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Report on Possible Therapy for Lipodystrophy
Written for NATAP by Cecilia Shikuma, MD, the University of Hawaii and the ACTG
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No major break-throughs in therapy for lipodystrophy was reported at this year's 3rd International Workshop.
A Calmy et al. (Abs 43) presented the results of a small open label prospective trial to evaluate the safety and efficacy of pioglitazone in 9 subjects on HAART (5 on PI and 6 on d4T containing regimens) with lipodystrophy. Pioglitazone was given as 30 mg/d x 3 months followed by 45 mg/d x 3 months. Insulin resistance index was normal at baseline and remained unchanged following 6 months of Rx. The therapy was well-tolerated with no serious side effects. Lipid values remained stable with a tendency towards decreasing triglyceride levels. Over a 6 month period, "subjective improvement" of lipodystrophy symptoms in 6/9 subjects was reported. However this was not substantiated by any improvement in anthropometric measurements or in DEXA measurements of total, arm or leg fat mass. Comments: This small study did not demonstrate any objective data that pioglitazone had any efficacy in improving either visceral adiposity or peripheral subcutaneous lipoatrophy. The results may have been influenced by the fact that this study did not pre-select individuals with baseline insulin resistance or glucose intolerance, the usual indication for therapy with PPARg agonists. As suggested by the authors, a randomized placebo controlled trial is required to demonstrate the potential beneficial effect of pioglitazone in preventing or treating HAART induced lipodystrophy.
F Visnegarwala and MR Maldonado (Abs 124) screened all patients in a HIV-Metabolic Clinic at Thomas St Clinic and identified 28 subjects treated with PPAR-g modulators (rosiglitazone). Of these 28 subjects 9 were normoglycemic. All nine had baseline insulin resistance and lipodystrophy. After a median duration of therapy of 24 weeks, 4 of the 9 subjects had subjective improvement in facial fat wasting and/or thinning of extremities. There was a trend towards a decrease in waist/hip ratios. No changes in IR HOMA, total, HDL choledsterol or triglycerides were observed. Comments: This retrospective study again illustrates the need for a carefully done randomized placebo controlled trial to demonstrate the potential efficacy of PPAR-g agonists in the prevention or treatment of HAART associated lipodystrophy.
(Editorial comments: the authors reported there were nodiscontinuations due to hepatotoxicity, and there was no loss of virologic control during the follow-up).
UR Hengge et al (Abs 70) presented the results of the effect of oxymetholone (50 mg twice and three times daily) in a double-blind, placebo-controlled Phase II study of 92 subjects for the treatment of HIV wasting and lipodystrophy. Entry criteria required unintended weight loss > 10% of ideal weight. Following therapy of 16 weeks duration, significant increases were seen in body cell mass and lean body mass. However total body fat was unchanged. Adverse events were mainly hepatic occurring in 14% of oxymetholone-treated patients with significant elevations of AST, ALT and GGT. (Editoial comment: 2 patients (7.4%) in the twice daily regimen experienced grade 3 and 4 liver toxicity compared with 6 (21%) in the 3 times per day regimen). Comments: This study does not appear to have been designed to assess for improvement in regional fat composition; thus while efficacy for wasting was demonstrated, no conclusions as to its efficacy in lipodystrophy can be made.
C Hadigan et al. (Abs 69) reported on the continued tolerability and efficacy of metformin through 9 months of therapy in 19 individuals who completed a double-blind randomized 3 month trial of metformin for HIV infected patients with lipodystrophy and insulin resistance and were eligible to receive a 6 month open label metformin treatment extension. Metformin continued to be well tolerated. No increase in lactic acid levels was seen. Improvement in insulin AUC was seen. Furthermore, the reduction in waist circumference and BMI tended to be greater in patients who received 9 vs 6 months of metformin. Comment: This small but carefully conducted study suggests the efficacy of metformin in reducing visceral adiposity in individuals with central obesity and insulin resistance.
(Editorial comment: The ACTG is planning a combination study of rosiglitazone and Metformin because rosiglitazone may improve fat loss (lipoatrophy) and Metformin may improve fat accumulation in the belly).
E Martinez et al. (Abs 29) reported on 51 subjects on stable PI-containing HAART with abdominal fat accumulation and plasma triglycerides > 200 mg/dl who were randomized to receive blinded medication of metformin 850 mg/12h, gemfibrozil 600 mg/12 h or placebo/12h. One year follow up revealed negligible effects on triglycerides as well as on insulin resistance. In addition, no effect was found in regional fat by sonography. Comment: This study utilized a modality for regional fat assessment that has yet to be validated. The difference in results between this study and that of C Hadigan et al above for metformin may have been secondary to differences in patient entry selection. In particular, note that insulin resistance was not a criteria for entry into this particular study.
Effects of growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation was studied by JM Schwarz et al. (Abs 26) by stable isotope tracer studies, indirect calorimetry, and measurements of lipid concentrations performed under both fasting and hyperinsulinemic-euglycemic clamp conditions, before and after 1 and 6 months of growth hormone dosed at 3 mg/day in 5 patients. Improvement in lipid profile (significant increase in HDL cholesterol and decreases in total and LDL cholesterol and triglyceride levels) was found. However, worsened glucose homeostasis under both fasting and hyperinsulinemic conditions were also found which were driven predominantly by increased hepatic gluconeogenesis but by peripheral insulin resistance as well. The authors concluded that the combined implications of these positive and negative metabolic effects for cardiovascular disease risk remain unknown. Comments: Based on this study, extreme caution should be exercised in the use of growth hormone in individuals with insulin resistance/glucose intolerance
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