Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome?

Lipodystrophies are a diverse group of congenital or acquired clinical disorders characterized by a complete or partial lack of adipose tissue (lipoatrophy), and/or a combination of lack of adipose tissue in certain body areas with excess adipose tissue (lipohypertrophy) elsewhere. Insulin resistance and associated clinical features, including dyslipidemia, are present in nearly all lipodystrophies. The most common form of partial, acquired lipodystrophy is the HIV-associated lipodystrophy syndrome (HALS), which was first reported 11 yr ago (1,2). The prevalence of HALS has been difficult to quantify precisely due to the lack of uniform and universally accepted criteria for its diagnosis. It is reported to occur more frequently with longer duration of exposure to highly active antiretroviral therapy and is estimated to be present in up to 40–84% of patients on antiviral treatment for more than 1 yr (1,2,3). HIV-associated lipoatrophy usually manifests as peripheral fat wasting involving the face, arms, legs, and buttocks; is clinically recognizable; and is a source of concern or even embarrassment for patients who are usually anxious to be treated (2). Most patients have dyslipidemia, especially hypertriglyceridemia, and in more severe cases one can observe clinically evident features of insulin resistance, abnormal glucose tolerance, and even more rarely overt diabetes. Hepatic steatosis may also develop but, in contrast to congenital lipodystrophy, acanthosis nigricans seems to be extremely rare. Both HALS and HIV-associated lipoatrophy are linked to endothelial dysfunction and accelerated atherosclerosis (3). The pathogenesis of the underlying metabolic syndrome is thought to be multifactorial and has not been fully elucidated (1,2). Cross-sectional studies have shown that levels of both leptin and adiponectin are decreased in patients with HIV-associated lipoatrophy (4,5) and are closely and inversely correlated with features of the metabolic syndrome, including dyslipidemia and insulin resistance (4,5). Although data from observational studies cannot prove causality, animal experiments have demonstrated that administration of either leptin or adiponectin improves insulin resistance in hypoleptinemic and hypoadiponectinemic lipoatrophic mice, whereas the combined administration of both leptin and adiponectin fully normalizes insulin sensitivity (6). Similarly, relatively small, open-label clinical trials have shown that sc injection of leptin in physiological replacement doses (0.04–0.08 mg/kg·d) in severely hypoleptinemic subjects with rather severe congenital or acquired non-HIV-related lipodystrophies (7,8,9) results in significant and sustained weight loss (mainly due to loss of fat mass) and improved insulin sensitivity and leads to decreased fasting glucose, improved glucose tolerance, reduced hemoglobin A1c, and decreased hepatic steatosis. Leptin administration also results in decreased requirements for insulin or oral hypoglycemic agents (7,8,9,10,11,12) and a decrease in hypertriglyceridemia, which is usually refractory to traditional lipid-lowering agents (8). Given the design of these studies, it still remains to be proven beyond any doubt whether the beneficial effects observed are due to leptin per se and/or whether the magnitude of any effect is in fact less, as would be determined in a placebo-controlled trial. However, performing clinical trials in this population could prove extremely difficult because the number of patients with these syndromes is relatively small, i.e. only a few hundred worldwide. In contrast, the prevalence of partial lipodystrophies, and most importantly of HIV-associated lipoatrophy, is much higher. Thus, relevant clinical trials should be easier to perform, and it is likely that the results would be applicable to more patients worldwide. However, one could expect to observe a less dramatic response to leptin treatment given that patients with HIV-associated lipoatrophy do not have an absolute leptin deficiency that needs correction (usually <3 ng/ml in men and <4 ng/ml in women, but only infrequently <1 ng/ml), in contrast to the rare congenital syndromes. The paper by Khatami et al. published in this issue of JCEM (13) evaluates the effects of recombinant human leptin therapy in HIV-associated lipoatrophy. Khatami et al. (13) performed a 6-month, open-label, pilot study administering recombinant human leptin to eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and relative leptin deficiency (<3 ng/ml). Recombinant human leptin was administered by sc injection twice a day for the first 3 months at a low dose (0.01 mg/kg) and then for an additional 3 months at a dose of 0.03 mg/kg, which would be expected to restore circulating leptin levels to the high normal range. Leptin treatment was associated with a significant 32% decrease in visceral fat as well as improvements in insulin sensitivity, endogenous glucose production, and fasting insulin and glucose levels. In addition, fasting levels of total, direct low-density lipoprotein and non-high-density lipoprotein (HDL) cholesterol decreased by 15–20%, and HDL cholesterol increased significantly (13). Triglyceride levels, whole body lipolysis, and free fatty acids also decreased. These data are consistent with and also extend previously published data from a double-blind, placebo-controlled, crossover clinical trial involving recombinant human leptin administration in replacement doses (0.04 mg/kg·d, administered in two divided doses daily). After 2 months of treatment, truncal fat mass decreased by 15%, and inflammatory markers and insulin sensitivity improved significantly (14), whereas the lipid profile of the patients (especially HDL) showed a trend toward improvement. These changes were less pronounced than those reported by Khatami et al. (13) and could be explained by the fact that this earlier study placed an upper limit on triglyceride levels at entry, and/or that the study described in this issue of JCEM involved a higher dose of leptin that was administered for a longer period of time.