Author + information
- Received June 25, 2019
- Revision received December 11, 2019
- Accepted December 17, 2019
- Published online March 9, 2020.
- Steven P. Marso, MDa,∗ (, )@Steve_Marso,
- Florian M.M. Baeres, MDb,
- Stephen C. Bain, MDc,
- Bryan Goldman, MSb,
- Mansoor Husain, MDd,
- Michael A. Nauck, MDe,
- Neil R. Poulter, FMedScif,
- Richard E. Pratley, MDg,
- Anne Bloch Thomsen, MD, PhDb,∗,
- John B. Buse, MD, PhDh,
- on behalf of the LEADER Trial Investigators
- aMidwest Heart and Vascular Institute, HCA Midwest Health, Overland Park, Kansas
- bNovo Nordisk A/S, Søborg, Denmark
- cSwansea University Medical School, Swansea, Wales, United Kingdom
- dTed Rogers Centre for Heart Research, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- eDiabetes Center Bochum-Hattingen, St. Josef-Hospital (Ruhr University), Bochum, Germany
- fFaculty of Medicine, School of Public Health, Imperial College London, London, United Kingdom
- gAdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, Florida
- hUniversity of North Carolina School of Medicine, Chapel Hill, North Carolina
- ↵∗Address for correspondence:
Dr. Steven P. Marso, Midwest Heart and Vascular Institute, HCA Midwest Health, 12200 West 106th Street, Suite 320, Overland Park, Kansas 66215.
Background More data regarding effects of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes (T2D) and heart failure (HF) are required.
Objectives The purpose of this study was to investigate the effects of liraglutide on cardiovascular events and mortality in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) participants, by HF history.
Methods In the multinational, double-blind, randomized LEADER trial, 9,340 patients with T2D and high cardiovascular risk were assigned 1:1 to liraglutide (1.8 mg daily or maximum tolerated dose up to 1.8 mg daily) or placebo plus standard care, and followed for 3.5 to 5 years. New York Heart Association (NYHA) functional class IV HF was an exclusion criterion. The primary composite major adverse cardiovascular events outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Post hoc Cox regression analyses of outcomes by baseline HF history were conducted.
Results At baseline, 18% of patients had a history of NYHA functional class I to III HF (liraglutide: n = 835 of 4,668; placebo: n = 832 of 4,672). Effects of liraglutide versus placebo on major adverse cardiovascular events were consistent in patients with (hazard ratio [HR]: 0.81 [95% confidence interval (CI): 0.65 to 1.02]) and without (HR: 0.88 [95% CI: 0.78 to 1.00]) a history of HF (p interaction = 0.53). In both subgroups, fewer deaths were observed with liraglutide (HR: 0.89 [95% CI: 0.70 to 1.14] with HF; HR: 0.83 [95% CI: 0.70 to 0.97] without HF; p interaction = 0.63) versus placebo. No increased risk of HF hospitalization was observed with liraglutide, regardless of HF history (HR: 0.98 [95% CI: 0.75 to 1.28] with HF; HR: 0.78 [95% CI: 0.61 to 1.00] without HF; p interaction = 0.22). Effects of liraglutide on the composite of HF hospitalization or cardiovascular death were consistent in patients with (HR: 0.92 [95% CI: 0.74 to 1.15]) and without (HR: 0.77 [95% CI: 0.65 to 0.91]) a history of HF (p interaction = 0.19).
Conclusions Based on these findings, liraglutide should be considered suitable for patients with T2D with or without a history of NYHA functional class I to III HF. (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]; NCT01179048)
- heart failure
- GLP-1 receptor agonist
- major adverse cardiovascular events
- type 2 diabetes
↵∗ At the time of the study.
This study was sponsored by Novo Nordisk A/S, Søborg, Denmark. Dr. Marso has received consulting fees from Abbott Vascular, Boston Scientific, and Novo Nordisk. Dr. Baeres is an employee of and holds stock in Novo Nordisk. Dr. Bain has received honoraria, teaching, and research sponsorship/grants from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cellnovo, Diartis, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Schering Plough, Servier, and Takeda; has received funding for development of educational programs from Cardiff University, Doctors.net, Elsevier, Onmedica, Omnia-Med, and Medscape; is a shareowner of Glycosmedia; and has provided expert advice to the All-Wales Medicines Strategy Group and National Institute for Health and Care Excellence (NICE) UK. Dr. Goldman is an employee of and holds stock in Novo Nordisk. Dr. Husain has received research grants from AstraZeneca, Merck, and Novo Nordisk; has received consulting fees and/or honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Roche; is coinventor of 2 provisional patents related to GLP-1; and has served as an investigator on 2 clinical trials related to GLP-1RA: EMPRES (NCT01938235) (funded by AstraZeneca) and PIONEER-6 (NCT02692716) (sponsored by Novo Nordisk). Dr. Nauck has received fees for serving on advisory boards from AstraZeneca, Berlin-Chemie, Eli Lilly, Fractyl, Hanmi, Merck Sharp & Dohme, Novo Nordisk, and Intarcia Therapeutics/Servier; has received lecture fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Eli Lilly, Medscape, Merck Sharp & Dohme, and Novo Nordisk; has received travel support from Berlin-Chemie, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Intarcia Therapeutics/Servier; and has received grant support (to his institution) from AstraZeneca, Eli Lilly & Co., GlaxoSmithKline, Intarcia Therapeutics/Servier, Merck Sharp & Dohme, Novartis, and Novo Nordisk. Dr. Poulter is the Immediate Past President of the International Society of Hypertension; has received personal speaker fees from Servier, Takeda, and Novo Nordisk; has served on Advisory Boards for AstraZeneca and Novo Nordisk; has received consultancy fees from Servier; has received research project support from Servier and Pfizer; has received research grants for his research group relating to type 2 diabetes from Diabetes UK, NIHR EME, Julius Clinical, and the British Heart Foundation; and has a pending grant from Novo Nordisk. Dr. Pratley has received research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi, and Takeda; has served as a speaker for AstraZeneca, Novo Nordisk, and Takeda; and has served as a consultant for AstraZeneca, Boehringer Ingelheim, Eisai, Inc., GlaxoSmithKline, Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Pfizer, and Takeda; all payments were made directly to his employer (Florida Hospital/AdventHealth). Dr. Thomsen is a former employee of and holds stock in Novo Nordisk; and is an employee of Pfizer. Dr. Buse has contracted consulting fees paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, and Zafgen; has received grant support from Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; has served as a consultant to and received personal compensation from Cirius Therapeutics, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics, and Stability Health; has stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio, and Stability Health; and has been supported by grants from the National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612), PCORI, and ADA. This article extends observations presented previously at the American Diabetes Association 76th Scientific Sessions (Session 3-CT-SY24; June 13, 2016; New Orleans, Louisiana) and European Association for the Study of Diabetes (EASD) 52nd Annual Meeting (Oral Presentation #S27.1; September 15, 2016; Munich, Germany), and published by Marso et al. (12). The data were also presented in part at the American College of Cardiology 67th Annual Scientific Session (1318M-05; March 12, 2018; Orlando, Florida), the EASD 54th Annual Meeting (#1155, October 2, 2018; Berlin, Germany), and at a further 8 local congresses.
- Received June 25, 2019.
- Revision received December 11, 2019.
- Accepted December 17, 2019.
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