Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia

Abstract

Importance: Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant.

Objective: To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo.

Design, setting, and participants: This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance.

Interventions: Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks.

Main outcomes and measures: Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins.

Results: In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was -16.0% with bempedoic acid vs 1.8% with placebo (difference, -17.8%; 95% CI, -19.5% to -16.0%; P < .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were -23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, -24.5%; 95% CI, -27.8% to -21.1%; P < .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of -12.7% at week 52; patients with statin intolerance, difference of -22.2% at week 24). Decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs <0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%).

Conclusions and relevance: Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients.

Trial registration: ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Banach reported receiving personal fees from Esperion Therapeutics Inc during the conduct of the study; receiving grants, personal fees, or nonfinancial support from Abbott/Mylan, Abbott Vascular, Amgen, Daiichi Sankyo, Esperion Therapeutics Inc, Krka, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Polpharma, Polfarmex S.A., Regeneron Pharmaceuticals, Resverlogix Corp, Sanofi-Aventis, Servier Laboratories, and Valeant Pharmaceuticals outside the submitted work. Dr Duell reported receiving institutional research grants or financial support from Regeneron Pharmaceuticals, Regenxbio, and Retrophin; and receiving personal fees from Akcea Therapeutics, AstraZeneca, Esperion Therapeutics Inc, Regeneron Pharmaceuticals, Regenxbio, and Retrophin. Dr Gotto reported being an Esperion Therapeutics Inc board member; chairing the Akcea Therapeutics Data and Safety Monitoring Board; and receiving personal fees from Amarin Pharmaceuticals, Esperion Therapeutics Inc, Ionis Pharmaceuticals, and Kowa Pharmaceuticals during the conduct of the study and outside the submitted work. Dr Laufs reported receiving personal fees from Amgen, Daiichi Sankyo, Esperion Therapeutics Inc, and Sanofi outside the submitted work. Dr Leiter reported receiving grants and personal fees from Amgen, AstraZeneca, Kowa Pharmaceuticals, Merck & Co, Sanofi/Regeneron, and The Medicines Company outside the submitted work; and receiving personal fees from AstraZeneca, Amgen, Esperion Therapeutics Inc, Kowa Pharmaceuticals, HLS Therapeutics, Merck & Co, Sanofi/Regeneron, and The Medicines Company outside the submitted work. Dr Mancini reported receiving grants and personal fees from, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Novo Nordisk, Merck & Co, and Sanofi; and receiving personal fees from Esperion Therapeutics Inc, HLI Therapeutics, Novartis, and Servier Laboratories outside the submitted work. Dr Ray reported receiving personal fees from Esperion Therapeutics Inc and from the National Institute for Health Research Imperial Biomedical Research Centre during the conduct of the study; receiving grants and personal fees from Amgen, Daiichi Sankyoi, Pfizer, Regeneron Pharmaceuticals, and Sanofi; and receiving personal fees from AbbVie, Akcea Therapeutics, Algorithm Pharmaceutical Manufacturers, AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy’s, Kowa Pharmaceuticals, Novo Nordisk, Silence Therapeutics, The Medicines Company, and Zuellig Pharma outside the submitted work. Dr Flaim and Dr Ye are employees of Esperion Therapeutics Inc and may own stock or stock options. Dr Catapano reported receiving grants from Amgen, Pfizer, Merck & Co, Mylan, Sanofi, Regeneron, and Mediolanum Farmaceutici SpA; receiving nonfinancial support from Eli Lilly and Company, Kowa Pharmaceuticals, Menarini Group, Recordati, and Sigma-Tau Pharmaceuticals; and receiving personal fees from Akcea Therapeutics, Aegerion Pharmaceuticals, Amyrt Pharma, Amgen, AstraZeneca, Eli Lilly and Company, Esperion Therapeutics Inc, Sanofi Genzyme, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Medco Pharmacy, Menarini Group, Merck & Co, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Regeneron, Recordati, Sanofi, Sankyo, and Sigma-Tau Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Changes in Low-Density Lipoprotein Cholesterol (LDL-C) Levels Associated With Bempedoic Acid Administration

A, Percentage change from baseline in LDL-C levels at week 12. Data are least-squares (LS) mean (SE) values. The difference between placebo-corrected LS mean changes from baseline in LDL-C levels in the pool of patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) or both receiving a maximally tolerated statin (−17.8%) and the pool of patients with statin intolerance (−24.5%) was significant (nominal P < .001). B and C, Mean LDL-C levels over time by treatment group. Data are observed mean (SE) values through week 52 in the pool of patients with ASCVD or HeFH or both receiving a maximally tolerated statin, and through week 24 in the pool of patients with statin intolerance. BA indicates bempedoic acid; PBO, placebo. To convert LDL-C to millimoles per liter, multiply by 0.0259.

Figure 2.. Percentage Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) by Patients With Atherosclerotic Cardiovascular Disease (ASCVD) or Heterozygous Familial Hypercholesterolemia (HeFH)

BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); eGFR, estimated glomerular filtration rate; and LS, least squares. To convert LDL-C to millimoles per liter, multiply by 0.0259.

Figure 3.. Percentage Change From Baseline to Week 12 in Low-Density Lipoprotein Cholesterol (LDL-C) by Patients With Hypercholesterolemia and Statin Intolerance

BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); eGFR, estimated glomerular filtration rate; and LS, least squares. To convert LDL-C to millimoles per liter, multiply by 0.0259.