Metreleptin for the treatment of lipodystrophy: leading the way among novel therapeutics for this unmet clinical need

1. Leptin discovery and principles

Leptin, discovered in 1994¹, is the prototype adipokine that fundamentally advanced our knowledge of the pathophysiology of adipose tissue, opening new avenues in the diagnosis and treatment of metabolic diseases². Until then, the function of adipose tissue was considered to be largely that of an inert, depot storage organ, i.e. acting mainly as an organ storing energy in the form of triglycerides and possibly contributing in part to insulating the body from cold. Following the discovery of leptin, numerous adipokines have been discovered, thereby rendering the adipose tissue the largest and most active endocrine organ².

Leptin is mainly secreted by the white adipocytes. Its circulating levels are associated with total fat mass in adults: the higher the fat mass, the higher the leptin levels. It seems that subcutaneous fat produces more leptin than the visceral adipose tissue, which may, at least partly, explain the higher leptin levels observed in women than men³. The production of leptin from brown adipose tissue remains controversial and leptin expression in brown adipose tissue may derive from white adipocytes that reside within brown adipose tissue⁴.

Leptin levels are also influenced, secondarily, by other factors⁵. For example, leptin levels decrease while on a hypocaloric diet, therefore, under normal circumstances, they not only reflect long-term energy availability by reflecting total energy stored as fat, but they reflect short-term energy availability⁶. By binding to and activating leptin receptors, leptin has multiple central and peripheral actions. By acting centrally, primarily in the arcuate nucleus of the hypothalamus, on the basis of experiments in rodents, leptin decreases appetite⁷. Through its complex actions and interactions, leptin is considered to play a key role in the pathogenesis of obesity and related comorbidities, including type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases, but also has a distinct role in regulating other systems, such as the neuroendocrine, musculoskeletal, gastrointestinal, reproductive and immune systems⁷.

2. Introduction of leptin in therapeutics: initial expectations

Immediately after the discovery of leptin, expectations were raised that leptin would be the “magic bullet” for the treatment of obesity and related comorbidities². However, these expectations soon proved not to apply to humans, since clinical trials revealed that recombinant leptin failed to cause significant weight loss⁸. The failure of leptin treatment in common obesity has been attributed to the development of leptin tolerance or resistance, i.e. unresponsiveness of central and peripheral tissues to leptin, accompanied by high circulating leptin levels, as in the case of obesity and related comorbidities⁹. In other words, obese individuals have hyperleptinemia, but central and peripheral actions of leptin are reduced⁹. Leptin treatment is thus not recommended for common obesity and related comorbidities, e.g. T2DM, dyslipidemia and/or NAFLD with normal or high circulating leptin levels⁷. For example, patients with NAFLD typically have higher leptin levels than non-NAFLD individuals¹⁰. In addition, leptin administration in certain animal models may prevent hepatic steatosis, but, could, on the other hand, contribute to the progression of hepatic steatohepatitis and fibrosis, as a proinflammatory adipokine⁹. Thus, although its efficacy has not been definitively studied in humans with NAFLD, leptin administration is currently not recommended in NAFLD patients with normal or high leptin levels⁷.

3. Leptin treatment for lipodystrophy

Despite the disappointment that followed the failure of initial expectations, subsequent studies deepened and broadened our knowledge of the pathophysiology of adipose tissue, thus leading to improvement in our understanding of energy deficiency states, in which leptin plays a much more important role, including, but not limited to, lipodystrophy². Lipodystrophy refers to a group of heterogeneous diseases, inherited or acquired, characterized by total or partial loss of adipose tissue, and thus the loss of storage capacity of the organism, which, in turn, results in inappropriate, dystopic accumulation of fat in other organs, including the liver¹¹. Lipodystrophy leads to multiple metabolic and non-metabolic aberrations, which impair the quality of life and increase the mortality of affected individuals^11,12. Low leptin levels are a hallmark of lipodystrophy; leptin levels may be very low or even undetectable in patients with more severe forms (e.g. congenital or acquired generalized lipodystrophy)¹³. However, leptin levels vary in patients with less severe forms (e.g. congenital or acquired partial lipodystrophy), and some of them may have leptin levels within the normal range¹³. Low leptin levels in lipodystrophy reflect the low mass of adipose tissue, and may not respond appropriately to acute changes in energy intake⁶.

Lipodystrophy has been a rather difficult to manage disease, characterized by high insulin resistance, diabetes that usually requires high insulin doses to control, hypertriglyceridemia that responds only partially to common hypolipidemic medications, and advanced NAFLD^7,11. Multiple other manifestations from other systems may coexist, adding to the overall complexity of morbidity and mortality of lipodystrophy⁷.

Physiology studies indicate that there is a certain amount of adipose tissue, which is absolutely necessary for metabolic health, and that the resulting low leptin levels would correspond to a relative deficiency of its pleiotropic functions in central and peripheral tissues. The subsequent introduction of recombinant human methionyl leptin (metreleptin, administered subcutaneously daily) has contributed significantly to the treatment of patients with lipodystrophy, leading to a decrease in insulin resistance, a lower dose of insulin needed to treat diabetes and more efficient management of hypertriglyceridemia^14,15. Metreleptin treatment may possibly result in beneficial effects in other systems, e.g. musculoskeletal, reproductive, immune, etc., which, however, remain to be definitively shown⁷. The effect of metreleptin on glycemic control was shown to be independent of the use of concomitant anti-diabetic medications, and its lipid-lowering effect independent form concomitantly used hypolipidemic medications at baseline¹⁶. Importantly, metreleptin treatment was shown to substantially improve the quality of life¹⁷ and reduce mortality¹⁸ in non-randomized studies with both congenital and acquired lipodystrophy. Returning to NAFLD, metreleptin may be beneficial for NAFLD in patients with lipodystrophy and low leptin levels, apparently contrary to the administration to non-lipodystrophic individuals with NAFLD and normal or high leptin levels, the latter being the majority of NAFLD patients^11,19. More specifically, following metreleptin treatment, histological improvement of NAFLD was shown in patients with lipodystrophy^20,21, i.e. in cases with low leptin levels. On the contrary, no study has shown improvement of NAFLD in non-lipodystrophic patients. This may resemble most other hormone replacement therapy, in which the administration of the hormone may be beneficial only in cases of hormonal deficiency.

Metreleptin has been approved as a replacement therapy for leptin deficiency in patients with congenital or acquired generalized lipodystrophy by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). EMA and the Japanese PMDA have also approved metreleptin for patients with some forms of partial lipodystrophy, but not human immunodeficiency virus (HIV)-associated lipodystrophy. However, mainly due to the rarity of the disease, metreleptin approval was mainly based on uncontrolled, open-label clinical trials; thus, more and better designed and longer-term clinical trials, possibly on a multicenter basis, as well as a longer post-surveillance period, are required²². Although it remains to be definitely shown, patients with partial lipodystrophy may need lower leptin doses than those with generalized lipodystrophy to normalize their leptin levels, similar to any substitution therapy. Common adverse effects of metreleptin include local reactions at the injection site, weight loss, headache, abdominal pain and hypoglycemia, the latter indicating the necessity of adjusting the doses of insulin or other concomitant anti-diabetic medications². Importantly, metreleptin may in extremely rare circumstances induce the generation of neutralizing antibodies, which may neutralize its action in the long term². This has been attributed to the fact that metreleptin is a modified form of leptin with the addition of methionine to stabilize the molecule during its production from E. Coli, which, however, may induce changes in the tertiary structure of leptin that could possibly expose immunogenic parts of the molecule, leading to the development of autoantibodies against both metreleptin and possibly the endogenous leptin in an extremely small number of subjects²³. Another important consideration is the potential association of metreleptin with T-cell lymphoma, which, however, has not been established, since T-cell lymphoma has been observed in patients with acquired generalized lipodystrophy, both treated and untreated with metreleptin².

Apart from the above-mentioned multicenter clinical trials for metreleptin, what would be desirable to have in the future are better recombinant leptin formulations or leptin mimetics, which would ideally not have the above mentioned common adverse effects and would not lead to the generation of neutralizing, inactivating antibodies. Furthermore, different leptin formulations that would allow simpler dosage regimens would be welcomed, e.g. administration once weekly or monthly, or administration through alternative routes (transdermal, sublingually or per os). Other medications are also under consideration for the management of lipodystrophy and/or its manifestations, as summarized elsewhere in detail²⁴. These medications include, but are not limited to, insulin-like growth factor-1 against insulin resistance, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and angiopoietin-like 3 inhibitors (e.g. evinacumab) against hypercholesterolemia of lipodystrophy²⁴, or antisense oligonucleotide therapies targeting APOC3 mRNA (anti-APOC3; e.g. volanesorsen) against hypertriglyceridemia²⁵. It remains to be seen through interventional studies whether the pathways activated by leptin vs. the above compounds are overlapping or parallel and whether metreleptin could offer more benefits or not in combination with any of these, which should be the focus of future research efforts.

Leptin treatment may be also used in the acquired forms of lipodystrophy in the future, the most common one being that associated with HIV and the related highly active antiretroviral therapy²⁶. This may be also applied to other diseases characterized by relatively low leptin levels, including anorexia nervosa and hypothalamic amenorrhea²⁷; despite encouraging results of leptin replacement in these diseases, more and larger clinical trials are required to establish the efficacy and safety of metreleptin, or even safer leptin analogs. For example, there are concerns that leptin treatment in patients with anorexia nervosa or hypothalamic amenorrhea may result in further weight loss, but we have previously shown that there is a hierarchy of physiological responses to increasing leptin levels in the circulation with activation of the neuroendocrine axis occurring prior to any changes in energy homeostasis and that we can adjust circulating leptin levels by adjusting the dose of leptin administered²⁸.

4. Closing remarks

The discovery of leptin launched a new era in human pathophysiology, diagnosis and therapeutics. Despite initial high expectations, leptin treatment did not lead to significant weight loss in clinical trials of common obesity or favorable results in trials of metabolic syndrome-related comorbidities. However, leptin treatment was finally shown to be valuable in the management of lipodystrophy, a heterogeneous group of diseases characterized by high morbidity and mortality. Much remains to be discovered in the context of both basic and applied/clinical research and much is expected in terms of pharmaceutical technology and leptin formulations in the years to come.

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other relationships

SAP: None. CSM has been a shareholder of and reports grants through his institution and personal consulting fees from Coherus Inc and AltrixBio, grants through his institution from Merck, he reports grants through his institution and personal consulting fees from Novo Nordisk, reports personal consulting fees and support with research reagents from Ansh Inc, reports personal consulting fees from Genfit, Lumos, Amgen, Corcept, Intercept, Astra Zeneca and Regeneron, reports travel support and fees from TMIOA, Elsevier, the California Walnut Commission, College Internationale Researcher Servier and the Cardio Metabolic Health Conference. None is related to the work presented herein.

Author contributions

SAP: conception and design of the editorial, acquisition of data, interpretation of data, drafting the article and revising it critically for important intellectual content, final approval of the version to be submitted.

CSM: acquisition of data, interpretation of data, revising the manuscript critically for important intellectual content, final approval of the version to be submitted.