April 16, 2015
3 min read

FDA panel recommends label changes for Nesina

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An FDA advisory panel recommended label changes for the diabetes drug Nesina after results from a cardiovascular outcomes trial revealed an increased risk for heart disease.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 13-3 Tuesday in favor of including new safety information for Nesina (alogliptin, Takeda Pharmaceuticals). The recommendation follows EMDAC review of the results of the EXAMINE trial, which found an increase in the rate of hospitalization for heart failure in patients who were assigned the drug.

The panel stopped short of taking more serious action, including label changes with restricted distribution of the drug or withdrawing alogliptin from the market. Three members of the panel voted for no change to the labeling.

The panel also voted unanimously (16-0) that the EXAMINE trial demonstrated that alogliptin has an acceptable CV risk profile.

The vote follows a similar recommendation calling for label changes in the diabetes drug Onglyza (saxagliptin, AstraZeneca), after a CV outcomes trial for that drug identified a 27% increase in hospitalization for heart failure, as well as an increase in all-cause mortality.

Researchers for the EXAMINE trial analyzed data from 5,400 patients with type 2 diabetes with established CVD in a multinational, randomized, double blind, placebo-controlled trial. The trial, conducted for 18 months, enrolled patients at high CV risk, including participants who had experienced an acute coronary syndrome event within 15 to 90 days before randomization.

During the trial, 106 patients assigned alogliptin (2.6%) experienced at least one hospitalization for heart failure vs. 89 patients assigned placebo (2.2%; HR = 1.19; 95% CI, 0.9-1.58).

“Although the FDA does not find this estimate to be particularly reassuring, FDA acknowledges that results from [hospitalization for heart failure] analyses have limitations. … In addition, the trial was not primarily designed to formally evaluate this endpoint,” the researchers wrote.

The study did not reveal an increased risk for either CV mortality or all-cause mortality.

“Takeda is pleased with the recommendation of the committee and we remain confident in alogliptin as an important treatment option for patients living with type 2 diabetes,” Robert Jackson, MD, MBA, vice president, global medical head, CVM-respiratory therapy, Takeda Pharmaceuticals, said in a press release after the panel’s decision. “Today’s outcome reinforces that the global EXAMINE trial met the FDA postmarketing guidance requirements. The trial is important as it assesses [CV] safety in patients known to be at a high risk for [CVD].”

Approved by the FDA in 2013, alogliptin is part of a class of diabetes drugs known as DPP-IV inhibitors used to control glucose levels in patients. Since 2008, the FDA has required manufacturers of diabetes drugs to conduct additional studies to examine their safety after concerns of a link between the drugs and an increased risk for heart failure.

Addressing the panel during public comment, Anne Leddy, MD, FACE, a board member with the American Association of Clinical Endocrinologists, said AACE does not advocate for or against any specific drug, but called DPP-IV inhibitors “a very important part of our care plan.”

“AACE is concerned about the findings of the [CV] outcome trials,” Letty said. “We await with interest any recommendations or warnings for safe use.”

Robert J. Smith, MD, chair of the EMDAC and a professor of endocrinology at Brown University’s Alpert Medical School, said there was a “sense of confusion” among panelists on how to best interpret the study findings, particularly because the study participants were already at significant risk for a cardiac event.

“The committee expressed a sense that [trial results are] not at all conclusive and, in fact, might raise significant doubt about whether there is a significant risk of heart failure for this drug,” Smith said. “But, it remains a concern.”

Panelists who voted in favor of a change in labeling said they were not overly concerned with the cardiac risk findings, but wanted the findings noted.

“It gets to the basic question of what should be in a package insert,” said panelist Kenneth Burman, MD, of Georgetown University. “Should it be any minor but potentially impactful [event]? ... My personal view is it’s better to include the information, especially if it’s couched in the proper preliminary tones.”

Burman said the findings could be listed as a “precautionary note” for prescribers.

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions. – by Regina Schaffer

Editor’s Note: On April 28, we corrected wording in the eleventh paragraph to reflect that the standard applies to all diabetes drugs. The Editors regret this error.