1246-OR: Efficacy and Safety of Enlicitide, an Oral PCSK9 Inhibitor, in Participants with and without Diabetes Mellitus in a Pooled Analysis of Two Phase 3 Trials

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. Disclosure 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.