Leptin Analog for treatment of lipodystrophy - now available in Canada!

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Lipodystrophy refers to a group of ultra-rare congenital (born with) or acquired conditions characterized by either complete or partial lack of adipose (fat) tissue. Given that these individuals are lacking fat, it seems perhaps paradoxical that people with lipodystrophy often have severe metabolic problems, including severe insulin resistance and diabetes, severely elevated triglycerides (a type of cholesterol), and fatty liver disease, which are health issues that we typically associate with excess fat tissue (obesity).

The reason why lipodystrophy is associated with severe metabolic disease is becase fat cannot collect in fat tissue, so instead, fat collects in places that were not meant to store fat such as the liver and muscles, called ectopic depots. Overflow of fat deposits into ectopic tissues leads to insulin resistance, diabetes, high cholesterol, and fatty liver disease. The deficiency of fat tissue also results in very low levels of a hormone called leptin, which is normally produced by fat tissue. Leptin works to signal overall body energy availability, suppressing glucose production by the liver, promoting sugar uptake in muscle, and promoting fatty acid oxidation in liver, muscle and fat. Thus, leptin deficiency contributes to the metabolic abnormalities of lipodystrophy. Leptin is also one of our satiety hormones, telling our brain that we feel full. Thus, people with generalized lipodystrophy have voracious insatiable hunger, called hyperphagia.

Metreleptin (trade name Myalepta) is a human leptin analog, now approved and available in Canada for treatment of generalized lipodystrophy (congenital or acquired) in adults or kids age 2 or older, and for familial or acquired partial lipodystrophy in adults or kids age 12 or older, with significant associated metabolic disease. It is given as a daily subcutaneous injection (under the skin).

In a cohort of 66 patients aged 6 months or older with generalized lipodystrophy, low leptin, and at least one of diabetes, insulin resistance, or high triglycerides, the effect of metreleptin was assessed. At one year, A1c was reduced by a mean of -2.2%, triglycerides were reduced by 32%, and liver volume was decreased by -34% (due to fat coming out of the liver). Weight decreased by a mean of about -2.5kg at one year. Many patients were able to stop insulin, diabetes medication, and cholesterol medication. Hypoglycemia (all were also on insulin) and decreased appetite were noted as side effects.

People with acquired generalized lipodystrophy are at higher risk of lymphoma, likely due to underlying autoimmunity. Over the 14 year long term follow up, three cases of lymphoma developed, one of which was assessed as treatment related. There is a warning on the product monograph that T-cell lymphoma has been reported in people with acquired generalized lipodystrophy, both treated and not treated with metreleptin.

In 41 people with partial lipodystrophy age 6 months or older with leptin levels <12 ng/mL and diabetes, insulin resistance, or elevated triglycerides, metreleptin was admistered in a long term study, with effect on metabolic parameters evaluated at one year. In the subgroups with higher A1c (>6.5%) or triglycerides (>5.65 mmol/L) at baseline, statistically significant improvements in A1c (-0.9%), triglycerides (-37.4%), fasting glucose (-1.9mmol/L), and liver volume (-12.4%) were seen. None of the 19 patients who received insulin at baseline were able to discontinue it after starting metreleptin. Only 1/28 people on oral diabetes medication and 1/34 people on cholesterol medication were able to discontinue these medications. The most common side effects reported were abdominal pain, hypoglycemia (only seen in those on insulin), and nausea, and were mostly mild to moderate in severity. There were no cases of lymphoma in this study.

Anti-metreleptin antibodies with neutralizing activity have been identfied in people taking metreleptin, which could result in loss of effect of the medication. It is possible that neutralizing antibodies may develop at a time of a severe or serious infection. Thus, it is recommended to test for these antibodies if loss of effect or severe infection occurs while taking metreleptin.

Important note: people with obesity have high leptin levels and leptin resistance, so metreleptin is not an appropriate treatment for people with obesity.

BOTTOM LINE: Metreleptin is an exciting and effective new treatment that can provide impressive metabolic benefits for people with lipodystrophy.

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