BOSTON – The glucose-lowering drug sitagliptin, part of a class of drugs whose cardiovascular safety has been cast into doubt based on findings in trials of similar agents, was shown not to increase the risk of heart failure or other adverse cardiovascular outcomes in a large randomized trial.
Results presented June 8 at the annual scientific sessions of the American Diabetes Association and published simultaneously in the New England Journal of Medicine (doi:10.1056/NEJMoa1501352) revealed “no evidence of harm one way or another” for cardiovascular events or heart failure, Dr. Rury F. Holman, professor of diabetic medicine and diabetes trials unit director at the Oxford (England) Centre for Diabetes, Endocrinology & Metabolism, the study’s corresponding author, said at a press conference.
Dr. Rury F. Holman
Though the manufacturer announced the main cardiovascular findings on sitagliptin (Januvia), earlier this year, the details of this trial – driven by concerns about a signal for increased risk of heart failure in two earlier trials of dipeptidyl peptidase 4 (DPP-4) inhibitors – were presented for the first time.
TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) enrolled 14,671 patients with type 2 diabetes in combination with cardiovascular disease who were age 50 years or older. Patients were recruited in 38 countries and randomized to add-on therapy with
sitagliptin or placebo in addition to other antihyperglycemic therapies used openly at physician discretion. At mean 3 years’ follow-up, sitagliptin was noninferior to placebo for a combined cardiovascular endpoint comprising first time to CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina (hazard ratio, 0.98; 95% confidence interval, 0.88-1.09, P < .001).
Hospitalizations for heart failure did not differ between the placebo and sitagliptin arms (HR, 1.0; 95% CI, 0.83-1.20, P = .98), and no significant differences were seen in rates of pancreatitis or pancreatic cancer.
All patients in both the control and intervention arms were treated to similar glucose targets by their physicians. Levels of glycated hemoglobin between the groups were close throughout the study period, with a difference of –0.29 for the sitagliptin arm (95% CI, –0.32 to –0.27). “That’s important because we didn’t want a glucose difference that might have influenced the cardiovascular outcomes one way or another,” Dr. Holman commented.
Dr. Eric D. Peterson, executive director of the Duke Clinical Research Institute as well as professor in the departments of medicine and cardiology and the Fred Cobb, MD, Distinguished Professor of Medicine of Duke University, Durham, N.C., who was a coauthor on the study, commented on its heart failure finding. TECOS had been prompted by unexpected
heart-failure signals seen in two earlier trials of DPP-4 inhibitors, saxagliptin and alogliptin.
“Given the size of our study, and the longer duration of follow-up, as well as the higher risk of our population, we feel that this puts to bed the question – at least with sitagliptin – that there’s any risk for heart failure increases,” Dr. Peterson said.
The investigators were careful to assert that few conclusions could be drawn for the class of drugs as a whole based on the TECOS findings but suggested chance could have played a role in the earlier studies.
The study was funded by sitagliptin’s manufacturer, Merck Sharp & Dohme. Dr. Holman disclosed a financial relationship with the study sponsor. Dr. Peterson disclosed financial relationships with other manufacturers.