Metreleptin

Also known as Myalept, Myalepta, r-metHuLeptin, recombinant methionyl human leptin

Recombinant leptin analogue used as hormone replacement in lipodystrophy, not for common obesity.

clinically proven Metabolic & weight approved drug

At a glance

Category: Metabolic & weight
Status: approved drug
Made from: recombinant Recombinant methionyl human leptin, produced in Escherichia coli.
Route: subcutaneous, once or twice daily
Half-life: approximately 3.8-4.7 hours after subcutaneous administration in healthy subjects, with peak concentrations at about 4.0-4.3 hours 1
Onset: triglycerides and glycaemic markers improve within weeks; hepatic steatosis over months
Molecular weight: approximately 16.15 kDa 1
Sequence: 147-amino-acid recombinant analogue of human leptin, produced in E. coli, with an additional N-terminal methionine residue and a single disulfide bond

Approved by the FDA in February 2014 as Myalept for generalised lipodystrophy, and by the EMA in 2018 as Myalepta for generalised lipodystrophy and, in patients aged 12 and above, certain partial lipodystrophies. In the United States it is available only through a restricted distribution programme, the Myalept REMS Program, because of the risks associated with the development of anti-metreleptin antibodies 1. It is not approved and does not work for ordinary obesity.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Leptin is secreted by adipocytes in proportion to fat mass and signals energy sufficiency to the hypothalamus through the long form of the leptin receptor (LEPR, ObRb) and the JAK2-STAT3 pathway. In the arcuate nucleus it stimulates POMC/CART neurons and inhibits AgRP/NPY neurons, reducing food intake and permitting normal reproductive, thyroid and immune function.

In lipodystrophy, adipose tissue is largely absent or dysfunctional, so circulating leptin is very low. The brain reads this as starvation and drives intense hyperphagia, while lipid that cannot be stored in adipocytes accumulates ectopically in liver and muscle. The result is severe hypertriglyceridaemia, hepatic steatosis, and insulin resistance that is often refractory to conventional therapy.

Metreleptin corrects the deficiency rather than adding a supraphysiological signal. Restoring leptin suppresses hyperphagia, reduces hepatic de novo lipogenesis and VLDL output, improves insulin sensitivity and can markedly reduce liver fat. This is why it works in leptin-deficient states and does not work in common obesity, where leptin is already high and the brain is resistant to it.

Because metreleptin is a recombinant protein, patients can develop antibodies against it. Some of these antibodies neutralise both the drug and endogenous leptin, which can abolish efficacy and, in principle, worsen the underlying deficiency. This immunogenicity is the reason for one half of the boxed warning.

What the research shows

The evidence base is unusual: no conventional randomised placebo-controlled phase 3 trial was performed, because generalised lipodystrophy is extremely rare and withholding treatment was considered unacceptable. Approval rested mainly on a long-running open-label study at the US National Institutes of Health, begun in 2000, plus expanded-access data. The metabolic improvements are large and consistent, but they come from uncontrolled data.

Research in humans

The foundational report is the New England Journal of Medicine study of leptin-replacement therapy for lipodystrophy published in 2002, which showed substantial reductions in triglycerides and HbA1c in a small cohort 2. The NIH open-label cohort and its extensions, together with expanded-access programmes, provided the pivotal dataset of roughly 100 patients with generalised or partial lipodystrophy, reporting reductions in HbA1c of around 2 percentage points and in triglycerides of roughly 30-40% in generalised disease, along with reduced hepatic fat and reduced or discontinued insulin requirements. Results in partial lipodystrophy are more variable and generally smaller, which is reflected in the narrower EU indication.

Animal and lab research

The ob/ob mouse, which lacks functional leptin, is fully corrected by leptin administration; lipodystrophic mouse models similarly show reversal of hepatic steatosis and insulin resistance. This animal work directly predicted the human result and is unusually well aligned with it.

Caveats. Open-label and uncontrolled: no placebo arm, so placebo effects, regression to the mean and concurrent changes in diet and other medication cannot be fully separated. Cohorts are small and heterogeneous, mixing congenital and acquired forms. Long-term safety is monitored through a registry rather than a controlled trial. Cases of T-cell lymphoma in patients with acquired generalised lipodystrophy complicate causal attribution, because that condition itself carries lymphoma risk. Efficacy in partial lipodystrophy with near-normal leptin levels is poorly established.

What it is used for

Adjunct to diet as replacement therapy for the complications of leptin deficiency in generalised lipodystrophy, congenital or acquired 1
In the EU, also for certain partial lipodystrophies in patients aged 12 and above when standard treatments have failed
Investigated, without approval, in hypothalamic amenorrhoea and functional hypoleptinaemia, and historically in common obesity where it failed

Dosing

Dose

Body weight 40 kg or less: start at 0.06 mg/kg once daily, maximum 0.13 mg/kg. Above 40 kg: men start at 2.5 mg daily and women at 5 mg daily, with adjustment in steps and a maximum of 10 mg daily

Frequency

Once daily; the total daily dose is sometimes divided into two injections at higher doses

Route

Subcutaneous, into the abdomen, thigh or upper arm with site rotation

Duration

Long-term replacement therapy

Doses are titrated against metabolic response — triglycerides, HbA1c, fasting glucose — rather than against weight loss.
Insulin and other glucose-lowering drugs commonly need substantial reduction as insulin sensitivity improves, to avoid hypoglycaemia; the label notes that possibly large reductions may be necessary 1.
In the United States the drug is dispensed only through the Myalept REMS programme, with prescriber and pharmacy certification 1.
These figures are from the approved US and EU product information and describe supervised specialist treatment; they are not a self-administration protocol.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Myalept dosing by body weight (generalised lipodystrophy)

approved product information

Source: FDA prescribing information for Myalept (DailyMed)

Starting dose, body weight 40 kg or less	0.06 mg/kg subcutaneously once daily
Adjustment, body weight 40 kg or less	in 0.02 mg/kg steps, to a maximum of 0.13 mg/kg once daily
Starting dose, males over 40 kg	2.5 mg once daily
Starting dose, females over 40 kg	5 mg once daily
Adjustment, body weight over 40 kg	in 1.25 mg to 2.5 mg steps, to a maximum of 10 mg once daily

This is not a tolerability titration like the incretin ladders: the dose is set by body weight and sex, then adjusted on clinical response. Metreleptin is replacement therapy for generalised lipodystrophy and is not a weight-loss drug for common obesity.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes: 11.3 mg lyophilised powder per vial (delivering up to 5 mg per ml after reconstitution)
Solvent: Sterile water for injection for once-daily dosing, or bacteriostatic water for injection (0.9% benzyl alcohol) when a vial is to be used for two doses within the same day
Storage: Unreconstituted vials refrigerated at 2-8 °C, protected from light. Reconstituted with sterile water: use immediately and discard any remainder. Reconstituted with bacteriostatic water: refrigerated and used within three days.

Worked example

An 11.3 mg vial reconstituted with 2.2 ml of diluent yields approximately 5 mg/ml; a 5 mg dose is therefore 1 ml.

The vial is swirled gently, not shaken, and the solution should be clear. Bacteriostatic water containing benzyl alcohol must not be used in neonates or infants. The very short in-use stability compared with typical research peptides reflects the absence of preservative in the standard preparation.

Work it out for Metreleptin

Safety

Side effects

Development of anti-metreleptin antibodies, including antibodies with neutralising activity — the subject of the first half of the boxed warning 1
T-cell lymphoma, reported in patients with acquired generalised lipodystrophy both treated and untreated — the second half of the boxed warning 1
Hypoglycaemia, particularly when insulin doses are not reduced; hypoglycaemia is among the reactions reported in at least 10% of patients 1
Headache
Weight loss and reduced appetite
Abdominal pain, nausea, diarrhoea
Injection site reactions, including erythema and urticaria
Fatigue
Hypersensitivity reactions including anaphylaxis, urticaria and generalised rash, uncommon 1
Pancreatitis, typically in the context of pre-existing severe hypertriglyceridaemia and sometimes on abrupt discontinuation; the label recommends tapering the dose over one week in patients with pancreatitis risk factors 1

Do not use if

BOXED WARNING, part 1: anti-metreleptin antibodies with neutralising activity have been identified in treated patients. The label states that their consequences are not well characterised but could include inhibition of endogenous leptin action and loss of efficacy 1. Test for neutralising antibodies where efficacy is lost or severe infection occurs.
BOXED WARNING, part 2: T-cell lymphoma has been reported in patients with acquired generalised lipodystrophy, both treated and not treated with metreleptin. Weigh the benefits and risks carefully in patients with significant haematological abnormalities or acquired generalised lipodystrophy 1.
General obesity not associated with congenital leptin deficiency — one of only two contraindications in the US label 1
HIV-related lipodystrophy without confirmed generalised lipodystrophy
Metabolic disease including diabetes and hypertriglyceridaemia without concurrent evidence of congenital or acquired lipodystrophy
Hypersensitivity to metreleptin or to any of the product components — the other labelled contraindication 1
Pre-existing lymphoma; caution with significant haematological abnormalities such as lymphadenopathy or bone marrow abnormalities
Abrupt discontinuation risks rebound hypertriglyceridaemia and pancreatitis; tapering is advised

Interactions

Because metreleptin markedly improves insulin sensitivity, concurrent insulin and insulin secretagogues frequently require dose reduction — possibly a large one — to avoid hypoglycaemia 1. Leptin receptors are expressed on immune cells, and antibodies raised against metreleptin may cross-react with endogenous leptin, which complicates the response to other biologics and to infection; the label advises caution when co-administering other immunogenic biologics. The label states that leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 enzymes, and that this should be taken into account when prescribing concomitant drugs metabolised by CYP450, such as oral contraceptives and narrow-therapeutic-index agents 1; the effect has not been quantified in humans.

Sources

MYALEPT (metreleptin) for injection — US prescribing information, including boxed warningDailyMed, Chiesi USA, Inc.
Leptin-replacement therapy for lipodystrophyThe New England Journal of Medicine, 2002
Metreleptin and generalized lipodystrophy and evolving therapeutic perspectivesExpert Opinion on Biological Therapy, 2015
Metreleptin treatment of non-HIV lipodystrophy syndromesPresse Medicale, 2021
Myalepta (metreleptin) — EPAR, product informationEuropean Medicines Agency