Leptin in commercial form for insulin resistance

From UpToDate  Literature reviewed through March 2018

My comments in purple

LIPODYSTROPHIES AND INSULIN RESISTANCE — The results of studies of the pathogenesis of insulin resistance in the context of lipoatrophy have varied regarding the presence or absence of defects at the level of insulin receptor expression, function, and signaling 

Transgenic mice devoid of white adipose tissue have 

1-hypermetabolism, 

2-increased appetite,

3- hyperinsulinemia, 

4-diabetes, and 

5-hepatomegaly, 

i.e., phenotypes remarkably similar to those of humans with generalized lipodystrophy [54,55]. 

These mice have decreased expression of several molecules, including 

1-peroxisome proliferator-activator receptor gamma (PPARG), 

2-insulin receptors, 

3-insulin receptor substrates 1 and 2, and 

4-leptin, 

5-whereas expression of tumor necrosis factor alpha is increased. 

Thus, it has been proposed that possible mediators of insulin resistance in lipodystrophy include

1- increased tumor necrosis factor,

2- free fatty acids, or 

3-leptin and/or adiponectin deficiency 

In his interview with Dr. Gabor, Ivor Cummings referred to this fat transplant experiment in mice.

Transplantation of even small amounts of adipose tissue or leptin treatment in diabetic, insulin-resistant mice with lipodystrophy and low serum leptin concentrations results in improved glycemia and decreased serum insulin concentrations 

In addition, replacing either adiponectin or leptin in an animal model of lipodystrophy, insulin resistance, and the metabolic syndrome improves insulin resistance, whereas replacing both adiponectin and leptin fully normalizes insulin resistance. 

These results are consistent with the hypothesis that leptin, adiponectin, and/or other substances secreted by adipose tissue are critical mediators of insulin resistance but their role in humans remains to be fully elucidated.

TREATMENT OF LIPODYSTROPHY

General approach — The approach to treatment discussed below is based upon observational or interventional studies and clinical experience.

The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, diabetes, hypertriglyceridemia) is the same as in patients without lipodystrophy.

1-Lifestyle modification (appropriate diet and exercise as needed), 

2-metformin, and 

3-statins (and/orfibrates)

 are typically prescribed. 

Insulin or other antidiabetics (eg, thiazolidinediones, which increase adiponectin levels) can also be used if needed.

 If metabolic disturbances persist, one could potentially administer metreleptin to patients with acquired or congenital generalized lipodystrophy, as part of a Risk Evaluation and Mitigation Strategy (REMS) program, with careful monitoring. 

There are few data on the risks and benefits of metreleptin in this patient population. It is likely that more certainty regarding the risk-benefit ratio of using metreleptin will be obtained as results of the REMS program are published.

Persistent metabolic disturbances — For patients with acquired or congenital generalized lipodystrophy (not partial lipodystrophy) with persistent metabolic disturbances, one could potentially administer metreleptin, as part of an REMS program, with careful monitoring. The safety and efficacy of metreleptin (leptin analog) have only been evaluated in small numbers of patients with congenital or acquired generalized lipodystrophy.

Leptin (metreleptin by subcutaneous injection) is approved in Japan as a therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with congenital or acquired lipodystrophy. 

In 2014, the US Food and Drug Administration (FDA) approved metreleptin for injection, in conjunction with diet, to treat leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy. 

It is not approved for use in patients with human immunodeficiency virus (HIV)-related lipodystrophy or in patients with metabolic diseases (eg, diabetes mellitus and hypertriglyceridemia) or other lipodystrophies without concurrent evidence of generalized lipodystrophy.

 Metreleptin should not be used in patients with obesity, and it is not approved for partial lipodystrophy.

●Efficacy – Metreleptin is an analog of human leptin made through recombinant DNA technology. Leptin replacement therapy may be effective in patients with generalized lipodystrophy who are leptin-deficient. 

In open-label, non-randomized, uncontrolled studies that included small numbers of patients with congenital or acquired generalized lipodystrophy who had diabetes, hypertriglyceridemia, and/or elevated levels of fasting insulin, recombinant leptin administered subcutaneously once or twice daily for up to 12 months to achieve physiologic serum leptin concentrations resulted in significant clinical improvements. 

The studies showed reductions in glycated hemoglobin (A1C), fasting glucose, and triglycerides. 

In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis. Satiation (time to voluntary cessation of eating) and satiety (inter-meal interval) also improved with exogenous leptin therapy.

 Long-term (12 months) recombinant human leptin therapy was effective in treating insulin resistance in two subjects with type 1 diabetes and acquired lipodystrophy with insulin resistance.

Randomized trials of metreleptin in patients with various metabolic abnormalities and lipodystrophy are necessary to confirm its therapeutic role, mechanism of action, and longer-term safety.

●Adverse effects – The most common side effects observed in patients treated with metreleptin were fatigue, hypoglycemia, headache, decreased weight, and abdominal pain [2,65]. The development of non-neutralizing and, rarely, neutralizing antibodies to leptin has been reported [71,72]. Development of neutralizing antibodies is the reason underlying the FDA's restriction of metreleptin use exclusively to subjects with generalized lipodystrophy who have minimal, if any, circulating leptin levels to start with. In addition, the development of T-cell lymphoma has been described in patients with acquired lipodystrophy who had immunodeficiency before beginning metreleptin [65,71,75].

●REMS program – Given the reported risk for development of neutralizing antibodies and lymphoma, metreleptin is available in the United States only through an REMS program. 

Under this REMS program, prescribers must be certified by enrolling in and completing specific training. Pharmacies must also be certified and only dispense metreleptin after receipt of the REMS Prescription Authorization Form for each new prescription. Metreleptin will be accompanied by a medication guide and instructions for use that provide patients with important information about the medication, which will be distributed each time a patient fills a prescription. Health care professionals should carefully consider the benefits and risks of treatment with metreleptin in lipodystrophy.