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Cited by 19Lipoproteins and Cardiovascular HealthCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

The Clinical Efficacy and Safety of Bempedoic Acid in Patients at Elevated Risk of Cardiovascular Disease: A Meta-Analysis of Randomized Clinical Trials

Open access
Sayed, Ahmed, Shazly, Omar, Slipczuk, Leandro, Krittanawong, Chayakrit, Baloch, Farhala, Virani, Salim S.·2024·Cardiovascular Drugs and Therapy
DOI 10.1007/s10557-023-07474-9PMC PMC11680617
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Abstract

Purpose: Statins are first-line agents to reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, however, they are insufficient and/or intolerable in many patients. To that end, we conducted a meta-analysis of Bempedoic Acid (BA), a novel LDL-C lowering agent. Methods: We retrieved randomized clinical trials (RCTs) of BA by searching Pubmed, the Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov. We used the Mantel-Haenszel method to pool estimates. The I 2 measure was used to quantify heterogeneity. Treatment effects are provided as relative risks (RR), absolute risk differences (ARD), and number needed to treat/harm (NNTB/H). Analyses were conducted using R, version 4.1.2. Results: 11 trials enrolling 18,496 patients were included. Compared to placebo, BA reduced the risk of major adverse cardiovascular events (RR: 0.87; 95% CI: 0.80 to 0.95; ARD: -1.63%; NNT: 62), myocardial infarction (RR: 0.76; 95% CI: 0.66 to 0.89; ARD: -1.03%; NNT: 98), unstable angina hospitalization (RR: 0.70; 95%: CI: 0.55 to 0.89; ARD: -0.57%; NNT: 177), revascularization (RR: 0.81; 95% CI: 0.72 to 0.91; ARD: -1.31%; NNT: 77), and myalgia (RR: 0.85; 95% CI: 0.75 to 0.95; ARD: -0.99%; NNT: 102). BA significantly increased the risk of gout (RR: 1.56; 95% CI: 1.27 to 1.91; ARD: 0.99%; NNH: 101), renal impairment (RR: 1.35; 95% CI: 1.22 to 1.49; ARD: 2.54%; NNH: 40), and cholelithiasis (RR: 1.87; 95% CI: 1.43 to 2.44; ARD: 1.01%; NNH: 100). Conclusion: BA effectively reduces the risk of cardiovascular events and myalgia but increases the risk of gout, cholelithiasis, and renal impairment.

AI snapshot

Written from the paper’s full text.

TL;DR

In this meta-analysis of 11 randomized trials and 18,496 patients, bempedoic acid reduced major adverse cardiovascular events, myocardial infarction, unstable angina hospitalization, revascularization, and myalgia versus placebo. It increased gout, renal impairment, and cholelithiasis, with no significant differences in all-cause mortality, cardiovascular mortality, stroke, or new/worsening diabetes.

Key findings

  • Bempedoic acid significantly reduced MACE (RR 0.87; 95% CI 0.80–0.95; ARD −1.63%; NNT 62), myocardial infarction (RR 0.76; 95% CI 0.66–0.89; ARD −1.03%; NNT 98), unstable angina hospitalization (RR 0.70; 95% CI 0.55–0.89; ARD −0.57%; NNT 177), and revascularization (RR 0.81; 95% CI 0.72–0.91; ARD −1.31%; NNT 77).
  • Myalgia was less common with bempedoic acid (RR 0.85; 95% CI 0.75–0.95; ARD −0.99%; NNT 102).
  • Bempedoic acid significantly increased gout (RR 1.56; 95% CI 1.27–1.91; ARD 0.99%; NNH 101), renal impairment (RR 1.35; 95% CI 1.22–1.49; ARD 2.54%; NNH 40), and cholelithiasis (RR 1.87; 95% CI 1.43–2.44; ARD 1.01%; NNH 100).
  • Differences in all-cause mortality, cardiovascular mortality, stroke, and new/worsening diabetes mellitus did not reach statistical significance.

Methods

  • Systematic review and meta-analysis of randomized clinical trials; prospectively registered on PROSPERO (CRD 42023404231) and guided by PRISMA. Searches of PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were conducted in March 2023.
  • Included 11 unique RCTs with 18,496 patients (bempedoic acid 9,959; control 8,537) and a weighted median follow-up of 40.6 months. Efficacy outcomes included all-cause mortality and MACE, with MACE analyzed as a 5-component composite and by individual components; safety outcomes included gout, myalgia, renal impairment, cholelithiasis, and new/worsening diabetes.
  • Treatment effects were pooled using the Mantel-Haenszel method and reported as risk ratios, absolute risk differences, and number needed to treat/harm. Heterogeneity was quantified with I²; because heterogeneity ranged from 0 to 18%, a fixed-effect model was used. Risk of bias was assessed with RoB-II, and publication bias was assessed by funnel plots and Egger’s test for outcomes reported by 10 unique studies. Analyses used R version 4.2.1 with the “meta” package.

Limitations

  • The paper states that its subgroup analysis based on prevention status was not statistically significant and was limited by lack of access to patient-level data, allowing categorization of studies but not patients. It also states that most included trials had relatively short follow-up durations, with the exceptions of CLEAR Outcomes and CLEAR Harmony, and that even those were generally shorter than real-world use of lipid-lowering treatments.
  • The paper states that publication bias could be assessed only for myalgia, because it was the only outcome reported by 10 or more studies.
  • Evident from the text: renal impairment was variably defined across RCTs, and the meta-analysis relies on study-level rather than patient-level data, limiting adjustment for individual confounders.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s10557-023-07474-9

Cites

22 of 22 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 28 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured

  • Interpretationreasoning

    Differences between these results and previous meta-analyses are likely attributable to lack of statistical power and imprecise estimates because CLEAR Outcomes had not yet been published at the time of the previous meta-analyses but is included in this meta-analysis.

    “These differences are likely attributable to a lack of statistical power and imprecise estimates as the largest outcomes-based trial, CLEAR Outcomes, had not yet been published at the time of the previous meta-analyses but is included in our meta-analysis [7].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in statin-intolerant patients. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2215024. source
    • cites [19] Lin Y, Parco C, Karathanos A, et al. Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis. BMJ Open. 2022;12(2):e048893. https://doi.org/10.1136/bmjopen-2021-048893. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • Premisecitation

    The SAMSON trial showed that most statin-associated myalgias are due to the nocebo effect.

    “In the context of statin-associated myalgias, it is important to consider the findings of the SAMSON trial, which elegantly showed that most statin-associated myalgias are due to the nocebo effect [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Howard JP, Wood FA, Finegold JA, et al. Side effect patterns in a crossover trial of statin, Placebo, and no treatment. J Am Coll Cardiol. 2021;78(12):1210–22. https://doi.org/10.1016/j.jacc.2021.07.022. source

      The Abstract Conclusions and Discussion say that most symptoms attributed to statin tablets in SAMSON were nocebo, with similar symptom scores on statin and placebo. The Results (Participants) say muscle ache was the most common reason for prior statin abandonment, but the reported nocebo finding concerns symptoms overall, not myalgias specifically; the trial also enrolled people who had abandoned statins because of symptoms. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Study design and conductcitation

    Most included trials had relatively short follow-up durations, except CLEAR Outcomes and CLEAR Harmony.

    “Additionally, most of the trials included in this analysis had relatively short follow-up durations with the exception of CLEAR Outcomes [7] and CLEAR Harmony [12].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in statin-intolerant patients. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2215024. source
    • cites [12] Ray KK, Bays HE, Catapano AL, et al. Safety and Efficacy of Bempedoic Acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–32. https://doi.org/10.1056/NEJMoa1803917. source
  • Premisecitation

    In the CLEAR-Outcomes trial, bempedoic acid's relative risk reduction for the primary composite outcome differed significantly between primary and secondary prevention groups (hazard ratios 0.68 versus 0.91).

    “In the CLEAR-Outcomes trial, an intriguing observation was that BA’s relative risk reduction for the primary composite outcome differed significantly between the primary and secondary prevention groups (with hazard ratios of 0.68 versus 0.91 respectively) [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in statin-intolerant patients. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2215024. source

      The Discussion (page unavailable) says the hazard ratio for the primary endpoint was lower in the primary-prevention subgroup than in the secondary-prevention group. Our copy does not give the claimed subgroup hazard ratios of 0.68 and 0.91 or establish a statistically significant difference between them; it cautions that subgroup analyses were not adjusted for multiplicity and do not provide definitive conclusions. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The CLEAR Outcomes trial showed reductions in clinical events with bempedoic acid.

    “This was followed by recent data from the CLEAR Outcomes trial showing reductions in clinical events [7].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in statin-intolerant patients. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2215024. source
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Interpretationcitation

    The relative and absolute reductions in MACE observed in this analysis are similar in magnitude to those observed for ezetimibe in IMPROVE-IT and evolocumab in FOURIER, with similarly non-significant reductions in all-cause and cardiovascular mortality.

    “The relative and absolute reductions in MACE observed in our analysis are similar in magnitude to those observed for the seminal IMPROVE-IT [3] and FOURIER [4] trials for ezetimibe and evolocumab respectively, with similarly non-significant reductions in all-cause and cardiovascular mortality.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [4] Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    Bempedoic acid increased the risk of gout, renal impairment, and cholelithiasis, none of which were significantly increased with ezetimibe or evolocumab.

    “However, BA increased the risk of gout, renal impairment, and cholelithiasis, none of which were significantly increased with ezetimibe or evolocumab.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489. source

      The Safety section reports no significant difference in gallbladder-related adverse events between simvastatin alone and simvastatin plus ezetimibe, which supports the ezetimibe portion only for a broader category of events, not cholelithiasis specifically. The cited paper does not report the claimed gout or renal-impairment comparisons, and it does not study bempedoic acid or evolocumab. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664. source

      The Safety section reports no significant difference in overall adverse events between evolocumab and placebo, supporting the general safety comparison. It does not report separate results for gout, renal impairment, or cholelithiasis; bempedoic acid and ezetimibe were not the treatments compared in this trial. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Statins are used as first-line agents to reduce LDL-C levels.

    “HMG-CoA reductase inhibitors, also known as statins, are used as first-line agents to reduce LDL-C levels [1].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e143. https://doi.org/10.1161/CIR.0000000000000625 source

  • May combine two claims.

    Interpretationcitation

    These results contrast with the most recent meta-analysis of clinical outcomes with bempedoic acid, which found no statistically significant reductions in MACE, coronary revascularization, or unstable angina hospitalization and found a statistically significant reduction in new-onset diabetes not seen in the current analysis.

    “Our results contrast with those of the most recent meta-analysis assessing clinical outcomes with the use of BA [19]. In that meta-analysis, there were no statistically significant reductions with respect to MACE, coronary revascularization, or hospitalization for unstable angina. In addition, there was a statistically significant reduction in new-onset diabetes not seen in the current analysis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Lin Y, Parco C, Karathanos A, et al. Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis. BMJ Open. 2022;12(2):e048893. https://doi.org/10.1136/bmjopen-2021-048893. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Ezetimibe, evolocumab, and alirocumab reduce LDL-C and cardiovascular events, based on the IMPROVE-IT, FOURIER, and ODYSSEY Outcomes trials respectively.

    “The main alternative treatments indicated to lower LDL-C and cardiovascular risk are ezetimibe, evolocumab, and alirocumab based on the IMPROVE-IT [3], FOURIER [4], and ODYSSEY Outcomes [5] trials respectively, wherein the 3 treatments resulted in significant reductions in LDL-C and cardiovascular events.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [3] Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489. source
    • cites [4] Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664. source
    • cites [5] Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174. source

  • May combine two claims.

    Premisecitation

    LDL-C plays a causative role in atherosclerotic cardiovascular disease, the leading cause of death worldwide.

    “Low-density lipoprotein cholesterol (LDL-C) plays a causative role in atherosclerotic cardiovascular disease (ASCVD), the leading cause of death worldwide [1, 2].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [1] Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e143. https://doi.org/10.1161/CIR.0000000000000625 source

      The guideline’s Top 10 Take-Home Messages state that greater LDL-C reduction with statin therapy produces greater subsequent ASCVD risk reduction, supporting LDL-C’s role in the disease. The searched passages do not establish the separate claim that ASCVD is the leading cause of death worldwide. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [2] Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk factors, 1990–2019: Update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010. source

      The Modifiable Risk Factors section attributes 4.40 million deaths in 2019 to high LDL cholesterol, supporting its role in disease burden. The Abstract says cardiovascular diseases, principally ischemic heart disease and stroke, are the leading cause of global mortality; it does not establish that the narrower category of atherosclerotic cardiovascular disease is itself the leading cause. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductown data

    Overall risk of bias was low in 7 of 11 included trials and moderate in 4 trials.

    “The overall risk of bias was low 7 of 11 trials [7, 9–12, 15, 16], with 4 trials being assessed as having a moderate risk of bias [8, 13, 14, 17].”
    Quote in the paperNot a substantial claim6 of 10 sources checked
    • cites [7] Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in statin-intolerant patients. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2215024. source

      The Trial Organization and Oversight section describes one randomized, placebo-controlled trial, and the Statistical Analysis section describes its analysis. Our copy does not report a risk-of-bias assessment of 11 included trials or classify seven as low risk and four as moderate risk (searched for those counts and for risk-of-bias assessment of included studies). (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [9] Goldberg AC, Leiter LA, Stroes ESG, et al. 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. JAMA. 2019;322(18):1780–8. https://doi.org/10.1001/jama.2019.16585. source
    • cites [10] Lalwani ND, Hanselman JC, MacDougall DE, Sterling LR, Cramer CT. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: a randomized placebo-controlled trial. J Clin Lipidol. 2019;13(4):568–79. https://doi.org/10.1016/j.jacl.2019.05.003. source
    • cites [11] Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of Bempedoic Acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662. https://doi.org/10.1161/JAHA.118.011662. source

      The source paper’s Methods describe the design and analysis of a single bempedoic-acid trial, and its Results report outcomes for that trial. Searches for an overall risk-of-bias assessment of 11 trials, including the claimed low and moderate counts, found no passage addressing it. The Safety section’s reference to adverse events of mild or moderate intensity is not a risk-of-bias assessment. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [12] Ray KK, Bays HE, Catapano AL, et al. Safety and Efficacy of Bempedoic Acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–32. https://doi.org/10.1056/NEJMoa1803917. source
    • cites [15] Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195–203. https://doi.org/10.1016/j.atherosclerosis.2018.06.002. source
    • cites [16] Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27(6):593–603. https://doi.org/10.1177/2047487319864671. source

      The Methods (Statistical analysis) and Discussion describe this individual trial and its data-integrity concerns, but do not assess the risk of bias across 11 trials. Searches for the low/moderate risk-of-bias counts found no passage in our copy reporting them. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [8] Bays HE, Baum SJ, Brinton EA, et al. Effect of bempedoic acid plus ezetimibe fixed-dose combination vs ezetimibe or placebo on low-density lipoprotein cholesterol in patients with type 2 diabetes and hypercholesterolemia not treated with statins. Am J Prev Cardiol. 2021;8:100278. https://doi.org/10.1016/j.ajpc.2021.100278. source

      The Methods section (Study design and treatment; page unavailable) describes this paper as a single randomized trial. Our copy does not assess its risk of bias or report an assessment of 11 trials; searches for the stated low- and moderate-risk classifications found no supporting passage. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [13] Rubino J, MacDougall DE, Sterling LR, et al. Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: a randomized, controlled trial. J Clin Lipidol. 2021;15(4):593–601. https://doi.org/10.1016/j.jacl.2021.05.002. source

      The cited paper reports a single randomized trial. Its Study design and treatment and Statistical analysis sections describe that trial, but the passages do not assess risk of bias across 11 trials. Searches for the seven-low/four-moderate breakdown and for risk-of-bias assessment found no supporting passage in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [14] Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62(13):1154–62. https://doi.org/10.1016/j.jacc.2013.05.050. source

  • May combine two claims.

    Findingown data

    There were no statistically significant differences between bempedoic acid and control in all-cause or cardiovascular mortality.

    “There were no statistically significant differences in terms of all-cause or cardiovascular mortality.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Publication bias was assessed via visual inspection of funnel plots and Egger's test for outcomes reported by 10 unique studies.

    “Publication bias was assessed via visual inspection of funnel plots and use of Egger’s test for outcomes reported on by 10 unique studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Heterogeneity was low, ranging from 0 to 18%, so a fixed-effect model was used.

    “Because heterogeneity was low, ranging from 0 to 18%, a fixed-effect model was used.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Risk of bias was assessed using the Risk of Bias 2 (RoB-II) tool.

    “Risk of bias was assessed using the Risk of Bias 2 (RoB-II) tool.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    For myalgia, the only outcome reported by 10 or more studies, there was no evidence of publication bias on funnel plot inspection or Egger's test (P = 0.99).

    “Myalgia was the only outcome reported on by 10 studies or more, and there was no evidence of publication bias on visual inspection of the funnel plot (Supplementary Fig. 14) or by Egger’s test (P = 0.99).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The subgroup analysis based on prevention status was not statistically significant and was limited by lack of access to patient-level data and by the ability to categorize studies rather than patients.

    “It is important to note that our subgroup analysis based on prevention status, which was not statistically significant, was limited by the lack of access to patient-level data and could only categorize studies and not patients involved therein.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Bempedoic acid effectively reduces cardiovascular events and myalgia but increases the risk of gout, cholelithiasis, and renal impairment.

    “BA effectively reduces the risk of cardiovascular events and myalgia but increases the risk of gout, cholelithiasis, and renal impairment.”
    • Also stated in: § Discussion · plain
      “In conclusion, BA effectively reduces MACE in patients at an elevated risk for ASCVD; however, this needs to be weighed against adverse effects including gout, renal impairment, and cholelithiasis, particularly in the presence of alternative effective LDL-C-lowering medications.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was prospectively registered on PROSPERO and its conduct was guided by the PRISMA guidelines.

    “This study was prospectively registered on PROSPERO (CRD: 42023404231) and its conduct was guided by the PRISMA guidelines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Considering the progressive nature of atherosclerosis, the benefits of LDL-C lowering treatments are likely to be accentuated rather than attenuated during longer follow-up.

    “Nevertheless, considering the progressive nature of atherosclerosis, the benefits of LDL-C lowering treatments are likely to be accentuated -rather than attenuated- during longer follow-up durations.”
    Quote in the paperNot a substantial claim
16 of 16

  • The paper relies on this without support.

    Many patients cannot achieve adequate LDL-C reduction with statins because statins are insufficient and/or intolerable.

    “Statins are first-line agents to reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, however, they are insufficient and/or intolerable in many patients.”
    “However, additional interventions are needed in a substantial number of patients, such as patients who experience statin-associated adverse events.”

  • The paper relies on this without support.

    Statins have by far the greatest body of evidence on clinical safety and efficacy.

    “This is especially important as statins have by far the greatest body of evidence on clinical safety and efficacy, and therefore every effort should be made to maximize their use before looking to alternative/add-on treatments.”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Different R versions reported

    Minor

    The abstract reports R version 4.1.2, while the Statistical Analysis section reports version 4.2.1.

  • Risk-of-bias categories do not match the table

    Minor

    The text counts CLEAR Outcomes among seven trials assessed as low risk of bias, but Table 1 labels its risk of bias "Blinded" rather than "Low." The table likewise labels CLEAR Harmony, another trial in the low-risk count, "Blinded."

  • Thompson study has conflicting publication years

    Minor

    Table 1 lists 2015 in its publication-year column for Thompson et al., 2016; the cited journal reference also gives 2016.

3 of 3

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Authors
Sayed, A., Shazly, O., Slipczuk, L., Krittanawong, C., Baloch, F., & Virani, S. S.
Affiliations
  • Ain Shams University (EG)
  • Albert Einstein College of Medicine (US)
  • NYU Langone Health (US)
  • Aga Khan University (PK)
Corresponding author
Sayed, Ahmed
ORCID
Venue
Cardiovascular Drugs and Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-06-01
Volume
38
Issue
6
Pages
1415-1420
ISSN
  • 0920-3206 (ISSN-L)
  • 1573-7241
DOI
10.1007/s10557-023-07474-9
PMC
PMC11680617
OpenAlex
W4378952564
Semantic Scholar
58ceb081905e898f57ed229e4e5744e02607999e
Cited by
19
References
22
Citations by year
2026: 5 · 2025: 5 · 2024: 7 · 2023: 2
FWCI
1.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Cardiovascular Drugs and Therapy (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • eCommons - AKU (Aga Khan University) (submittedVersion, cc-by)
Funders
Ain Shams University
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
bempedoic acid, LDL cholesterol lowering, major adverse cardiovascular events, myocardial infarction, unstable angina, revascularization, gout, renal dysfunction, gallstones, myalgia, statin intolerance, cardiovascular risk reduction, drug safety, adverse events, hypercholesterolemia, hypertriglyceridemia
MeSH terms
Heart Disease Risk Factors, Cardiovascular Diseases, Dicarboxylic Acids, Fatty Acids, Humans, Cholesterol, LDL, Randomized Controlled Trials as Topic, Treatment Outcome

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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