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N Engl J Med. 2016 Mar 24;374(12):1145-54. doi: 10.1056/NEJMoa1506115.

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure.

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From the Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital (K.B.F., L.A., P.E.), the Departments of Medicine (K.B.F., P.E.), Oncology (L.A.), Pediatrics (R.W.P.), and Epidemiology, Biostatistics, and Occupational Health (R.W.P.), McGill University, and the Research Institute of the McGill University Health Centre (R.W.P.), Montreal, the Manitoba Centre for Health Policy, Department of Community Health Sciences (M.D., L.T.), and the Section of Gastroenterology, Division of Internal Medicine (L.T.), University of Manitoba, Winnipeg, the Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver (C.R.D.), the Department of Medicine, Western University, London, ON (K.K.C.), the Health Quality Council, Saskatoon, SK (N.H.), the Institute for Clinical Evaluative Sciences (J.M.P., J.A.U.), Institute of Health Policy, Management and Evaluation, University of Toronto (J.M.P.), and the Cardiovascular Division, Women's College Hospital, Peter Munk Cardiac Centre of the University Health Network, and the University of Toronto (J.A.U.), Toronto, the Department of Family Medicine, McMaster University, Hamilton, ON (J.M.P.), and the Department of Family Medicine, University of Calgary, Calgary, AB (T.C.T.) - all in Canada.



There is concern that antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue.


We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case-control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models.


The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues.


In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. (Funded by the Canadian Institutes of Health Research; number, NCT02456428.).

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