Background:  Leptin treatment improves lipid and glucose metabolism in non-HIV lipodystrophy. The present study was designed to determine whether leptin could produce similar benefits in HIV-infected patients with lipoatrophy. 

Methods:  In this open-label, proof-of-principle study, 8 HIV^± men with lipoatrophy (with or without fat accumulation), hypoleptinemia (<3 ng/mL), dyslipidemia (despite use of lipid lowering agents in 7 of 8), and insulin resistance, received recombinant human leptin for 6 months (0.01 mg/kg twice daily for 3 months, followed by 0.03 mg/kg twice daily for 3 months). Glucose and lipid metabolism was assessed under fasting conditions and during a euglycemic, hyperinsulinemic clamp with stable isotope infusions before and after 6 months of treatment. Visceral and subcutaneous abdominal fat (at L4-L5) were measured by magnetic resonance imaging and peripheral fat by DEXA.  Data are mean ±SE.  Results were analyzed by paired t-test.

Results:  There were significant decreases in fasting levels of total (229±16 to 187±12 mg/dL, p = 0.001), direct LDL (140±8 to 117±8 mg/dL, p = 0.002), and non-HDL (204±15 to 158±12 mg/dL, p = 0.001) cholesterol. HDL cholesterol tended to increase (25±2 to 29±3 mg/dL, p = 0.07). Triglyceride levels decreased significantly under fasting, hyperinsulinemic (clamp), and postprandial conditions. Whole-body lipolysis and free fatty acid levels decreased significantly during both fasting and hyperinsulinemia.  Fasting insulin (21±3 to 16±2 mIU/mL, p = 0.04), endogenous glucose production (2.8±0.1 to 2.5±0.1 mg/kg/minutes, p = 0.005), and glycogenolysis (2.2±0.1 to 1.9±0.1 mg/kg/minutes, p = 0.03) decreased significantly, as did glucose production, glycogenolysis, and gluconeogenesis measured during the clamp, providing evidence of improvements in hepatic insulin sensitivity. Peripheral glucose uptake (clamp) improved modestly but the increase was not statistically significant.  Visceral abdominal fat decreased by 30% (183±24 to 129±24 cm², p = 0.001) with no significant changes in subcutaneous or peripheral fat.  Leptin was well tolerated.

Conclusions:  Leptin treatment was associated with marked improvement in dyslipidemia in a group of patients already treated with lipid-lowering agents. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Hepatic insulin sensitivity improved and lipolysis decreased. Results from this pilot study suggest that leptin may have therapeutic potential in HIV-infected patients with metabolic and morphologic alterations.