Conference Coverage

ADA: DPP4 inhibitors and cardiovascular outcomes: connecting the dots




BOSTON – Findings presented at the annual scientific sessions of the American Diabetes Association showed that one widely used glucose-lowering agent, sitagliptin, was not associated with an increase in major atherosclerotic cardiovascular events or hospitalizations for heart failure, compared with placebo.

Results from TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) were reassuring to clinicians who consider sitagliptin (Januvia), like other dipeptidyl peptidase-4 (DPP-4) inhibitors, to be a well-tolerated, effective drug not associated with weight gain or hypoglycemia in patients with type 2 diabetes.

The TECOS findings, however, did raise questions about whether sitagliptin was different than other DPP-4 inhibitors in people with known cardiovascular disease.

A randomized controlled trial of saxagliptin (Onglyza) found a 27% increased risk of hospitalization for heart failure, compared with placebo.

A trial of alogliptin (Nesina) saw a numerical imbalance in hospitalizations for heart failure that did not reach statistical significance.

Speaking at the conference after the presentation of the TECOS findings, Dr. Allison B. Goldfine, head of the section of clinical, behavioral, and outcomes research at the Joslin Diabetes Center and of Harvard Medical School, both in Boston, who was not an investigator on any of the three trials, suggested several potential reasons that the signal for heart failure hospitalizations was inconsistent across the trials.

Dr. Goldfine pointed to important differences in trial design and duration. Patients in the alogliptin trial had acute coronary syndrome at baseline and hemoglobin A1c levels of between 6.5% and 11%, and they were followed up a median of 18 months.

Patients in the saxagliptin trial had either established cardiovascular disease or multiple risk factors for vascular disease, HbA1c of 6.5%-12%, and were followed 2 years. TECOS patients had a history of coronary artery disease, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease, and had an HbA1c between 6.5% and 8%. They were followed for 3 years.

Dr. Goldfine also noted the potential for differences in activity among the individual agents. “There are some different specificities and the potential for on- and off-target effects across these drugs,” she said, though these remain poorly understood.

“Is it a class effect? Maybe not, as there was no hospitalization for heart failure increase in TECOS,” Dr. Goldfine said. “But I want you to be very cautious in using this interpretation. These were not head-to-head studies, and there were differences in the patient illnesses and severities, comorbidities and concomitant therapies, sample sizes, duration of follow up, and a potential for altered attentiveness and therapeutic practices due to these baseline differences.”

Clinicians considering use of the DPP4 inhibitors “need to realize that there’s some uncertainty when evaluating the risk and benefit of any of our drugs,” she noted.

The TECOS findings will not be the last word on DPP-4 inhibitors and the mixed signals on heart failure seen to date, Dr. Goldfine said. “I think a lot of effort will go on in the very near future to try to understand these better to see if there’s an explanation.”

Dr. Goldfine disclosed past research support from Amneal, LifeScan, Nestle, Novo, and Nordisk.

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