While hospitalization for heart failure was not part of the primary MACE composite in EXAMINE, it was a prospectively defined, collected and adjudicated endpoint. Researchers reported that 89 patients in the placebo arm and 106 patients in the alogliptin arm experienced heart failure, yielding an HR of 1.19 (95% CI, 0.90-1.58).
“Although the FDA does not find this estimate to be particularly reassuring, FDA acknowledges that results from [hospitalization for heart failure] analyses have limitations,” according to the FDA briefing documents.
The panel also discussed the renal effects of alogliptin, pointing out that the potential for adverse events raises red flags but that there were not enough data to demonstrate a significant risk.
Ultimately, the committee unanimously determined that alogliptin had an acceptable CV risk profile, with a majority of panel members feeling that the safety concerns discussed during the meeting should be added to product labeling.
“This gets to the basic question of what should be in a package insert. Do we include any minor, potentially reasonable effect, like we heard today, or something more proven to guide the clinician?” committee member Kenneth D. Burman, MD, director of the section of endocrinology at MedStar Washington Hospital Center in Washington, D.C., said in discussing his decision to vote in favor of updating alogliptin’s labeling.
“My personal view is that it’s best to include information, especially when it’s couched in the proper cautionary tones,” he said, explaining that these concerns should be presented as very preliminary.
During discussion, advisory committee members noted that this increased risk for heart failure may be a class effect, as both saxagliptin and alogliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors. Further studies on the possible mechanisms would be helpful, panel members said.
Additionally, the FDA and the committee members said that more CV outcomes trials for diabetes drugs are on the horizon, with results from the TECOS trial — a randomized, placebo-controlled trial evaluating CV outcomes in patient with type 2 diabetes after treatment with sitagliptin — scheduled to be released in June.