Leptin in lipodystrophy, see link In humans, recombinant human leptin, metreleptin, has been extensively studied in the context of open-label clinical trials168. Pharmacokinetic and pharmacodynamic studies of metreleptin have allowed us to select appropriate doses to be administered to humans169–171. Physiological replacement doses of leptin (0.04–0.08 mg/kg·d) have provided tangible benefits to patients with severe leptin deficiency from congenital and non-HIV-related acquired generalized lipodystrophy. These include improvements in insulin sensitivity, fasting glucose, glucose tolerance, hemoglobin A1c, hypertriglyceridemia, and transaminitis, thus lessening the need for insulin or oral hypoglycemic agents172–179. Leptin replacement also favorably changes body composition (weight loss with decreased fat and lean masses)178,180, an effect which is partially due to increased satiety181. Furthermore, patients with partial lipodystrophy, including syndromes associated with LMNA and PPARγ gene mutations, also gain metabolic benefits with leptin treatment173,182,183. Although all studies in subjects with congenital lipodystrophy have been non-randomized, open-label trials, metreleptin is currently available for difficult-to-treat patients with lipodystrophy through an FDA-approved expanded access program168,177. Metreleptin may provide benefits beyond improvements in metabolic parameters. Metreleptin reduces proteinuria and ameliorates glomerular injury associated with generalized lipodystrophy184 and normalizes menstrual abnormalities, estradiol levels, and the leutinizing hormone response to gonadotropin-releasing hormone in young women with lipodystrophy and polycystic ovaries178,185. Leptin replacement may also have beneficial immunomodulatory effects in hypoleptinemic patients with severe lipodystrophy186. Although open-label trials have demonstrated benefits of metreleptin in these forms of lipodystrophy, larger, randomized, placebo-controlled trials are needed to conclusively prove its efficacy as well as safety, especially since there have been several side effects noted, including proteinuric nephropathy184 and T-cell lymphomas177,187 in a small number of subjects. Nevertheless, it appears as though the benefits of leptin replacement are sustained for as long as treatment continues (i.e., refractory changes in metabolic parameters and/or body composition have been largely attributed to treatment non-adherence) as patients followed for up to 8 years of continuous metreleptin treatment have continued to benefit from therapy173. To date, there have been only a small number of patients with CGL2 in which metreleptin treatment ceases to be efficacious, potentially from the development of leptin resistance188. In a randomized, placebo-controlled, double-blinded, crossover study evaluating the use of metreleptin in the most prevalent form of lipodystrophy, HALS, administration of physiological replacement doses of metreleptin to hypoleptinemic men with HALS was found to improve fasting insulin levels, insulin resistance, HDL cholesterol, and truncal obesity189. An independent trial of longer duration confirmed these results190. The improvements in visceral adiposity and lipid levels exhibited by HALS patients treated with metreleptin189,190 were comparable to improvements reported with other therapeutics, including metformin and TZDs78,79,97,125,132–134. Furthermore, the improvements in insulin resistance reported in patients with HALS treated with metreleptin189,190 provide an advantage over GH, which has been associated with glucose intolerance135,136. In both trials, metreleptin was well-tolerated and no side effects were observed with treatment up to 36 months174. It remains to be seen the extent to which patients with comparatively higher endogenous leptin levels would benefit from metreleptin therapy, but it is expected that the improvements would be less striking than those observed in patients with severe leptin deficiency191. Leptin’s beneficial effects are mediated independently of the GH-IGF-1 system192. Because the GH-IGF-1 system may also play a role in HALS, it is possible that combination therapy with leptin and GH or GHRH analogs could have additive metabolic benefits without adversely affecting glucose intolerance191, but this remains to be seen. Even more importantly, it is still not known whether the co-administration of metreleptin and adiponectin have synergistic effects on the normalization of insulin resistance in humans with lipodystrophy, as has been reported in mice155. Pilot studies investigating the combined administration of pioglitazone and metreleptin are underway, and preliminary data indicate that this combination further improves glycemic control (CS Mantzoros, unpublished data). ncbi.nlm.nih.gov/pmc/articles/PMC3150735/
Posted on: Sat, 15 Mar 2014 05:40:21 +0000
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