FDA Panel Backs New Safety Warnings on Two Diabetes Drugs

Alicia Ault

April 14, 2015

Silver Spring, Maryland — A majority of a US Food and Drug Administration (FDA) advisory committee recommended that two dipeptidyl peptidase-4 inhibitors (DPP-4s) for type 2 diabetes — saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and alogliptin (Nesina, Takeda) — have their labels updated to include information about new safety issues that have come to light through cardiovascular-outcomes studies.

For saxagliptin, 14 of 15 panelists from the Endocrinologic and Metabolic Drugs Advisory Committee voted during the morning session yesterday to update the label, primarily on the increased risk for heart failure. They also wanted to see information on the trend toward higher all-cause mortality. One panel member voted to withdraw the drug from the US market.

In the afternoon the committee included 16 members and was not as concerned about the safety of alogliptin, but still, 13 voted to add new data to the label for this agent, while three said there should be no change. The new safety information should focus on heart failure, said the majority, despite a lack of a real signal with that drug. Even so, some felt that heart failure could be a classwide problem.

Results of two outcomes studies — Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus —Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) — were first presented at the European Society of Cardiology meeting in 2013 and later published in the New England Journal of Medicine.

The trials were required by a 2008 FDA guidance that manufacturers of new type 2 diabetes medications should demonstrate that the products are not associated with an unacceptable increase in cardiovascular risk. The studies of saxagliptin and alogliptin were the first completed.

Heart Failure Primary Saxagliptin Worry

The panel was largely satisfied that AstraZeneca had proven that saxagliptin did not increase the risk for cardiovascular disease by 30% or more — as was required under the FDA guidance.

"Clearly they've met that mark very easily, even if there is an increase in heart failure," said panelist Erica H Brittain, PhD, deputy branch chief of the biostatistical research branch at the National Institute of Allergy and Infectious Diseases.

The panel agreed that SAVOR, conducted in 16,492 patients with type 2 diabetes mellitus who had established cardiovascular disease or were at high risk for cardiovascular disease, showed a less than 30% increased risk. There were 1222 composite primary-end-point major adverse cardiovascular events (MACE) of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke, at a median duration of 2.1 years of follow-up, giving a hazard ratio of 1.00.

But there was a 27% increase in the rate of the first event of hospitalization for heart failure and a potential increased risk for all-cause mortality, according to the FDA reviewers.

"An effect on all-cause mortality really cannot be ruled out," agreed Robert J Smith, MD, committee chair and professor of medicine at Alpert Medical School of Brown University, Providence, Rhode Island.

"I'm a little bit more concerned about the heart-failure finding than for all-cause mortality," said Thomas J Wang, MD, Gottlieb C Friesinger II Chair in Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. The "heart-failure events are real," he said.

Panelist Morris Schambelan, MD, professor emeritus of medicine, University of California, San Francisco, said, "I agree that this signal seemed like a real signal," but added that clinicians had the ability to predict which patients would be at higher risk. Still, a labeling change is necessary "to inform practitioners who they need to be careful about using this drug for," he said.

The committee said it was not clear whether saxagliptin also impaired renal function, "but there are enough data that one would want to keep looking," said Dr Smith.

Alogliptin Heart-Failure Data Confusing

Dr Smith voiced the same concern — that there just were not enough data about renal effects — with alogliptin, as did some other members of the committee.

The majority said that Takeda had demonstrated that alogliptin had an acceptable cardiovascular-safety profile. But the heart-failure data presented a conundrum.

"I do think that heart failure matters and that there may be a class effect," said panelist William R Hiatt, MD, professor of medicine at the University of Colorado School of Medicine, Aurora.

The FDA conducted additional exploratory analyses of heart failure in EXAMINE and found that 89 placebo patients had at least one heart-failure hospitalization event compared with 106 alogliptin patients, giving a hazard ratio of 1.19 (95% confidence interval, 0.90 – 1.58). The agency reviewers said they did "not find this estimate to be particularly reassuring" but acknowledged that EXAMINE was not primarily designed to formally evaluate heart failure.

Committee member Lamont G Weide, MD, PhD, said, "There's understandable focus on heart failure, given the findings in the other trial." But, he added, "looking at the data, there really doesn't seem to be a compelling result surrounding heart failure."

Dr Weide, professor, University of Missouri School of Medicine, Kansas City, said that the alogliptin data was confusing because heart failure seemed to be concentrated in patients who did not have a history — the opposite of what was seen in SAVOR.

"There's a very important and difficult communications challenge here," Dr Smith said. Although there are issues with both saxagliptin and alogliptin, clinicians should not come away with the idea that there are huge problems, he said. Instead, there are things to be careful about.

"The challenge is to have them understand what that means as they then make their own decisions about how they use or not use the drug," he said.

Other Studies Expected Soon

Both the FDA and committee members noted that cardiovascular outcomes studies for other antidiabetics are expected in the next year or so.

The next to be released — in June — will be A Randomized Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin in Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control on Mono- or Dual Combination Oral Antihyperglycemic Therapy (TECOS), conducted by Merck.


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