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Cited by 146Lipoproteins and Cardiovascular HealthCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients

Open access
Nissen, Steven E., Menon, Venu, Nicholls, Stephen J., Brennan, Danielle, Laffin, Luke, Ridker, Paul, Ray, Kausik K., Mason, Denise +7 more·2023·JAMA
DOI 10.1001/jama.2023.9696PMC PMC10336623
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Abstract

Importance: The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described. Objective: To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients. Design, Setting, and Participants: This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients. Interventions: Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106). Main Outcome Measures: The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. Results: Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels. Conclusions: In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT02993406

AI snapshot

Written from the paper’s full text.

TL;DR

In a prespecified primary prevention subgroup of statin-intolerant patients from CLEAR Outcomes, bempedoic acid reduced the primary 4-component MACE composite compared with placebo over a median 39.9 months. Benefits were also seen for 3-component MACE, MI, cardiovascular death, and all-cause mortality, with higher rates of gout, cholelithiasis, hyperuricemia, hepatic enzyme elevation, and kidney adverse events.

Key findings

  • The primary 4-component MACE end point occurred in 111 patients (5.3%) with bempedoic acid vs 161 (7.6%) with placebo (adjusted HR, 0.70 [95% CI, 0.55-0.89]; P = .002); NNT was 43.
  • Key secondary outcomes were reduced: 3-component MACE 83 (4.0%) vs 134 (6.4%) (HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI 29 (1.4%) vs 47 (2.2%) (HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death 37 (1.8%) vs 65 (3.1%) (HR, 0.61 [95% CI, 0.41-0.92]); all-cause mortality 75 (3.6%) vs 109 (5.2%) (HR, 0.73 [95% CI, 0.54-0.98]).
  • Stroke and coronary revascularization were not significantly reduced: stroke 27 (1.3%) vs 37 (1.8%) (HR, 0.76 [95% CI, 0.46-1.26]); coronary revascularization 50 (2.4%) vs 68 (3.2%) (HR, 0.71 [95% CI, 0.49-1.03]).
  • Bempedoic acid reduced LDL-C by 30.2 mg/dL (21.3%) from a mean baseline of 142.2 mg/dL and hsCRP by 0.56 mg/L (21.5%) from a median baseline of 2.4 mg/L; adverse events included hyperuricemia (12.1% vs 6.3%), gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), elevated hepatic enzymes (4.5% vs 2.6%), and kidney impairment (10.3% vs 8.1%).

Methods

  • Prespecified subgroup analysis of the masked, randomized CLEAR Outcomes trial, conducted at 1250 centers in 32 countries; enrollment was December 2016 to August 2019, and the analysis included 4206 primary prevention patients among 13,970 statin-intolerant patients.
  • Participants were randomized 1:1 to oral bempedoic acid 180 mg daily (n = 2100) or matching placebo (n = 2106); eligible primary prevention patients were aged 18 to 85 years with LDL-C ≥100 mg/dL and high-risk features, and had statin intolerance.
  • Efficacy was analyzed by Cox proportional hazards models adjusted for baseline characteristics, with log-rank P values, in the intent-to-treat population; outcomes were not adjusted for multiplicity, and safety analyses used all randomized patients who received at least 1 dose.

Limitations

  • Stated: this is a secondary analysis of a subpopulation in a larger randomized trial, so false-positive findings from multiple subgroup testing or chance are possible; the authors note consistency across end points strengthens reliability.
  • Stated: the sample size and event numbers were smaller than the full trial, producing wider confidence intervals; patients had high baseline LDL-C due to statin intolerance, so effects in populations with lower pretreatment LDL-C were not studied.
  • Stated: patients were selected by specific high-risk criteria, so outcomes with other risk criteria remain uncertain; the text also makes evident that efficacy outcomes were not adjusted for multiplicity.

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

Integrity signals

Registry

Crossref · 10.1001/jama.2023.9696

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

23 of 38 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    More than half of eligible patients do not currently receive lipid-lowering therapies.

    “More than half of eligible patients do not currently receive lipid-lowering therapies.9”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Gamboa, 2014, Statin underuse and low prevalence of LDL-C control among US adults at high risk of coronary heart disease., Am J Med Sci source

      The Discussion reports that fewer than half of the U.S. adults studied who were at high risk for coronary heart disease were taking statins. The study measured statin use, not use of all lipid-lowering therapies, and its finding is limited to that high-risk population rather than all eligible patients. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    The CLEAR Outcomes trial reported cardiovascular outcomes in a mixed population of primary and secondary prevention patients unable or unwilling to take guideline-recommended doses of statins.

    “The CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial reported cardiovascular outcomes in a mixed population of primary and secondary prevention patients unable or unwilling to take guideline-recommended doses of statins.11”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Nissen, 2023, Bempedoic acid and cardiovascular outcomes in statin-intolerant patients., N Engl J Med source
  • Premisecitation

    Recent data are limited on the effects of statins or other adjunctive treatments in patients without a history of a cardiovascular event.

    “Recent data are limited on the effects of statins or other adjunctive treatments in patients without a history of a cardiovascular event, leading some authors to question whether the benefits of cholesterol lowering exceed the harms in these patients.[4][5][6][7]”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [4] Redberg, 2017, Statins for primary prevention: the debate is intense, but the data are weak., JAMA Intern Med source
    • cites [5] Byrne, 2019, Statins for primary prevention of cardiovascular disease., BMJ source
    • cites [6] Yebyo, 2019, Finding the balance between benefits and harms when using statins for primary prevention of cardiovascular disease: a modeling study., Ann Intern Med source
    • cites [7] Byrne, 2022, Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment: a systematic review and meta-analysis., JAMA Intern Med source

      The Abstract and Conclusions say the absolute benefits of statins are modest and that heterogeneity limits certainty. The Results also report effects for primary-prevention patients, so the paper does not establish that data on statin effects in this group are generally limited. It does not assess other adjunctive treatments. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Most contemporary cardiovascular outcome trials of lipid-lowering therapies have enrolled only participants with a prior cardiovascular event.
  • Premisecitation

    Current recommendations for statin use in primary prevention are predominantly derived from clinical trials conducted several decades ago during the initial development of statins to reduce LDL-C levels.

    “However, the current recommendations are predominantly derived from clinical trials conducted several decades ago during the initial development of statins to reduce low-density lipoprotein cholesterol (LDL-C) levels.2,3”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Shepherd, 1995, Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia., N Engl J Med source
    • cites [3] Downs, 1998, Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS., JAMA source
  • Premisecitation

    Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes.

    “Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes, and 3 recent trials have demonstrated favorable effects with anti-inflammatory therapies.[21][22][23][24]”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [21] Mihaylova, 2012, 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., Lancet source
    • cites [22] Ridker, 2017, Antiinflammatory therapy with canakinumab for atherosclerotic disease., N Engl J Med source
    • cites [23] Tardif, 2019, Efficacy and safety of low-dose colchicine after myocardial infarction., N Engl J Med source

      The Methods (p. 1) and Discussion (p. 7) concern colchicine after myocardial infarction and cardiovascular events, not the effect of lowering LDL-C. A search for LDL cholesterol reduction and lipid lowering found no passage in our copy supporting the quoted claim; the paper does support the citing sentence’s separate point about anti-inflammatory therapy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 31
  • May combine two claims. 21

  • Classified as probably not a substantial claim.

    Premisecitation

    The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.

    “The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [4] Redberg, 2017, Statins for primary prevention: the debate is intense, but the data are weak., JAMA Intern Med source
    • cites [5] Byrne, 2019, Statins for primary prevention of cardiovascular disease., BMJ source
    • cites [6] Yebyo, 2019, Finding the balance between benefits and harms when using statins for primary prevention of cardiovascular disease: a modeling study., Ann Intern Med source
    • cites [7] Byrne, 2022, Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment: a systematic review and meta-analysis., JAMA Intern Med source

      The Abstract and Methods describe a review of statin trials, including primary-prevention trials, but do not address bempedoic acid or statin-intolerant patients. Searches for “bempedoic acid” and the claimed primary-prevention population found no passage assessing whether bempedoic acid’s cardiovascular effects had been fully described. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Most contemporary cardiovascular outcome trials of lipid-lowering therapies have enrolled only participants with a prior cardiovascular event.

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

    Premisecitation

    Currently, lipid-lowering therapies are underutilized in high-risk primary prevention patients, particularly women and patients from racial and ethnic minority populations.

    “Currently, lipid-lowering therapies are underutilized in high-risk primary prevention patients, particularly women and patients from racial and ethnic minority populations.[8][9][10]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [8] Navar, 2017, Lipid management in contemporary community practice: results from the Provider Assessment of Lipid Management (PALM) registry., Am Heart J source

      The Results (page unavailable) report that only 36.0% of eligible primary-prevention patients received guideline-recommended statin intensity, and the Discussion (page unavailable) says women were less likely than men to receive it. The passages do not establish that patients from racial or ethnic minority populations were particularly undertreated; they also concern statins rather than lipid-lowering therapies generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Gamboa, 2014, Statin underuse and low prevalence of LDL-C control among US adults at high risk of coronary heart disease., Am J Med Sci source

      The Discussion reports that only one in five participants with FRS >20% and no history of CHD, stroke, AAA, or diabetes was taking a statin, supporting underuse in high-risk primary prevention. It also identifies being a woman or Black as associated with not taking statins among high-risk participants overall, but does not establish those associations specifically in the primary-prevention subgroup or for racial and ethnic minority populations broadly. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [10] Jacobs, 2023, Prevalence of statin use for primary prevention of atherosclerotic cardiovascular disease by race, ethnicity, and 10-year disease risk in the US: National Health and Nutrition Examination Surveys, 2013 to March 2020., JAMA Cardiol source

  • May combine two claims.

    Premisecitation

    The HOPE-3 trial showed that low-dose statin therapy reduced the composite cardiovascular outcome by 24% but had no significant effect on mortality.

    “The Heart Outcomes Prevention Evaluation 3 (HOPE-3), published in 2016, showed that low-dose statin therapy reduced the composite cardiovascular outcome by 24% but had no significant effect on mortality.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Yusuf, 2016, Cholesterol lowering in intermediate-risk persons without cardiovascular disease., N Engl J Med source

      The Methods (p. 1) identify HOPE-3’s 10-mg-per-day rosuvastatin comparison, and the Results (p. 1) report a hazard ratio of 0.76 for the first composite cardiovascular outcome—a 24% relative reduction. The passages available in our copy do not report a separate mortality result, so they do not support the claim that mortality was unaffected; searches for mortality and all-cause death found no such result. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    This primary prevention cohort was a prespecified subgroup that represented 30% of the total enrolled within a larger trial that included a mixed population of primary and secondary prevention patients.

    “This primary prevention cohort was a prespecified subgroup that represented 30% of the total enrolled within a larger trial that included a mixed population of primary and secondary prevention patients.11”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Nissen, 2023, Bempedoic acid and cardiovascular outcomes in statin-intolerant patients., N Engl J Med source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    These findings emphasize the potential value of lipid-modulating therapy in patients who have had no prior cardiovascular event but who have a high risk for a first event, a population that is currently undertreated.

    “These findings emphasize the potential value of lipidmodulating therapy in patients who have had no prior cardiovascular event but who have a high risk for a first event, a population that is currently undertreated.[8][9][10][15][16][17][18]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [8] Navar, 2017, Lipid management in contemporary community practice: results from the Provider Assessment of Lipid Management (PALM) registry., Am Heart J source
    • cites [9] Gamboa, 2014, Statin underuse and low prevalence of LDL-C control among US adults at high risk of coronary heart disease., Am J Med Sci source
    • cites [10] Jacobs, 2023, Prevalence of statin use for primary prevention of atherosclerotic cardiovascular disease by race, ethnicity, and 10-year disease risk in the US: National Health and Nutrition Examination Surveys, 2013 to March 2020., JAMA Cardiol source

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

    Premisecitation

    The 2 classic trials of primary prevention patients published in the 1990s showed a reduction in morbidity but not mortality.

    “The 2 classic trials of primary prevention patients published in the 1990s showed a reduction in morbidity but not mortality.2,3”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Shepherd, 1995, Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia., N Engl J Med source

      The Results report significantly fewer nonfatal myocardial infarctions with pravastatin. Death from any cause was lower but did not meet the conventional threshold for statistical significance (P=0.051). However, the End Points section reports a significant reduction in cardiovascular deaths (P=0.033), so the unqualified statement that mortality was not reduced overstates this trial’s findings. This verdict concerns only the cited pravastatin trial, not the other trial mentioned in the sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [3] Downs, 1998, Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS., JAMA source

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

    Premisecitation

    Three recent trials have demonstrated favorable effects with anti-inflammatory therapies.

    “Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes, and 3 recent trials have demonstrated favorable effects with anti-inflammatory therapies.[21][22][23][24]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [21] Mihaylova, 2012, 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., Lancet source

      The Methods (Trials) describe studies of LDL-cholesterol-lowering interventions, and the Discussion reports improved vascular outcomes with statin therapy. Neither passage addresses the quoted claim that three trials found favorable effects of anti-inflammatory therapies; searches for anti-inflammatory therapies and inflammation found no such report in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [22] Ridker, 2017, Antiinflammatory therapy with canakinumab for atherosclerotic disease., N Engl J Med source
    • cites [23] Tardif, 2019, Efficacy and safety of low-dose colchicine after myocardial infarction., N Engl J Med source

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

    Premisecitation

    Another study of US patients eligible for treatment based on current guidelines reported that 53% of patients treated in cardiology practices were not taking a statin.

    “Another study of US patients eligible for treatment based on current guidelines reported that 53% of patients treated in cardiology practices were not taking a statin.16”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Pokharel, 2017, Adoption of the 2013 American College of Cardiology/American Heart Association cholesterol management guideline in cardiology practices nationwide., JAMA Cardiol source

      The Results report statin-treatment gaps among guideline-eligible patients in US cardiology practices. But the figure closest to 53% is the complement of the 46.9% receiving moderate- or high-intensity statins in one risk subgroup—not the percentage of all eligible patients taking no statin. The Discussion separately identifies eligible patients who received no statin, without giving the claimed 53% figure. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a registry that studied reasons why eligible patients were not taking a statin, 59% reported never being offered treatment, 10% declined a statin, and 31% discontinued therapy.

    “In a registry that studied reasons why eligible patients were not taking a statin, 59% reported never being offered treatment, 10% declined a statin, and 31% discontinued therapy.18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Bradley, 2019, Patient-reported reasons for declining or discontinuing statin therapy: insights from the PALM registry., J Am Heart Assoc source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The CTTC meta-analysis showed a 22% reduction in major coronary events for each 38.7-mg/dL (1-mmol/L) decrease in LDL-C level and a 15% reduction in vascular death.

    “The CTTC analysis showed a 22% reduction in major coronary events for each 38.7-mg/dL (1-mmol/L) decrease in LDL-C level and a 15% reduction in vascular death.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Nidorf, 2020, Colchicine in patients with chronic coronary disease., N Engl J Med source

      The References name a Cholesterol Treatment Trialists’ meta-analysis, but this paper does not report the claimed 22% and 15% reductions. Its Discussion and limitations (p. 1846) concern colchicine and state that lipid levels were not collected; searches for the LDL-C decrease and both percentages found no supporting passage. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The CTTC analysis reported that the benefits of lowering LDL-C level were consistent across a wide spectrum of baseline risk varying from less than 5% to 30% or greater.

    “The CTTC analysis reported that the benefits of lowering LDL-C level were consistent across a wide spectrum of baseline risk varying from less than 5% to 30% or greater.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Nidorf, 2020, Colchicine in patients with chronic coronary disease., N Engl J Med source

      The References list a Cholesterol Treatment Trialists’ meta-analysis, and the Discussion (p. 1846) mentions lipid-lowering therapies, but neither reports benefits across baseline-risk categories. The paper says it did not collect lipid levels and could not report outcomes by risk-factor control (p. 1846). Searches for the claimed <5% to ≥30% risk range found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Stroke and coronary revascularization were not significantly reduced.

    “Stroke and coronary revascularization were not significantly reduced.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There were no between-group differences in serious adverse events or adverse events leading to drug discontinuation.

    “There were no betweengroup differences in serious adverse events or adverse events leading to drug discontinuation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    Within the full analysis set, 4206 patients (30%) met primary prevention criteria, with 2100 randomized to bempedoic acid and 2106 to placebo.

    “Within the full analysis set, 4206 patients (30%) met primary prevention criteria, 2100 randomized to the bempedoic acid treatment group and 2106 to the placebo group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The time-averaged difference in LDL-C level in the primary prevention subgroup over the course of the trial was 23.2 mg/dL, with additional lipid-modifying therapies administered to 12.4% of placebo patients and 6.7% of bempedoic acid patients.

    “With administration of additional lipid-modifying therapies to 12.4% of patients in the placebo group and 6.7% in the bempedoic acid group (eTable 1 in Supplement 2), the time-averaged difference in LDL-C level in the primary prevention subgroup over the course of the trial was 23.2 mg/dL (eFigure 2 in Supplement 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rates of new-onset diabetes and the change in hemoglobin A1c levels in patients with diabetes at baseline were similar in both randomized groups.

    “Rates of new-onset diabetes and the change in hemoglobin A 1c levels in patients with diabetes at baseline were similar in both randomized groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    From a median baseline hsCRP of 2.4 mg/L, after 12 months of treatment, bempedoic acid reduced hsCRP level by 0.34 mg/L (95% CI, -0.42 to -0.29) compared with a reduction of 0.01 mg/L (95% CI, -0.04 to 0.09) for placebo, a difference of 0.56 mg/L (21.5%).

    “From a median baseline value of 2.4 mg/L, after 12 months of treatment, using Hodges-Lehman estimate of location shift, bempedoic acid reduced hsCRP level by 0.34 mg/L (95% CI, -0.42 to -0.29) compared with a reduction of 0.01 mg/L (95% CI, -0.04 to 0.09) for placebo, a difference of 0.56 mg/L (21.5%).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    In the current study, women comprised nearly 60% of the population.

    “In the current study, women comprised nearly 60% of the population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Treatment was also associated with significant reductions in MI, cardiovascular death, and all-cause mortality.

    “Treatment was also associated with significant reductions in MI, cardiovascular death, and all-cause mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The trial was a masked, randomized clinical trial that enrolled 13,970 statin-intolerant patients, including 4,206 primary prevention patients.

    “This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    All patients provided written informed consent before enrollment.

    “The protocol was approved by ethics committees at participating sites, and all patients provided written informed consent before enrollment”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Eligible patients entered a 4-week run-in period during which they were treated with single-masked placebo.

    “Eligible patients entered a 4-week run-in period during which they were treated with single-masked placebo.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The protocol was approved by ethics committees at participating sites.

    “The protocol was approved by ethics committees at participating sites, and all patients provided written informed consent before enrollment”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    An independent data monitoring committee monitored the trial.

    “An independent data monitoring committee monitored the trial.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Efficacy analyses included all randomized patients based on the intent-to-treat principle.

    “Efficacy analyses included all randomized patients based on the intent-totreat principle.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The full analysis set included 13,970 randomized patients after exclusion of 46 participants from a site determined to have created fraudulent patients.

    “Between December 2016 and August 2019, 22 084 patients were screened and 14 016 were randomized, with 13 970 included in the full analysis after exclusion of 46 participants from a site determined to have created fraudulent patients.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The current study was not designed to assess factors mediating the results.

    “Although the current study was not designed to assess factors mediating the results, both LDL-C and hsCRP levels were significantly reduced.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    End points were adjudicated by C5Research clinical end points committee personnel masked to treatment assignments.

    “End points were adjudicated by C5Research clinical end points committee personnel masked to treatment assignments.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Both the patient and site investigator were required to provide written confirmation that the patient was statin intolerant and aware of the benefits of statins to reduce the risk of cardiovascular events, including death, and acknowledge that many patients unable to tolerate a statin can tolerate a different statin or dose.

    “Both the patient and site investigator were required to provide written confirmation that the patient was statin intolerant and aware of the benefits of statins to reduce the risk of cardiovascular events, including death, and acknowledge that many patients unable to tolerate a statin can tolerate a different statin or dose.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Outcomes were not adjusted for multiplicity.

    “Outcomes were not adjusted for multiplicity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The current findings support the guideline recommendation that primary prevention patients with diabetes should be treated with statins to lower cholesterol levels.

    “The current findings support the guideline recommendation that primary prevention patients with diabetes should be treated with statins to lower cholesterol levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Complete assessment for the primary end point was available for 94.7% and vital status for 99.5% of these patients.

    “Complete assessment for the primary end point was available for 94.7% and vital status for 99.5% of these patients.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Efficacy end points at sites in Ukraine were censored after the start of the conflict on February 24, 2022.

    “Efficacy end points at sites in Ukraine were censored after the start of the conflict on February 24, 2022.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Patients who were intolerant to placebo treatment or had adherence less than 80% by tablet count were not eligible for randomization.

    “If patients were intolerant to placebo treatment or if adherence was less than 80% by tablet count, they were not eligible for randomization.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Patients who successfully completed the run-in period were randomly assigned in a 1:1 ratio to receive bempedoic acid 180 mg daily or matching placebo.

    “Patients who successfully completed the run-in period were randomly assigned in a 1:1 ratio to receive a 180-mg oral dose of bempedoic acid or matching placebo, administered daily.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The proportional hazards assumption for the Cox model was met, as the test P value was not statistically significant.

    “The P value was not statistically significant; therefore, the assumption of proportional hazards was determined to be met.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    High-risk primary prevention patients were followed up for a median of 39.9 months.

    “High-risk primary prevention patients were followed up for a median of 39.9 months.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    During the trial, LDL-C and high-sensitivity C-reactive protein results were masked.

    “During the trial, LDL-C and high-sensitivity C-reactive protein (hsCRP) results were masked.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The JUPITER study showed a 44% reduction in the primary composite outcome and a 20% reduction in all-cause mortality with statin therapy in primary prevention patients with an hsCRP level greater than 2.0 mg/L.

    “The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study published 15 years ago showed a 44% reduction in the primary composite outcome and a 20% reduction in all-cause mortality with statin therapy in primary prevention patients with an hsCRP level greater than 2.0 mg/L.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Ridker, 2008, Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein., N Engl J Med source

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

    Study design and conductnone given

    Adverse event summaries were based on the safety population that included all patients who underwent randomization and received at least 1 dose of study drug.

    “Adverse event summaries were based on the safety population that included all patients who underwent randomization and received at least 1 dose of study drug.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    The statistical analysis plan prespecified subgroup analyses for 4-component MACE and 3-component MACE, so P values are provided only for these end points.

    “The statistical analysis plan prespecified subgroup analyses for 4-component MACE and 3-component MACE.Therefore, P values are provided only for these end points.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Because the sample size represented a fraction of the total enrolled population, the number of events was smaller, resulting in wider confidence intervals.

    “Second, because the sample size represented a fraction of the total enrolled population, the number of events was smaller, resulting in wider confidence intervals.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    This study is a secondary analysis of a subpopulation in a larger randomized trial.

    “First, this is a secondary analysis of a subpopulation in a larger randomized trial.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain.

    “Whether outcomes would be similar in patients identified using other criteria for an increased risk remains uncertain.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The criteria used to select patients for a high level of risk of a first cardiac event are valid for identifying such risk.

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

    Interpretationreasoning

    Secondary analyses can result in false-positive findings due to testing multiple subgroups and may represent the play of chance.

    “Such analyses can result in false-positive findings due to the testing of multiple subgroups and may represent the play of chance.”
    Quote in the paperNot a substantial claim
45 of 45

  • The paper relies on this without support.

    Most contemporary cardiovascular outcome trials of lipid-lowering therapies have enrolled only participants with a prior cardiovascular event.

    “Most contemporary cardiovascular outcome trials of lipid-lowering therapies have enrolled only participants with a prior cardiovascular event.”

  • The paper relies on this without support.

    Censoring efficacy end points at sites in Ukraine after the start of the conflict on February 24, 2022, does not bias the estimated treatment effects.

    “Efficacy end points at sites in Ukraine were censored after the start of the conflict on February 24, 2022.”

  • The paper relies on this without support.

    Excluding 46 participants from a site determined to have created fraudulent patients does not bias the efficacy results.

    “with 13 970 included in the full analysis after exclusion of 46 participants from a site determined to have created fraudulent patients.”

  • The paper relies on this without support.

    Current guidelines do not specifically address the use of nonstatin treatments in high-risk primary prevention patients.

    “Current guidelines do not specifically address the use of nonstatin treatments in high-risk primary prevention patients.”

  • The paper relies on this without support.

    The CTTC analysis's predicted relationship between LDL-C lowering and cardiovascular event reduction applies to bempedoic acid and the current trial population.

    “In the current study, a timeaveraged reduction of 23.2 mg/dL (0.60 mmol/L) was associated with larger reductions in cardiovascular morbidity and mortality than predicted by the CTTC analysis.”

  • The paper relies on this without support.

    The criteria used to select patients for a high level of risk of a first cardiac event are valid for identifying such risk.

    “Fourth, the trial selected patients using specific criteria for a high level of risk of a first cardiac event.”

  • The paper relies on this without support.

    Patients' self-reported inability to tolerate statins accurately identifies statin intolerance.

    “Third, the inclusion of patients who reported inability to tolerate statins resulted in a high mean baseline LDL-C level.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • For individuals requiring primary prevention, bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo.

    “For individuals requiring primary prevention, the use of bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo (137).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [137]

    The Clinical End Points section reports a primary composite outcome hazard ratio of 0.70 for bempedoic acid versus placebo, supporting the stated 30% relative reduction. The Study Population and Conclusion sections limit this finding to high-risk primary prevention patients unable to tolerate recommended statin doses; the claim does not retain those population qualifiers. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • For individuals requiring primary prevention, the use of bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo.

    “For individuals requiring primary prevention, the use of bempedoic acid resulted in a 30% reduction in primary composite outcome compared with placebo (143).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [143]

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.

  • CTTC meta-analysis is cited to a colchicine trial

    Minor

    The text cites reference 24 for the CTTC statin meta-analysis, but reference 24 is a colchicine trial in patients with chronic coronary disease.

1 of 1

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Authors
Nissen, S. E., Menon, V., Nicholls, S. J., Brennan, D., Laffin, L., Ridker, P., Ray, K. K., Mason, D., Kastelein, J. J. P., Cho, L., Libby, P., Li, N., Foody, J., Louie, M. J., & Lincoff, A. M.
Affiliations
  • Cleveland Clinic (US)
  • Monash University (AU)
  • Brigham and Women's Hospital (US)
  • Imperial College London (GB)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Esperion Therapeutics (United States) (US)
Corresponding author
Nissen, Steven E.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2023-07-11
Volume
330
Issue
2
Pages
131
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2023.9696
PMC
PMC10336623
OpenAlex
W4381888526
Semantic Scholar
848bfab6da10e7efa5c7743224564429a99ff2c7
Cited by
146
References
26
Citations by year
2026: 34 · 2025: 42 · 2024: 39 · 2023: 30
FWCI
34.39
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • PubMed Central (submittedVersion)
Funders
Esperion Therapeutics
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, statin intolerance, primary prevention, cardiovascular events, LDL cholesterol lowering, high-sensitivity C-reactive protein, myocardial infarction, stroke, cardiovascular mortality, coronary revascularization, hypercholesterolemia, dyslipidemia, cardiovascular risk reduction
MeSH terms
Aged, Cardiovascular Diseases, Dicarboxylic Acids, Fatty Acids, Female, Humans, Male, Myocardial Infarction, Primary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Stroke

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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