HIV Articles  
Back 
 
 
Whither Recombinant Human Leptin Treatment for HIV-Associated Lipoatrophy and the Metabolic Syndrome? EDITORIAL
 
 
  The Journal of Clinical Endocrinology & Metabolism April Vol. 94, No. 4 1089-1091
 
Christos S. Mantzoros
 
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
 
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.
 
What Additional Information Do We Need?
 
It still remains unclear whether the population studied (subjects with leptin <3 ng/ml) is the only subset of patients with HIV-associated lipoatrophy that would benefit from leptin administration. Would one still expect a significant effect, albeit possibly smaller in magnitude, in patients with relatively higher leptin levels? Is the effect of leptin dose and/or time-dependent as suggested by comparing these two studies? Would, for example, a longer period of administration further enhance the beneficial effects of leptin and/or would a higher dose of leptin, possibly resulting in supraphysiological leptin levels, lead to a more pronounced response? In this context, what would be the optimum leptin dose and/or the optimum therapeutic target of leptin administration? Should one target a circulating leptin level within the expected normal range for healthy adults or should one raise leptin levels to higher, supraphysiological levels? Is twice a day administration optimal, or could one use a once daily regimen as used in the congenital lipodystrophies? Finally, for how long should a patient be treated since the effects of leptin treatment appear not to be sustainable after therapy is discontinued? All these clinically relevant questions need and can be answered by well-designed clinical trials.
 
How Does Leptin Work in Subjects with HIV-Associated Lipoatrophy?
 
Leptin regulates food intake and energy expenditure and plays an important role in the regulation of glucose homeostasis, possibly independent of its weight-reducing effects (15). In addition to its actions in the central nervous system, leptin may exert its insulin-sensitizing effects peripherally by decreasing gluconeogenesis in the liver and adipose tissue and/or by increasing glucose utilization in skeletal muscle (15). Leptin may also prevent the "lipotoxic" effects of intramyocellular lipid accumulation by activating fatty acids oxidation in skeletal muscle (7). The paper by Khatami et al. (13) suggests that the physiological improvements observed are largely independent of reductions in visceral adipose tissue and provides evidence for leptinfs action to improve hepatic insulin sensitivity without any significant effects on peripheral insulin sensitivity. Is this a matter of study design, dose administered, duration of treatment, other yet to be elucidated physiological mechanisms, or simply because of a lack of power due to the relatively small sample size? Intensive research efforts on mechanisms underlying leptinfs peripheral effects are ongoing and are expected to lead to significant breakthroughs in the not so distant future.
 
How Does Leptin Treatment Compare with Other Available Treatment Modalities, and Is There Room for Improvement?
 
Although no direct head-to-head comparisons are available, it appears that the decrease of visceral adipose tissue as well as the lipid-lowering effect of leptin are either comparable or better than those reported for metformin, GH, synthetic GHRH, or thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) (16, 17, 18). Moreover, similar to metformin and TZDs, but in contrast to GH or synthetic GHRH, leptin improves insulin sensitivity in the relatively short-term studies performed to date (13, 14). Thus, recombinant human leptin holds promise as an agent that could improve the HIV-associated lipoatrophy and features of the metabolic syndrome. Because other hormonal pathways, including adiponectin and the GH-IGF-I system, may also be operative in this syndrome, one could reasonably wonder whether combinations of leptin with other treatments may work even better than either agent alone. We have recently demonstrated that leptin acts independently from the GH-IGF-I pathway, implying that combination treatment may have additive effects (19). We have also found that not only leptin (14) but also pioglitazone (20), a TZD that increases adiponectin levels, may have beneficial effects in HIV-associated lipoatrophy and the metabolic syndrome. Thus, the findings of current ongoing pilot studies of combined administration of these agents will be of interest.
 
Last, But Not Least, Where Do We Stand with Respect to Leptin Availability for Our Patients?
 
Leptin is currently an investigational medication available through an Amylin-sponsored expanded access program for patients with severe lipodystrophy associated with diabetes mellitus and/or hypertriglyceridemia, but it is not available for patients with HIV-lipoatrophy and the metabolic syndrome. One would only hope that through larger and longer, well-designed, placebo-controlled, clinical trials, recombinant human leptin will eventually, alone or in combination, find its place in our therapeutic armamentarium providing tangible benefits to our patients.
 
Footnotes
 
The work of C.S.M. in this field is supported by National Institutes of Health Grants DK58785, DK79929, and DK81913, and by a clinical research grant from the American Diabetes Association.
 
For article see page 1137
 
Abbreviations: HALS, HIV-Associated lipodystrophy syndrome; HDL, high-density lipoprotein; TZD, thiazolidinedione.
 
Received February 12, 2009.
 
Accepted February 18, 2009.
 
References
 
1. Grinspoon S, Carr A 2005 Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352:48-62
2. Leow MK, Addy CL, Mantzoros CS 2003 Clinical review 159: human immunodeficiency virus/highly active antiretroviral therapy-associated metabolic syndrome: clinical presentation, pathophysiology, and therapeutic strategies. J Clin Endocrinol Metab 88:1961-1976
3. Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, Riesen W, Nicod P, Darioli R, Telenti A, Mooser V; Swiss HIV Cohort Study 2001 Premature atherosclerosis in HIV-infected individuals\focus on protease inhibitor therapy. AIDS 15:329-334
4. Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, Karchmer AW, Mantzoros CS 2003 Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis 36:795-802
5. Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, Mantzoros CS 2003 Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab 88:627-636
6. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941-946
7. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI 2002 Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345-1350
8. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P 2005 Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 54:1994-2002
9. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578
10. Andreev VP, Paz-Filho G, Wong ML, Licinio J2009 Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 41:142-151
11. Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, Tanaka T, Chusho H, Miyazawa T, Hayashi T, Hosoda K, Ogawa Y, DePaoli AM, Fukushima M, Nakao K 2007 Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 92:532-541
12. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P 2005 Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 41:753-760
13. Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, Wen MJ, Lee GA, Grunfeld C, Schambelan M 2009 The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with HIV-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 94:1137-1144
14. Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS 2006 Recombinant methinoyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab 91:2605-2611
15. Bluher S, Mantzoros CS 2009 Leptin in humans: lessons from translational research. Am J Clin Nutr 89:991S-997S
16. Lo J, You SM, Canavan B, Liebau J, Beltrani G, Koutkia P, Hemphill L, Lee H, Grinspoon S 2008 Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA 300:509-519 17. Kotler DP, Muurahainen N, Grunfeld C, Wanke C, Thompson M, Saag M, Bock D, Simons G, Gertner JM 2004 Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients. J Acquir Immune Defic Syndr 35:239-297
18. Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S2007 Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med 357:2359-2370
19. Brennan AM, Lee JH, Tsiodras S, Chan JL, Doweiko J, Chimienti SN, Wadhwa SG, Karchmer AW, Mantzoros CS 2009 r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur J Endocrinol 160:173-176
20. Gavrila A, Hsu W, Tsiodras S, Doweiko J, Gautam S, Martin L, Moses AC, Karchmer AW, Mantzoros CS 2005 Improvement in highly active antiretroviral therapy-induced metabolic syndrome by treatment with pioglitazone but not with fenofibrate: a 2 x 2 factorial, randomized, double-blinded, placebo-controlled trial. Clin Infect Dis 40:745-749
 
 
 
 
  iconpaperstack view older Articles   Back to Top   www.natap.org