A Randomized, Double-Blind, Placebo-Controlled Study of Metformin and Rosiglitazone, Alone or in Combination, in HIV-Infected Subjects With Hyperinsulinemia and Elevated Waist/Hip Ratio

Recent studies have documented hyperglycemia, insulin resistance, and glucose intolerance in a seemingly increasing proportion of patients with HIV infection. Other studies have described a variety of syndromes of fat accumulation and fat loss, including abdominal obesity. Although initially attributed specifically to protease inhibitors (PI), these abnormalities also have been observed in antiretroviral-experienced but PI-naive patients. Hyperinsulinemia and abdominal obesity are strong independent risk factors for coronary artery disease. In noninfected patients, metformin and thiazolidinediones have been shown to reduce insulin resistance by different mechanisms and also to reduce visceral adiposity. This study investigates the use of metformin and rosiglitazone, a member of the thiazolidinedione class, in HIV-infected patients with hyperinsulinemia and central fat accumulation.

At study entry, clinical and laboratory assessments are performed. A standard OGTT, with plasma samples drawn over 120 minutes, will be performed for glucose and insulin determinations. After completion of entry evaluations, patients are assigned randomly to 1 of 4 double-blinded treatment arms:

Arm A: Metformin plus rosiglitazone placebo. Arm B: Metformin placebo plus rosiglitazone. Arm C: Metformin plus rosiglitazone. Arm D: Metformin placebo plus rosiglitazone placebo. Patients who are still on study drugs at Week 16 (at either full or reduced dose) are switched to the open-label phase to receive the combination of metformin and rosiglitazone through Week 32. Patients have evaluations at Weeks 2, 4, 8, 12, 16, 18, 20, 24, 28, and 32. [AS PER AMENDMENT 02/05/02: Evaluations must be performed under fasting conditions.] Safety indices, fasting insulin and glucose levels, visceral [AS PER AMENDMENT 02/05/02: and subcutaneous abdominal] fat are assessed. [AS PER AMENDMENT 02/05/02: Patients who discontinue study treatment due to pregnancy during the study will have the Week 32 evaluations (except CT and DEXA scans).] [AS PER AMENDMENT 02/05/02: A mid-thigh measurement was added to the study as a secondary endpoint to look for changes in extremity subcutaneous fat from therapy with rosiglitazone. Rosiglitazone and other peroxisome proliferator-activated receptor (PPAR) gamma activators increase subcutaneous adipogenesis and may thus increase subcutaneous fat and improve insulin resistance in this way.]