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Randomized Controlled Trial
. 2022 May;24(5):868-880.
doi: 10.1111/dom.14645. Epub 2022 Feb 3.

Bempedoic acid in patients with type 2 diabetes mellitus, prediabetes, and normoglycaemia: A post hoc analysis of efficacy and glycaemic control using pooled data from phase 3 clinical trials

Lawrence A Leiter  1 , Maciej Banach  2 , Alberico L Catapano  3 , P Barton Duell  4 , Antonio M Gotto Jr  5 , Ulrich Laufs  6 , G B John Mancini  7 , Kausik K Ray  8 , Jeffrey C Hanselman  9 , Zhan Ye  9 , Harold E Bays  10
Affiliations
Randomized Controlled Trial

Bempedoic acid in patients with type 2 diabetes mellitus, prediabetes, and normoglycaemia: A post hoc analysis of efficacy and glycaemic control using pooled data from phase 3 clinical trials

Lawrence A Leiter et al. Diabetes Obes Metab. 2022 May.

Abstract

Aim: To evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia.

Methods: A patient-level pooled analysis of four phase 3, randomized, double-blind, placebo-controlled trials evaluated changes in glycaemia, change from baseline in LDL-C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia).

Results: The annual rate of new-onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P < .0001) reduced HbA1c by -0.12% and -0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significantly and consistently lowered LDL-C levels versus placebo, regardless of baseline glycaemic status (placebo-corrected difference range, -17.2% to -29.6%; P < .001 for each stratum). The safety of bempedoic acid was comparable with placebo and similar across glycaemic strata.

Conclusions: Bempedoic acid significantly lowered LDL-C across glycaemic strata and did not worsen glycaemic variables or increase the incidence of new-onset diabetes versus placebo over a median follow-up of 1 year.

Keywords: cardiovascular disease; lipid-lowering therapy; statins; type 2 diabetes.

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Conflict of interest statement

LAL has received research grant(s)/support from AstraZeneca, Amgen, Esperion, Kowa, The Medicines Company, Novartis, and Sanofi/Regeneron. He has also served as an advisor for Amarin, AstraZeneca, Amgen, Esperion, HLS, Merck, Novartis, and Sanofi/Regeneron. MB has received research grant(s)/support from Amgen, Mylan, Sanofi, and Valeant, and has served as a consultant for Amgen, Daiichi Sankyo, Esperion, Freia Pharmaceuticals, Herbapol, KRKA, Mylan, Novartis, Novo Nordisk, Polpharma, Polfarmex, Sanofi‐Aventis, Servier, and Valeant. ALC has received research grant(s)/support from Akcea, Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi/Regeneron, and has served as a consultant for Amgen, Amarin, Daiichi‐Sankyo, Eli Lilly, Esperion, Kowa, Ionis Pharmaceuticals, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi. PBD has received institutional research grant(s)/support from Retrophin/Travere, Regeneron, and Regenxbio, and served as a consultant for Akcea, Amryt, Esperion, Kaneka, and Regeneron. AMG is an Esperion board member and Akcea DSMB chair, and has served as a consultant for Kowa. UL has received an institutional research grant from Daiichi Sankyo and served as a consultant for Amgen, Esperion, Novartis, and Sanofi. GBJM received research grant(s)/support from Amgen, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, and Sanofi, and has served as a consultant for these companies as well as for Esperion, HLS Therapeutics, Novartis, and Servier. KKR has received research grant(s)/support from Amgen, MSD, Pfizer, Regeneron, and Sanofi (all paid to his institution), and has served as a consultant for or received honoraria from AbbVie, Akcea, Algorithm, Amgen, AstraZeneca, Boehringer Ingelheim, Cerenis, Cipla, Dr Reddy's Laboratories, Eli Lilly, Esperion, Kowa, Medco, MSD, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda, and Zuellig Pharma. JCH is an employee of Esperion Therapeutics Inc. and may own Esperion stock or stock options. ZY is a former employee of Esperion Therapeutics Inc. and may own Esperion stock or stock options. HEB has received research grant(s)/support from Acasti, Akcea, Allergan, Amarin, Amgen, AstraZeneca, Esperion, Matinas, Merck, Metavant, Novartis, Pfizer, Regeneron, and Sanofi, and has served as a consultant/advisor for Amarin, Esperion, and Matinas, and as a speaker for Esperion.

Figures

FIGURE 1
FIGURE 1
Change in: A, glycated haemoglobin (HbA1c); B, Fasting glucose; and C, Weight. Data are mean ± standard error. P value based on t test for change from baseline (bempedoic acid vs. placebo). Patients were randomized 2:1 to receive bempedoic acid 180 mg or placebo once daily for 12 weeks (CLEAR Tranquility), 24 weeks (CLEAR Serenity) or 52 weeks (in CLEAR Harmony and CLEAR Wisdom). Primary endpoint was the change from baseline in low‐density lipoprotein cholesterol (LDL‐C) levels at week 12
FIGURE 2
FIGURE 2
Development of diabetes among patients with prediabetes and improvement to glycated haemoglobin (HbA1c) less than 6.5% (48 mmol/mol) among patients with diabetes. A, Time to postbaseline diabetes (defined as at least one HbA1c value of ≥6.5%; two or more fasting serum glucose values of ≥126 mg/dl; an investigator‐reported diabetes‐related adverse event; and/or initiation of diabetes medication at any point after baseline) among patients with prediabetes at baseline; B, Time to first HbA1c of 6.5% or higher among patients with prediabetes at baseline; and C, Time to first HbA1c less than 6.5% (48 mmol/mol) among patients with diabetes and HbA1c of 6.5% or higher (48 mmol/mol) at baseline. Patients were randomized 2:1 to receive bempedoic acid 180 mg or placebo once daily for 52 weeks in CLEAR Harmony and CLEAR Wisdom and 24 weeks in CLEAR Tranquility and CLEAR Serenity
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