TY - JOUR
T1 - Effects of liraglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus with or without history of myocardial infarction or stroke
T2 - Post hoc analysis from the leader trial
AU - Verma, Subodh
AU - Poulter, Neil R.
AU - Bhatt, Deepak L.
AU - Bain, Stephen C.
AU - Buse, John B.
AU - Leiter, Lawrence A.
AU - Nauck, Michael A.
AU - Pratley, Richard E.
AU - Zinman, Bernard
AU - Ørsted, David D.
AU - Monk Fries, Tea
AU - Rasmussen, Søren
AU - Marso, Steven P
N1 - Funding Information:
Dr Verma is President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization; holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Valeant. Dr Poulter is president of the International Society of Hypertension; has received personal speaker fees from Servier, Takeda, and Novo Nordisk A/S; is on advisory boards for AstraZeneca and Novo Nordisk A/S; and receives research grants for his research group relating to T2DM from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, Julius Clinical, and the British Heart Foundation, with a pending grant from Novo Nordisk A/S. Dr Bhatt reports the following: advisory board, Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors, Boston Veterans Affairs Research Institute and Society of Cardiovascular Patient Care; chair, American Heart Association Quality Oversight Committee; data monitoring committee, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Si- nai School of Medicine, and Population Health Research Institute; honoraria, American College of Cardiology (senior associate editor, Clinical Trials and News, ACC. org; vice-chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial [Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention] steering committee funded by Boehringer Ingel-heim); editor in chief, Harvard Heart Letter, Belvoir Publications; clinical trial steering committees, Duke Clinical Research Institute; editor in chief, Journal of Invasive Cardiology, HMP Global; guest editor and associate editor, Journal of the American College of Cardiology; clinical trial steering committee, Population Health Research Institute; chief medical editor, Cardiology Today’s Intervention, Slack Publications; secretary/treasurer, Society of Cardiovascular Patient Care; Continuing Medical Education steering committees, WebMD; deputy editor, Clinical Cardiology; chair, National Cardiovascular Data Registry–Acute Coronary Treatment and Interventions Outcomes Network Registry Steering Committee; chair, Veterans Affairs Clinical Assessment Reporting and Tracking Research and Publications Committee; research funding, Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; royalties, Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site coinvestigator, Biotronik, Boston Scientific, St Jude Medical (now Abbott), and Svelte; trustee, American College of Cardiology; and unfunded research, FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr Bain reports research grants (includes principal investigator, collaborator, or consultant and pending grants, as well as grants already received) from Healthcare and Research Wales (Welsh Government) and Novo Nordisk A/S; other research support from Healthcare and Research Wales (Welsh Government) and infrastructure support; honoraria from Novo Nordisk A/S, Sanofi, Lilly, Boehringer Ingelheim, and Merck; and ownership interest in Glycosmedia (diabetes online news service). Dr Buse reports consulting fees paid to his institution and travel support from Novo Nordisk A/S, Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Elcelyx, Merck, Metavention, vTv Therapeutics, PhaseBio, AstraZeneca, Dance Biopharm, Quest Diagnostics, Sanofi-Aventis, Lexicon Pharmaceuticals, Orexigen Therapeutics, Takeda Pharmaceuticals, Adocia, and Roche; grant support from Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic, Sanofi, Tolerex, Osiris Therapeutics, Halozyme Therapeutics, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, Astellas Pharma, MacroGenics, Intarcia Therapeutics, Lexicon, Senseonics, Scion NeuroStim, Orexigen Therapeutics, Takeda Pharmaceuticals, Theracos, Roche, and the National Institutes of Health (UL1TR002489); fees and stock options from PhaseBio and Mellitus Health; and boards of the AstraZeneca Healthcare Foundation and Bristol-Myers Squibb Together on Diabetes Foundation. Dr Leiter reports consultant and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk A/S, Sanofi, and Servier, as well as research grants or support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk A/S, and Sanofi. Dr Nauck reports advisory boards or consultancy for AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Fractyl, GlaxoSmithKline, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and Novo Nordisk A/S, as well as speakers’ bureaus for AstraZeneca, Boehringer Ingel-heim, Eli Lilly & Co, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and Novo Nordisk A/S. His institution has received grant support from AstraZeneca, Eli Lilly & Co, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, Novartis Pharma, and Novo Nordisk A/S. Dr Pratley reports research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc, Lilly, Merck, Novo Nordisk A/S, Sanofi-Aventis US LLC, and Takeda; speaker fees from AstraZeneca, Novo Nordisk A/S, and Takeda; and consultant fees from AstraZeneca, Boehringer Ingelheim, Eisai, Inc, GlaxoSmithKline, Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc, Lilly, Merck, Novo Nordisk A/S, Pfizer, and Takeda. All payments are made directly to his employer (Florida Hospital). Dr Zinman reports consulting fees from Merck, Novo Nordisk A/S, Sanofi-Aventis, Eli Lilly, AstraZeneca, Janssen, and Boehringer Ingel-heim. Drs Ørsted, Rasmussen, and Monk Fries are Novo Nordisk A/S employees and shareholders. Dr Marso reports consulting fees from Novo Nordisk A/S and St Jude Medical and research support from Novo Nordisk A/S, Terumo, The Medicines Company, AstraZeneca, and Bristol-Myers Squibb.
Funding Information:
The authors thank all trial personnel and patients. Editorial and submission support, limited to formatting and collation of coauthor comments, was provided by Watermeadow Medical, an Ashfield Company, part of UDG Healthcare plc, funded by Novo Nordisk A/S. We thank Dr Hwee Teoh from St Michael’s Hospital for editorial assistance. Drs Verma, Marso, Ørsted, Fries, and Rasmussen had full access to the study data and take responsibility for its integrity and data analysis. The authors were fully responsible for all content and editorial decisions, involved at all stages of manuscript development, and have approved the final version. Drs Verma, Marso, and Bhatt wrote the first draft of the paper. Drs Nauck, Poulter, Bain, Buse, Pratley, Zinman, and Rasmussen were involved in the design, performance, and statistical analysis of the LEADER trial. All authors were involved in reviewing and interpreting the data and providing further comments and revisions. All authors approved the final version of the manuscript.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018
Y1 - 2018
N2 - Background: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. Methods: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. Results: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. Conclusions: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone.
AB - Background: The glucagon-like peptide-1 analog liraglutide reduced cardiovascular events and mortality in patients with type 2 diabetes mellitus in the LEADER trial (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes). In a post hoc analysis, we evaluated the efficacy of liraglutide in those with and without a history of myocardial infarction (MI) and/or stroke. Methods: LEADER was a randomized trial of liraglutide (1.8 mg or maximum tolerated dose) versus placebo in 9340 patients with type 2 diabetes mellitus and high cardiovascular risk, with a median follow-up of 3.8 years. The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (major adverse cardiovascular events). Risk groups in this post hoc analysis were defined by history of MI/stroke, established atherosclerotic cardiovascular disease without MI/stroke, or cardiovascular risk factors alone. Results: Of the 9340 patients, 3692 (39.5%) had a history of MI/stroke, 3083 (33.0%) had established atherosclerotic cardiovascular disease without MI/stroke, and 2565 (27.5%) had risk factors alone. Major adverse cardiovascular events occurred in 18.8% of patients with a history of MI/stroke (incidence rate, 5.0 per 100 patient-years), 11.6% of patients with established atherosclerotic cardiovascular disease without MI/stroke (incidence rate, 3.0 per 100 patient-years), and 9.8% of patients with cardiovascular risk factors alone (incidence rate, 2.6 per 100 patient-years). Liraglutide reduced major adverse cardiovascular events in patients with a history of MI/stroke (322 of 1865 [17.3%] versus 372 of 1827 patients [20.4%]; hazard ratio, 0.85; 95% CI, 0.73-0.99) and in those with established atherosclerotic cardiovascular disease without MI/stroke (158 of 1538 [10.3%] versus 199 of 1545 patients [12.9%]; hazard ratio, 0.76; 95% CI, 0.62-0.94) compared with placebo. In patients with risk factors alone, the hazard ratio for liraglutide versus placebo was 1.08 (95% CI, 0.84-1.38, Pinteraction=0.11). Similar results were seen for secondary outcomes across risk groups. Conclusions: In this post hoc analysis of patients with type 2 diabetes mellitus and high cardiovascular risk, liraglutide reduced cardiovascular outcomes both in patients with a history of MI/stroke and in those with established atherosclerotic cardiovascular disease without MI/stroke. The cardiovascular effect appeared neutral in patients with cardiovascular risk factors alone.
KW - Cardiovascular system
KW - Diabetes mellitus, type 2
KW - Glucagon-like peptide-1
KW - Liraglutide
KW - Randomized controlled trial as topic
UR - http://www.scopus.com/inward/record.url?scp=85058870723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058870723&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.118.034516
DO - 10.1161/CIRCULATIONAHA.118.034516
M3 - Article
C2 - 30566004
AN - SCOPUS:85058870723
SN - 0009-7322
VL - 138
SP - 2884
EP - 2894
JO - Circulation
JF - Circulation
IS - 25
ER -