Onglyza Heart Safe

DPP-4 Inhibitor Onglyza (saxagliptin) Does Not Increase Heart Disease Risks

The dipeptidyl peptidase-4 (DDP-4) inhibitor saxagliptin (Onglyza) had neither a positive nor negative impact on the risk of cardiovascular events in a study involving more than 16,000 patients with type 2 diabetes mellitus and a history of, or who were at risk for, cardiovascular events. The findings, reported in the New England Journal of Medicine, showed a slightly increased risk for hospitalization for heart failure.

“This is the first fully large cardiovascular outcome study to show that DPP-4 inhibitors don’t raise ischemic risk,” said coauthor Deepak L. Bhatt, MD, MPH, Professor of Medicine at Harvard Medical School, Chief of Cardiology at VA Boston Healthcare System, and Senior Physician at Brigham and Women’s Hospital, Boston.

“I think [this study] is useful when one views the larger context of diabetes medicines where we don’t have great safety data,” he said. For example, there are no large outcomes trials evaluating the cardiovascular safety of sulphonylureas, he said.

“In 2008, the FDA and the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee required new glucose agents to demonstrate cardiovascular safety. As such, the SAVOR-TIMI 53 trial was designed to evaluate both the safety and efficacy of saxagliptin in a high-risk type 2 diabetes population,” commented Michael Cobble, MD, primary care physician and Director of Canyons Medical Center in Sandy, Utah.

“I applaud the robust nature of this study, conducted at 788 sites in 26 countries including 16,492 patients with type 2 diabetes randomized to either addition of saxagliptin therapy or placebo therapy,” said Dr. Cobble, who is also Chief Medical Officer for Atherotech Diagnostics Labs. “The study population was fairly typical of very high-risk type 2 diabetes groups:  average age, 65 years; BMI, 31; duration of diabetes, 10 years; established atherosclerosis, 80%; hypertension, 80%; dyslipidemia, 70%; prior heart attack, 40%; revascularization, 45%; congestive heart failure, 13%; and A1C of 8%,” he added.

Key Study Findings

The rates of the primary outcome—a composite of cardiovascular death, myocardial infarction, or ischemic stroke—were similar in the saxagliptin and placebo groups (7.3% and 7.2%, respectively). The groups also showed similar rates on a secondary endpoint that combined the primary outcome plus hospitalization for unstable angina, coronary revascularization, or heart failure (12.8% and 12.4%, respectively).

“There was no evidence that saxagliptin treatment resulted in cardiovascular benefit or cardiovascular harm as a whole,” Dr. Cobble commented.

“We did rather unexpectantly see a slight but statistically significant increased risk of hospitalization for heart failure,” Dr. Bhatt said. The rates of hospitalization for heart failure in the saxagliptin and placebo groups were 3.5% and 2.8% (hazard ratio, 1.27; P=0.007).

“It is important to put this risk into context, as the absolute risk excess of hospitalization for heart failure was 0.7% over 2 years. The average physician, and even a physician with a busy diabetes practice, probably wouldn’t detect that. It is only because we did a mega trial that we found this outcome,” Dr. Bhatt said.

He suggested that this excess risk may be a drug-specific side effect or, more likely, a class specific effect. “When trials of other DPP-4 inhibitors are done, assuming they look [at this outcome] and have adequate statistical power, I think we’ll see that DPP-4 inhibitors slightly raise the risk of hospitalization for heart failure,” he said. Another possibility is that intense glycemic control may cause heart failure in susceptible patients as this increased risk has also been found in trials of thiazolidinediones.

Non-Cardiac Outcomes

While the lack of protection against cardiovascular events found in the study “may be discouraging,” Dr. Cobble said, “concerns of blood cell changes, severe infections, opportunistic infections, pancreatitis, fractures, skin reactions, liver abnormalities, and cancer were not significant between the groups in this study.”

The risk for hospitalization for hypoglycemia was similar among the two groups; however, the percentage of patients reporting at least one hypoglycemic event was significantly higher in the saxagliptin group than in the placebo group (15.3% vs 13.4%; P<0.001).

“Overall, I think the findings can provide reassurance to doctors who are treating diabetes that this class of medication is reasonably safe. If a patient has already tried diet, lifestyle, and metformin, saxagliptin is a reasonable second-line or third-line agent,” Dr. Bhatt said.

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