In the spring, an FDA advisory committee recommended adding a warning about heart failure to the label of the popular diabetes medication Onglyza.

Manufactured by AstraZeneca PLC, Onglyza has been in use since the FDA first approved it in July 2009.

The agency’s Endocrinologic and Metabolic Drugs Advisory Committee announced its recommendation in April. By a vote of 14-to-1, the committee recommended adding information about an increased incidence of hospitalization for heart failure in users of saxagliptin, the generic name for the active ingredient in Onglyza. One committee member recommended taking saxagliptin off the market altogether.

The committee made the same recommendation for Takeda Pharmaceutical Co.’s Nesina. Both Onglyza and Nesina are in a class of diabetes medications known as DPP-4 (dipeptidyl peptidase-4) inhibitors. Some of the FDA committee members expressed concern that risk of heart failure might be a class effect of DPP-4 inhibitors, not just Onglyza or Nesina.

Other DPP-4 inhibitors include Merck’s Januvia and Boehringer Ingelheim’s Tradjenta. These medications work by decreasing the activity of DPP-4, a naturally-occurring enzyme. After a person eats, the body releases a hormone called incretin that triggers release of insulin, which itself lowers blood sugar. The body uses DPP-4 to remove incretin. By decreasing the activity of DPP-4, these medications allow incretin to stay in the body, causing more release of insulin and a lowering of blood sugar.

The FDA’s attention was drawn by the results of a clinical trial called SAVOR, the results of which were published in the American Heart Association’s journal Circulation. The trial reviewed two years’ worth of follow-up records for almost 16,500 persons with type 2 diabetes and either a history of or current risk for cardiovascular events. Researchers found a higher rate of hospitalization for heart failure among those who took saxagliptin than among those who took a placebo. The researchers noted this finding was a secondary outcome; they did not find any increase with saxagliptin over placebo of cardiovascular death, myocardial infarction, or ischemic stroke.

Heart failure is a decrease in the heart’s ability to move an adequate amount of blood through the body. This inadequacy can most commonly result in shortness of breath and fatigue. Depending on the type of heart failure, it can lead to accumulation of fluid  in the lungs, lower limbs, lower back, liver, or abdomen. Heart failure may lead to blood clots that travel through the body and may cause embolism or stroke.

The committee’s review falls under FDA’s general recommendation issued in December 2008 that manufacturers of new type 2 diabetes drugs provide evidence that those drugs will not increase patients’ risk of cardiovascular events. Type 2 diabetes patients already have two to four times the risk of heart disease than those without diabetes, and no treatment for type 2 diabetes has been able to reduce that risk. By creating new design and data collection standards for clinical trials, the new FDA recommendations are intended to spur pharmaceutical companies to be more forthcoming about the risks of cardiovascular events associated with their medications.