Background:  Changes in fat distribution and insulin resistance are common complications in HIV-infected patients on HAART. Use of insulin-sensitizing agents may improve body composition and metabolic abnormalities in this setting.

Methods:  We assessed the effects of metformin (500 mg twice daily, increasing to 1000 mg twice daily) and rosiglitazone (4 mg once daily) alone and in combination vs placebo, in a randomized, blinded 16-week study in HIV⁺ subjects with elevated waist-to-hip ratio (>0.95 for men and 0.85 for women; or waist circumference >100 cm) and hyperinsulinemia (>15 μIU/mL or 2-hour glucose >140 mg/dL post-oral glucose tolerance test and fasting insulin >10 μIU/mL). Primary endpoints included safety parameters and changes in abdominal visceral and subcutaneous adipose tissue by computed tomography. Secondary endpoints included whole body and regional fat distribution by DEXA. Intent-to-treat analysis used Kruskal-Wallis test (continuous data) and Fisher’s Exact test (binary data).

Results:  We randomized 105 subjects to metformin/rosiglitazone placebo (M/P, n = 26), rosiglitazone/metformin placebo (R/P, n = 27), metformin/rosiglitazone (M/R, n = 25), or dual placebo (P/P, n = 27). Subjects were 66% male, 67% Caucasian, median age 45, CD4 count 567 cells/mm³, and waist-to-hip ratio 1.01 (males) or 0.99 (females). Demographic and body composition characteristics were similar across groups at baseline. A total of 91 subjects completed the study. Premature discontinuation of study drug was significantly greater in M/P (n = 12) than other groups (R/P = 3; M/R = 4; PP = 8 [p = 0.02]). Diarrhea was more common in the metformin groups (M/P = 65%; R/P = 8%; M/R = 52%; PP = 15% [p <0.001]). Adverse events for lactate and LFT were similar among groups.  There were no statistically significant differences among groups in changes in abdominal visceral and subcutaneous adipose tissue. Changes in trunk, upper extremity, and total extremity fat were also not significant among groups. Lower extremity fat increased significantly in the rosiglitazone group compared to placebo (+4.8 vs –8.3% ,p = 0.034), but not in the combined group or metformin group vs placebo.

Conclusions:  Neither rosiglitazone alone, metformin alone, nor the combination significantly changed abdominal visceral or subcutaneous adipose tissue over 16 weeks, but significant dose reductions and discontinuations in the metformin arm may have affected these results. Rosiglitazone increased lower extremity fat compared to placebo.