monotherapy. Secondary endpoints moved with it: 'Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001).' Sponsor-run: Esperion Therapeutics funded the trial and two co-authors give their affiliation as 'Clinical Development, Esperion Therapeutics, Inc.' Abstract-only - full text not obtainable (not in PMC, subscription required), so baseline lipids, dropout handling and the disclosure statement are unverified. ↩ SUPERSEDED — pooled in the review above, counted once |
| Heikal M, Ali W, Mahdy MA, Gomaa E 2026 · Pharmaceutics | animal | supports | low | Pharmaceutical formulation study (MDPI Pharmaceutics 2026) whose in vivo arm gave 25 Sprague-Dawley rats (n = 5/group) a bempedoic acid + ezetimibe combination at 18/1 mg/kg for one week after acute hyperlipidemia induction with a single 100 mg/kg intraperitoneal Triton X-100 injection. Serum LDL fell from 170.39 ± 18.40 mg/dL in untreated hyperlipidemic rats to 30.25 ± 1.93 mg/dL on the test tablet and 27.89 ± 3.41 mg/dL on Nexlizet (p < 0.0001 for all treated groups vs untreated), and was statistically indistinguishable from the 14.92 ± 3.68 mg/dL uninduced control. The test formulation was NOT superior to the reference product — that comparison was explicitly non-significant (p = 0.9847); equivalence to Nexlizet was the study's objective. Directionally consistent with the claim but weak evidence for it: bempedoic acid was never given alone, so the LDL fall cannot be attributed to it rather than to ezetimibe; the Triton X-100 detergent model inhibits lipoprotein lipase rather than reproducing human dyslipidemia; and nothing here bears on the claim's ~20-25% human effect size. |
| 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 statin-intolerant): bempedoic acid cut LDL-C ~21% vs placebo at 6 mo (baseline 139 mg/dL), durable over trial. |
| Ballantyne CM, Banach M, Bays HE, Catapano AL, Laufs U, Stroes ESG, Robinson P, Lei L, Ray KK 2022 · Am J Cardiol | observational | supports | low | CLEAR Harmony 78-week OPEN-LABEL EXTENSION, single-arm (no concurrent control; efficacy = % change from parent-study baseline). Of 1,462 OLE enrollees, 970 prior bempedoic acid: 'reductions in LDL-C, other lipid parameters, and hsCRP observed in the parent study remained stable through 130 weeks of treatment'; the 492 former-placebo patients 'experienced reductions in LDL-C, other lipid parameters, and hsCRP, mirroring reductions observed in patients who received bempedoic acid in the parent study'. DIRECTION ONLY - no LDL-C effect size is reported in the available text, so this cannot corroborate the claim's ~20-25% object. Two authors are Esperion Therapeutics employees; abstract-grade provenance. |
| Hsieh IC, Chen DY, Chu CS, Chang YY, Tzeng BH, Huang TC, Lin HH, Chuang WP, Huang CC, Yeh JK, Chu CY, Ho MY, Huang CY, Chen YW, Yang WC, Lin TH, Wu YW 2026 · J Am Heart Assoc | observational | supports | moderate | CLEAR Taiwan (NCT06925100): prospective, pragmatic, phase 4, multicenter SINGLE-ARM open-label study — no randomization, no comparator arm — n=180 enrolled, 160 (88.9%) completers analyzed (complete-case, no imputation). Bempedoic acid 180 mg/d added to background lipid-lowering therapy for 12 weeks: median LDL-C change -19% (IQR -36.4% to -3.6%), 117.5 to 92 mg/dL, P<0.01; 31.3% reached LDL-C targets. Because there is no control arm this is a within-person pre/post change, not a placebo-corrected effect, and adherence explained part of the spread (poor adherence accounted for 25% of patients whose LDL-C rose >10%). Funded by Daiichi Sankyo Taiwan; three sponsor employees are authors and one wrote the first draft. |
| Ridker, Lei, Ray, Ballantyne, Bradwin, Rifai 2023 · J Clin Lipidol | RCT | supports | moderate | Post-hoc biomarker substudy of CLEAR Harmony (NCT02666664), restricted to the 817 statin-treated patients with residual inflammatory risk (hsCRP >=2 mg/L), randomized 2:1 to bempedoic acid 180 mg vs placebo for 12 weeks: placebo-corrected median LDL-C change -21.1% (-23.7 to -18.5), ApoB -13.1% (-15.5 to -10.6). LDL result is randomized and CI-clear, but this is a subgroup of a trial already represented in the corpus by s30865796, an Esperion Therapeutics employee is a co-author, and the abstract's 'pattern ... almost identical to ... statin therapy' framing rests on one inflammatory hit (hsCRP -26.5%) against two nulls (IL-6 -3.7% [-11.5, 4.3]; fibrinogen 2.1% [-2.0 to 6.4]). |
| Khattak S, Ochoa-Ferraro A, Khan N, George S, Khan SQ, Townend JN, Dawson C, Thomas MR 2025 · J Clin Med | observational | supports | low | Single-centre retrospective observational cohort (University Hospitals Birmingham lipid clinic, 2017-2024), n=256 across four agents, of whom '30 patients received bempedoic acid'. Direction is clear: 'In patients treated with bempedoic acid, LDL-C decreased by 36% compared to baseline' ... 'to a mean of 2.68 mmol/L after 12-24 months, with 12% of patients reaching the ESC target and 29% reaching the NICE target' (baseline LDL-C 4.1 mmol/L). Magnitude is NOT usable and runs well above the randomised evidence, as the authors themselves note: 'Our study showed that bempedoic acid reduced plasma LDL-C levels by approximately 35%, a greater reduction than the 18% reported in clinical trials' - their explanation (80% female subgroup) is post-hoc, and there is no control arm, no adjustment, and no treatment of regression to the mean, with patients compared only to their own pre-initiation value ('Data were extracted retrospectively from electronic medical records.'). The subgroup is also unusually lightly pre-treated for an add-on agent (22.7% on a high-intensity statin, 72.7% on ezetimibe, Table 1), which would further inflate the observed drop. Reporting is unreliable at the margins: the abstract's interval is incoherent ('bempedoic acid with a reduction of 36% (95% CI, 22 to 69'), and the Discussion restates the target attainment as 'only 30% and 10% of patients, respectively, achieved the ESC- and NICE-recommended LDL-C targets on bempedoic acid', contradicting its own Results. Authors concede 'The sample size was relatively small for patients treated with bempedoic acid but was sufficiently powered to detect a 30% reduction in LDL-C'. J Clin Med (MDPI) 2025;14(22):7946; no manufacturer funding for bempedoic acid disclosed. Counts as real-world directional corroboration only; the ~20-25% magnitude in the claim object should continue to come from the randomised/meta-analytic evidence, not from here. |
| Nelson J, Bloedon L, Lewandowski D, Vaduganathan M, Ajose M, Bonafede M, Sarnes E 2026 · Atherosclerosis Plus | observational | supports | moderate | Retrospective, UNCONTROLLED pre-post cohort in the Veradigm Network EHR linked to Komodo open claims, US 2020-2024; n=900 bempedoic acid alone, n=615 BA+ezetimibe fixed-dose combination. Median baseline LDL-C 137 (100-167) and 127 (93-163) mg/dL. By 3 months median LDL-C fell to 108 (80-138) mg/dL on BA alone, a 21.2% reduction 'maintained at 6 and 12 months'; the combination fell to 85 (61-114) mg/dL (33.1%) at 3 months but WANED to 96 (67-128) mg/dL (22.4%) by 12 months, so 'sustained' holds for BA monotherapy and not for the combination. Attainment of LDL-C <70 mg/dL rose from 6.3%/8.5% at baseline to 16.8%/33.3% at 3 months and 18.0%/27.5% over 12 months. Reductions were larger without prior statin use (-24.2% / -36.7% vs -16.7% / -29.8%) and with continuous use (-26.1% / -40.2%). A closed-claims sensitivity analysis (n=178/163) reproduced the direction (-24.5% / -28.4% at 3 months). WHY THIS IS ONLY MODERATE, NOT HIGH: (1) no comparator whatsoever - 'The major limitation of the analysis is the inability to make causal inference based on these observational results due to the lack of a control cohort of alternative LLT initiators' - so with an elevated-selecting baseline draw, regression to the mean is uncontrolled and unmentioned; (2) requiring >=2 follow-up LDL-C labs including one at 12 months meant 'this resulted in a loss of ∼75% of the sample population, potentially biasing towards patients who receive more comprehensive care'; (3) an inference mismatch the authors state outright - 'For descriptive reporting in this paper, median laboratory levels are described though mean lipid values were used for inferential testing' - combined with unpaired t-tests across timepoints where 'patients were not required to have lab tests available at every timepoint', so the p<0.0001 values compare partly different people rather than within-patient change; (4) the primary analysis runs on open claims that 'are not all fully adjudicated'; (5) funding and authorship: 'This study was funded by Esperion Therapeutics, Inc.', the manufacturer, with all seven authors reporting Esperion financial support. The direction is nonetheless corroborated externally - 21.2% here matches the 21% mean LDL-C reduction in CLEAR Outcomes - which is why this stays supports rather than being discounted further. |
| Masuda D, Kajinami K, Sakayoshi N, Yokota D, Nagamine M, Morikawa-Isogai Y, Yamashita S 2026 · J Atheroscler Thromb | observational | supports | moderate | Phase 3 long-term single-arm study (CLEAR-J LONG), n=130 Japanese patients, bempedoic acid 180mg/day for 52 weeks; LDL-C decreased 21.6% overall (25.3% in newly enrolled subgroup), well tolerated. |
| Venkatraman, Das, Eerike, Cherian, Bagepally 2023 · Eur J Clin Pharmacol 2023;79(11):1453-1463 | meta-analysis | supports | moderate | SR + random-effects MA of 17 RCTs (n = 21,131) to June 2023: 'Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [- 34.41 mg/dl (95% CI: - 42.43 to - 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [- 33.91 mg/dl (95% CI: - 39.66 to - 28.17), p < 0.001]'. 'The GRADE of evidence was moderate for all outcomes.' Supports the direction; the abstract gives no baseline LDL-C, so the claim's ~20-25% magnitude cannot be checked from available text. Author-independent (ICMR/JIPMER/AIIMS) but pools the CLEAR programme, so not data-independent of CLEAR-based appraisals. |
| 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): LDL-C mean difference -22.4% (95% CI -25.9 to -18.8) vs placebo; total cholesterol -13.9%. |
| De Filippo O, D'Ascenzo F, Iannaccone M, Bertaina M, Leone A, Borzillo I, Ravetti E, Solano A, Pagliassotto I, Nebiolo M, Bruno F, Giacobbe F, Muscoli S, Monticone S, Brizzi MF, Biondi Zoccai G, De Ferrari GM 2023 · Cardiovasc Diabetol | meta-analysis | supports | high | Systematic review + meta-analysis of 11 RCTs / 18,315 patients (9,854 bempedoic acid 180 mg/day vs 8,461 placebo or no treatment; PRISMA, PROSPERO 399,867; 'Funding None' and 'Competing interests None declared'). LDL-C at 12 weeks pooled across 8 trials / 18,130 participants: mean difference -22.42% vs control (95% CI -24.0% to -20.8%) - inside the claim's stated ~20-25% band. Companion atherogenic-lipid endpoints move the same way: total cholesterol -16.5% (-19.2 to -13.8), non-HDL-C -20.3% (-22.6 to -18.0), ApoB -19.6% (-22.7 to -16.4), hs-CRP -28.1% (-31.7 to -24.4), and the effect held at latest follow-up as well as at 12 weeks. The size of the LDL-C effect depends on background therapy: -24.1% with no statin, -19.6% on low/moderate-intensity statin, -15.7% on high-intensity statin (the drug shares the statin pathway upstream), while ezetimibe background made no difference (-19.0% with vs -18.5% without). Two caveats the authors state themselves: 'Significant heterogeneity was observed for all the laboratory efficacy outcomes' (low heterogeneity applies to the clinical-event endpoints, not the lipid ones), and over 70% of the pooled sample is the single CLEAR OUTCOMES trial (Nissen 2023), so this is not an independent vote alongside that trial. |
| Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LT, Lalwani ND, Patel PM, Zhao X, Duell PB 2019 · JAMA | RCT | supports | high | CLEAR Wisdom (n=779, on max-tolerated statin): LDL-C placebo-corrected -17.4% at wk 12; also lowered non-HDL-C, ApoB, hsCRP. ↩ SUPERSEDED — pooled in the review above, counted once |
| Feingold KR. 2026 · MDText.com, Inc., South Dartmouth (MA) | observational | supports | low | Endotext textbook chapter (Feingold KR, chapter revised 2026 Apr 23), not a study: 'Bempedoic acid lowers LDL-C by 15-25% by inhibiting hepatic ATP citrate lyase activity resulting in a decrease in cholesterol synthesis in the liver, a decrease in hepatic cholesterol content, and an up-regulation of LDL receptors.' No new data, no trial named, no n; mono vs add-on still not specified. Regraded observational to review to match the evidence_role already set; either way. |
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