Introduction and Objective: Enlicitide is an oral PCSK9 inhibitor that, in two Phase 3 randomized, placebo-controlled trials, demonstrated LDL-C reduction of approximately 60% and was well tolerated. Here we report the efficacy of enlicitide in participants with and without diabetes mellitus (DM) at baseline, and the incidence of new onset or worsening diabetes.Methods: CORALreef Lipids included adults with and without a history of a major atherosclerotic cardiovascular disease (ASCVD) event on stable lipid lowering therapy. CORALreef HeFH required a clinical or genetic HEFH diagnosis. Participants were randomized 2:1 to enlicitide 20 mg daily or placebo for 52 weeks. Participant-level data from the two trials were integrated; mean percent change in LDL-C at Week 24 was analyzed for participants with and without DM at baseline. Incidence of new onset or worsening DM was also assessed.Results: Of 3212 randomized participants, 40% were female, 55% had a history of a major ASCVD event, 97% were receiving statins (57% high intensity) and 30% cholesterol-absorption inhibitors. Efficacy was consistent in participants with (n=1490) and without (n=1722) DM: mean percent change in LDL-C at Week 24 was -65% and -61%, respectively. The incidence of new-onset or worsening DM was similar between treatment groups: 5.8% with enlicitide vs 5.5% with placebo (relative difference 0.2% [95% CI: -1.5, 1.9]). Among participants without baseline DM, the incidence of new onset of diabetes was 2.7% with enlicitide and 2.6% with placebo. Among participants with baseline diabetes, the incidence of worsening of DM was 9.3% with enlicitide and 8.8% with placebo. There were no meaningful differences in hemoglobin A1C over time.Conclusion: Enlicitide was associated with robust LDL-C reductions in participants with DM and without DM and did not increase the risk of new-onset or worsening diabetes compared with placebo. Oral PCSK9 inhibition with enlicitide offers an effective option for LDL-C management without adverse effects on glycemia.
N. Lepor: Consultant; Current; Amgen Inc., Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc. J. Parham: Employee; Current; Merck & Co., Inc. A.L. Catapano: Consultant; Current; Merck & Co., Inc. Research Support; Current; Viatris Inc., Chiesi USA, Inc., Amarin Corporation. Consultant; Current; AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, NewAmsterdam Pharma; Novartis; NovoNordisk; Regeneron; Recordati; Sanofi; Ultragenyx. A. Cadena: None. S. Baum: Consultant; Current; Merck & Co., Inc., Altimmune, Amgen Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc. A. Navar: Consultant; Current; Merck & Co., Inc. Research Support; Current; ESPERION Therapeutics, Inc., Amgen Inc. Consultant; Current; Arrowhead Pharmaceuticals, Inc., Bayer AG, ESPERION Therapeutics, Inc., Janssen Research & Development, LLC, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk; Pfizer; Roche; Silence Therapeutics. P. Banka: Employee; Current; Merck & Co., Inc. L. Gellis: Employee; Current; Merck & Co., Inc. M. Kang: Employee; Current; Merck & Co., Inc. E. Mikhailova: Employee; Current; Merck & Co., Inc. R. Scott: None. J. Tardif: Consultant; Current; Merck & Co., Inc. Research Support; Current; Boehringer Ingelheim International GmbH, Ceapro Inc., DalCor Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc. Consultant; Current; DalCor Pharmaceuticals. Research Support; Current; Merck & Co., Inc. Consultant; Current; Pfizer Inc. Other – Patent licensed to DalCor Pharmaceuticals; Current; DalCor Pharmaceuticals. C.M. Ballantyne: Consultant; Current; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Boehringer Ingelheim International GmbH, Novo Nordisk, Gilead Sciences, Inc., Genentech, Inc., Amgen Inc., ESPERION Therapeutics, Inc., Novartis AG.
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