DDP-4 Inhibitor Advisory Committee Update
April 14, 2015 – During a meeting of the U.S. Food and Drug Administration’s (FDA) Endocrine and Metabolic Drugs Advisory Panel, members voted for labeling changes on some drugs for diabetes. The panel recommended that information about the risk of heart failure be added to the labeling for AstraZeneca’s Onglyza (saxagliptin) and Kombiglyze XR (saxagliptin/metformin) and Takeda’s Nesina (alogliptin), Kazano (alogliptin/metformin) and Oseni (alogliptin/pioglitazone). The drugs are dipeptidyl peptidase-4 (DPP-4) inhibitors, a relatively new class that is used to treat type 2 diabetes. DPP-4 inhibitors increase insulin production and reduce glucose production to improve blood sugar levels. Other DDP-4 inhibitor and DPP-4 inhibitor-containing products currently available on the U.S. market include Merck’s Januvia (sitagliptin), Janumet (sitagliptin/metformin), and Juvisync (sitagliptin/simvastatin); as well as three Lilly/Boehringer Ingelheim products — Tradjenta (linagliptin), Jentadueto (linagliptin/metformin), and Glyxambi (linagliptin/empagliflozin).
In 2008, an FDA guidance on the cardiovascular safety of all drugs used to treat diabetes directed manufacturers of new drugs to provide evidence that cardiovascular risk, already elevated for patients with diabetes, was not worsened by using their drugs. Results of the first post-marketing studies found no increases in cardiovascular-related deaths, heart attacks or strokes with alogliptin or saxagliptin. However both drugs increased the risk of heart failure. The increase did not reach statistical significance with alogliptin, but saxagliptin users were 27% more likely to be hospitalized for heart failure. Additionally, they had a higher risk of death from any cause than participants using a placebo along with their usual diabetes therapies. Although the increase in deaths among patients on saxagliptin concerned the panel members, the causes of death did not have a clear pattern. Panel members also commented that the increased risks may be common to all DDP-4 inhibitors. If results from Merck’s study, which are expected later this quarter, also show increased risks of heart failure, death or both; FDA could require label and, possibly, prescribing changes for all DDP-4 inhibitors.
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