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FDA Panel Recommends New CV Safety Warnings on Onglyza and Nesina DPP-4s

Updated label information recommendation is in light of completed cardiovascular-outcomes studies…

For saxagliptin (Onglyza), 14 of 15 panelists from the Endocrinologic and Metabolic Drugs Advisory Committee voted to update the label, primarily on the increased risk for heart failure. The panel 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.

The committee also discussed the safety of alogliptin (Nesina), but 13 voted to add new data to the label for this agent, while three said there should be no change.

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.

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.

The majority of the panel said that Takeda had demonstrated that alogliptin had an acceptable cardiovascular-safety profile.

However, 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.

“Patients with diabetes are at an increased risk of cardiac related comorbidities such as heart disease and stroke, as well as hospitalized heart failure and cardiac death,” said William B. White, MD, Professor, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, U.S., on behalf of the EXAMINE Steering Committee and Investigators. “Today’s Advisory Committee recommendation provides important information about alogliptin that may be useful for prescribing physicians as they consider appropriate treatment options for patients with type 2 diabetes.”

The FDA is not bound by the Advisory Committee’s recommendations but takes its advice into consideration when reviewing sNDAs. Cardiovascular outcomes studies for other antidiabetics are expected in the next year or so.

Practice Pearls:

  • 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.
  • 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.

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