Protease Inhibitors: FDA Warns Doctors of Diabetes Risk

On June 11 the U.S. Food and Drug Administration warned AIDS physicians that there might be a small risk of developing diabetes due to use of protease inhibitors. Eighty three cases had been found, of which 27 required hospitalizationand six were life-threatening, out of an estimated 110,000 U.S. patients now prescribed these drugs. Even allowing for major under reporting, the "attack rate" appears to be well under one percent -- and it is not known for sure that the drugs caused the illness. There is no evidence that any of the four available protease inhibitors is better or worse than any other.

The FDA did NOT recommend stopping protease inhibitors as a result of this information, but wanted health professionals to be aware of the possible problem, so that patients will be tested early for diabetes if symptoms develop.

"HIV patients on protease inhibitor therapy should know the warning signs of hyperglycemia and diabetes: increased thirst and hunger, unexplained weight loss, increased urination,fatigue and dry, itchy skin." (quoted from FDA Talk Paper,"Health Advisory for Newest Class of AIDS Drugs," June 11,1997).

Letter to Doctors

The following letter was sent to about 13,000 physicians and other health-care professionals, who account for about 95% of all HIV prescribing in the U.S.

"Subject: Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of human immunodeficiency virus (HIV)

"Dear Health Care Professional:

"The Food and Drug Administration would like to call to your attention recent post marketing reports of new onset diabetes mellitus, hyperglycemia or exacerbation of existing diabetes mellitus occurring in HIV-infected patients receiving protease inhibitor therapy. At the present time there exists no conclusive evidence establishing a definite causal relationship between protease inhibitor therapy and the incidence of diabetes and hyperglycemia. Based on present reporting, we believe the occurrence of this event is relatively infrequent. As such, patients for whom these products are indicated should not discontinue therapy without consulting their health care professional. However, given the potential seriousness of this complication, we believe that patients and health care professionals should be notified of this information.

"Summary of Reports

"* As of May 12, 1997, there have been 83 cases reported to FDA of diabetes mellitus or hyperglycemia in HIV-infected patients who were receiving anti-retroviral protease inhibitor therapy; 27 of the 83 cases were reported to require hospitalization. Fourteen patients were known to be diabetic at baseline; for these patients, there was a loss of glucose control. The average time of onset was approximately 76 days after initiating protease inhibitor therapy, but occurred as early as four days after starting therapy. Five cases of diabetic ketoacidosis occurred, including patients who were not reported to be diabetic at baseline; however, the baseline status of these patients is not well characterized.

"* Some patients required either initiation or dose adjustment of insulin or oral hypoglycemic agents for the treatment of these events. On an average, fifty percent of patients discontinued their protease inhibitor therapy as a result of this acute adverse event. Hyperglycemia persisted in some patients after protease inhibitor therapy was withdrawn including patients not known to be diabetic at baseline; however a causal relationship between protease inhibitor therapy and these events has not been established.

"* Many of these reports occurred in patients with confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia.

"* Diabetes and hyperglycemia have been reported to varying degrees for Crixivan(R) (indinavir), Invirase(R) (saquinavir), Norvir(R) (ritonavir) and Viracept(R) (nelfinavir).

"FDA will continue close monitoring for additional events. We encourage all health care professionals to report any cases of diabetes or hyperglycemia, or any other serious toxicity associated with the use of protease inhibitors, to the FDA's MEDWATCH program at 1-800-FDA-1088/fax 1-800-FDA-0178; or to the respective pharmaceutical manufacturers: [phone numbers included in the letter]."