In two separate decisions, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the labeling for saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda) be updated to include information on additional safety concerns that surfaced during cardiovascular (CV) outcomes trials.
For saxagliptin, the advisory panel voted 13-1 with one abstention that results from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus (SAVOR) study showed that the drug has an acceptable CV risk profile.
However, in a follow-up vote, 14 of 15 committee members favored the addition of new safety information, including the potential increased risk for heart failure, to the drug’s labeling. One panel member also voted to withdraw saxagliptin from the U.S. market.
For alogliptin, the committee voted 16-0 that the Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) demonstrated the drug’s CV safety.
Yet, as with saxagliptin, a majority of panel members — 13 of 16 — voted to update the product labeling to include additional safety information. The other three members favored no change.
The FDA often follows the recommendations of its advisory committees, but it is not required to do so.
Saxagliptin in SAVOR
For their discussion of saxagliptin, the panel was asked to consider results from SAVOR. This was a large, prospective, multicenter, randomized, double blind, placebo-controlled trial that included 16,492 patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at high risk for CVD.
After a median 2.1 years of follow-up and 1,222 major adverse CV events (MACE), defined as a composite of CV death, nonfatal myocardial infarction or nonfatal ischemic stroke, the researchers were able to rule out a 30% relative increase in CV risk. Even so, data indicated no CV benefit, according to FDA briefing documents.
While a secondary analysis of MACE plus hospitalization for unstable angina or hospitalization for coronary revascularization yielded data similar to that of the primary endpoint, results also revealed a 27% increased rate of hospitalization for heart failure as well as a potential increased risk for all-cause mortality in patients treated with saxagliptin.
Panel members generally agreed that the trial met its primary endpoint but noted the increased heart failure rate is a concern that should be reflected in updated labeling.
Alogliptin in EXAMINE
For alogliptin, the committee discussed data from EXAMINE, a multicenter, multinational, randomized, double blind, placebo-controlled trial involving about 5,400 patients with type 2 diabetes and established CVD.
As with SAVOR, results from the trial excluded a 30% excess CV risk. Nevertheless, heart failure once again emerged as a concern.