Background: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4–1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1–12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)—defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. Findings: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20–2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25–2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78–2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65–2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, −0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89–1·11). HRs were 0·97 (95% CI 0·87–1·09) for patients with prediabetes and 1·30 (95% CI 0·93–1·81) for those with normoglycaemia (pinteraction=0·11). Interpretation: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65–1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Funding: Sanofi and Regeneron Pharmaceuticals.
Bibliographical noteFunding Information:
KKR reports personal fees from AbbVie, AstraZeneca, Medco, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddy's, Lilly, Bayer, and Zuellig Pharma; and research grants and personal fees from Amgen, Sanofi, Regeneron Pharmaceuticals, MSD, and Pfizer. HMC reports research support and honoraria from, and membership of advisory panels or speakers' bureaus for, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, Novo Nordisk, and Eli Lilly; reports non-binding research support from Pfizer, AstraZeneca, and Novo Nordisk; and is a shareholder of Roche and Bayer. MS reports serving as a consultant or on advisory boards (or both) for CiVi, Resverlogix, Baxter, Esperion, and Regeneron Pharmaceuticals. MB-D is an employee of Sanofi. DLB reports serving on advisory boards for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; serving on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; chairing the American Heart Association Quality Oversight Committee; serving on data monitoring committees for Baim Institute for Clinical Research, Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; honoraria from the American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim), Belvoir Publications, Duke Clinical Research Institute (clinical trial steering committees), HMP Global, Journal of the American College of Cardiology, Medtelligence/ReachMD (continuing medical education steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leadership, funded by Bayer), Slack Publications, Society of Cardiovascular Patient Care, and WebMD; serving as Deputy Editor for Clinical Cardiology, on the NCDR-ACTION Registry steering committee, and on the VA CART research and publications committee; research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi-Aventis, Synaptic, and The Medicines Company; royalties from Elsevier; serving as a site co-investigator for Biotronik, Boston Scientific, St Jude Medical, and Svelte; serving as a trustee for the American College of Cardiology; and completing unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. VAB reports research grants from Amgen, DalCor, Esperion, Sanofi, AstraZeneca, Bayer Healthcare, and The Medicines Company; honoraria from the American College of Cardiology, American Heart Association, and National Lipid Association; and serving as a consultant and on an advisory board for Sanofi. AJB reports personal fees, investigator fees, honoraria for lectures, advisory board membership, and travel and accommodation from Sanofi-Aventis, AstraZeneca, and Bristol-Myers Squibb–Pfizer; investigator fees, honoraria for lectures, and advisory board membership from GlaxoSmithKline; investigator fees and honoraria for lectures from Novartis; honoraria for lectures, advisory board membership, and travel and accommodation from Bayer; and investigator fees from Eisai. RD reports research grants from Sanofi, DalCor, Population Health Research Institute, Duke Clinical Research Institute, the TIMI group, Amgen, Cirius, Montreal Health Innovations Coordinating Center, and Lepetit; and personal fees from Amgen and Cirius. SGG reports research grants from Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, and Tenax Therapeutics; honoraria from Bristol-Myers Squibb, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Servier, Regeneron Pharmaceuticals, Sanofi, Amgen, AstraZeneca, Bayer, and Boehringer Ingelheim; and serving as a consultant or on advisory boards (or both) for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics, Sanofi, Amgen, and Bayer. CH is an employee of Sanofi. RAH reports research grants from Apple, CSL, Sanofi, AstraZeneca, Portola, Janssen, Bristol-Myers Squibb, Novartis, and The Medicines Company; serving as a consultant or on advisory boards (or both) for Amgen, Bayer, Gilead, MyoKardia, and WebMD; and serving on the boards of directors (unpaid) for the American Heart Association and Stanford HealthCare. JWJ reports research grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Commission Seventh Framework Programme; and research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi. VL is an employee of and shareholder in Sanofi. RDL reports research grants from Amgen and Sanofi-Aventis; personal fees from Bayer, Portola, and Boehringer Ingelheim; and research grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer. AM is employed by Sanofi. JM reports personal fees from Sanofi, Novartis, Sandoz, Boehringer Ingelheim, Novo Nordisk, and Roche. RP is an employee of and shareholder in Regeneron Pharmaceuticals. ADR reports research grants and investigator fees from Sanofi, Regeneron Pharmaceuticals, Arena Pharmaceuticals, Pfizer, Novo Nordisk, CSL Behring, and the Ministry of Science and Education of the Republic of Serbia; serving on advisory boards for Arena Pharmaceuticals, Pfizer, Actavis, Boehringer Ingelheim, and GSK; and honoraria for lectures from Servier, Pfizer, Boehringer Ingelheim, Novartis, Merck, AstraZeneca, MSD, Richter Gedeon, Mylan, Hemofarm Stada, Berlin Chemie Menarini, and Abbott Laboratories; conference grants from Actavis, Servier, Pfizer, AstraZeneca, MSD, and Bayer. MTR reports research grant funding from Sanofi-Aventis, Janssen, AstraZeneca, Patient-Centered Outcomes Research Institute, Ferring Pharmaceuticals, MyoKardia, American College of Cardiology, American Heart Association, Familial Hypercholesterolemia Foundation; and consulting fees or honoraria from AstraZeneca, Amgen, Eli Lilly, Roche–Genentech, Janssen, Regeneron Pharmaceuticals, Ardea Biosciences, Novo Nordisk, Flatiron, Merck, Pfizer, Sanofi-Aventis, Signal Path, and Elsevier. JT reports personal fees from Sanofi, Amgen, and Diasorin Iberia. HDW reports receiving grant support (paid to institution) and fees for serving on a steering committee from Sanofi-Aventis and Regeneron Pharmaceuticals (for the ODYSSEY OUTCOMES trial), Eli Lilly (for the ACCELERATE trial), Omthera Pharmaceuticals (for the STRENGTH trial), Pfizer (for the SPIRE trial), American Regent (for the HEART-FID trial), Eisai (for the CAMELLIA-TIMI trial), DalCor (for the dal-GenE trial), CSL Behring (for the AEGIS-II trial), Sanofi-Aventis (for the SCORED and SOLOIST trials), and Esperion Therapeutics (for the CLEAR Outcomes trial). AMZ reports receiving fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi, and advisory board membership, speaker fees, or both from Sanofi, Amgen, Boehringer Ingelheim, Bayer, Novartis, Pfizer, AstraZeneca, and Vifor. GGS reports research grants (to the University of Colorado) from Resverlogix, Sanofi, and Roche; and is co-inventor of pending US patent 14/657192 (“Methods of Reducing Cardiovascular Risk”) assigned in full to the University of Colorado. PGS reports grants and non-financial support from Sanofi (co-chair of the ODYSSEY OUTCOMES trial; no personal fees, but his institution has received funding for his time devoted to trial coordination, and he has received support for travel related to trial meetings); research grants and personal fees from Bayer (steering committee for the MARINER trial, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (co-chair of the ODYSSEY OUTCOMES trial, co-chair of the SCORED trial, consulting, speaking), Servier (chair of the CLARIFY registry, grant for epidemiological research), and Amarin (executive steering committee for the REDUCE IT trial, consulting); and personal fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca. PGS also has a European patent application (number 15712241.7) for a method for reducing cardiovascular risk.
This work was supported by Sanofi and Regeneron Pharmaceuticals. We thank the patients, study coordinators, and investigators who participated in this trial ( appendix ). KKR acknowledges support from the Imperial Biomedical Research Centre (London, UK). Sophie K Rushton-Smith (MedLink Healthcare Communications, London, UK) provided editorial assistance in the preparation of the report (funded by Fondation Assistance Publique–Hôpitaux de Paris, Paris, France).
All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism