Metabolic Effects of Rosiglitazone in HIV Lipodystrophy

Context Antiretroviral therapy often causes metabolic abnormalities characterized by lipoatrophy and HIV lipodystrophy. Thiazolidinediones (such as rosiglitazone) are peroxisome proliferatoractivated receptor- agonists that improve insulin sensitivit... show more

Context Antiretroviral therapy often causes metabolic abnormalities characterized by lipoatrophy and HIV lipodystrophy. Thiazolidinediones (such as rosiglitazone) are peroxisome proliferatoractivated receptor- agonists that improve insulin sensitivity and stimulate adipogenesis. Contribution In a randomized, double-blind, placebo-controlled study of HIV-infected individuals, rosiglitazone improved insulin sensitivity, increased adiponectin levels, decreased free fatty acid levels, and improved peripheral fat deposition during 3 months of treatment with antiretroviral agents. Implications Rosiglitazone seems to reverse some of the metabolic abnormalities that accompany antiretroviral therapy and may help prevent or moderate HIV lipodystrophy. Cautions The small sample size and short duration of treatment limit the generalizability of the findings. The Editors Treating HIV-infected patients with combination antiretroviral therapy is often associated with metabolic abnormalities, including insulin resistance, hypertriglyceridemia, and loss of subcutaneous fat (1-8). Because of the combined use of antiretroviral medications, identifying exact mechanisms responsible for these metabolic disturbances has been difficult, but increasing evidence supports direct metabolic toxicity from each class of antiretroviral agents. For example, exposure to protease inhibitors impairs glucose uptake by cultured adipocytes (9) and indinavir administration decreases glucose utilization in healthy volunteers (10, 11). Nucleoside reverse transcriptase inhibitors are implicated in the development of lipoatrophy (12-14) and are associated with increased basal lipolysis among HIV-infected individuals (15, 16). Furthermore, nucleoside reverse transcriptase inhibitors may also affect fat-cell differentiation and apoptosis rates through mitochondrial DNA depletion (17). While several studies show increased lipid levels in association with protease inhibitor use (18, 19), protease inhibitors, as well as non-nucleoside reverse transcriptase inhibitors, reduce fractional clearance of very-low-density lipoproteins, thereby contributing to hyperlipidemia (20). Direct effects of antiretroviral medications, as well as their indirect effects through altered fat distribution, contribute to metabolic abnormalities that may increase patients' risk for cardiovascular disease (4, 21). Loss of subcutaneous fat may be an important mechanism that contributes to the metabolic abnormalities in these patients (22-24). Furthermore, obvious loss of subcutaneous fat is an important cosmetic concern for HIV-infected patients. Recent studies suggest that potential disruption of adipogenesis in the subcutaneous fat occurs through altered sterol regulatory element-binding protein-1 and the peroxisome proliferatoractivated receptor- (PPAR-) signaling cascade (25). Adiponectin levels are reduced in association with decreased subcutaneous fat in HIV-infected patients with lipodystrophy, and this may be one mechanism that mediates altered insulin sensitivity in these patients (26-31). In addition, previous studies found increased lipolysis and free fatty acid levels in patients with HIV lipodystrophy and suggest effects of increased free fatty acid levels on insulin sensitivity in these patients (15, 16, 32). Thiazolidinediones, which are PPAR- agonists, improved insulin sensitivity and stimulated adipogenesis in individuals with congenital lipodystrophy (33) and may therefore be useful for HIV-infected patients with lipodystrophy. In a previous 6- to 12-week open trial of rosiglitazone in 8 HIV-infected patients with fat redistribution, Gelato and colleagues (34) observed increased subcutaneous adipose tissue in conjunction with improved glucose disposal. Yki-Jrvinen and colleagues (35) completed a 24-week randomized, controlled trial of rosiglitazone (8 mg/d) in 30 HIV-infected patients with fat redistribution and did not observe a statistically significant effect on body fat, although liver fat and aminotransferase levels improved. We report what we believe to be the first randomized, placebo-controlled trial to demonstrate a statistically significant benefit of PPAR-agonist therapy for lipoatrophy in a sample of HIV-infected patients with insulin resistance. Methods Patients A total of 72 HIV-infected men and women were screened to determine eligibility for a 3-month randomized, double-blind, placebo-controlled trial of rosiglitazone (4 mg once daily) for treating hyperinsulinemia and fat redistribution between March 2001 and December 2002. Eligibility requirements included previously documented HIV infection; hyperinsulinemia (fasting insulin level 104 pmol/L, or > 521 pmol/L after a 2-hour glucose challenge); evidence of fat redistribution, including lipoatrophy in the face, arms, hips, or legs, by patient self-report and confirmed on physical examination by an investigator; and stable antiretroviral regimen for more than 3 months. Patients were excluded if they had a previous diagnosis of kidney or heart failure or diabetes, current or previous use of a thiazolidinedione or other antidiabetic agents, fasting glucose level greater than 7.0 mmol/L (>126 mg/dL), liver aminotransferase levels at least 2.5 times the upper limit of normal, creatinine level greater than 176.8 mol/L (>2.0 mg/dL), hemoglobin level less than 90 g/L, current use or use within the past 12 weeks of anabolic therapies (except physiologic testosterone replacement in men or estrogen replacement in women), active drug or alcohol abuse, or pregnancy. Patients were recruited through the multidisciplinary HIV clinics at the Massachusetts General Hospital and the Brigham and Women's Hospital, Boston, Massachusetts, and through advertisements in the greater Boston region. Twenty-eight of 29 patients who were eligible for enrollment entered the study. Patients provided informed written consent, and the Massachusetts General Hospital Human Research Committee and the Massachusetts show less