RPB

Leptin

metreleptin (recombinant methionyl human leptin), Myalept (US brand), Myalepta (EU brand), r-metHuLeptin, OB protein, LEP gene product

Metabolic & weight
Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates
Note on this profile. Metreleptin is an approved prescription medicine for a rare condition (lipodystrophy) in the US, EU, UK and Japan, not a research-only compound. It is dispensed under restricted programmes because of serious risks described below. This page explains the published science; use outside those programmes is unapproved and, for the common goal of weight loss in people with normal leptin, has been shown not to work.

1What it is

Leptin is a hormone released by fat tissue in proportion to how much fat there is. It was discovered in 1994 when the gene behind the massively obese ob/ob mouse was cloned (Zhang 1994, Nature); those mice lack leptin and giving it back cured their obesity, which triggered hopes of a human obesity drug. Those hopes were disappointed: most people with obesity already have high leptin and are resistant to it, and injecting more produced only small, dose-related weight loss (Heymsfield 1999, JAMA).

Where leptin replacement does work is in people who genuinely lack it: the rare children with congenital leptin deficiency (Farooqi 1999, NEJM), and people with lipodystrophy, who have too little fat tissue to make it and suffer severe insulin resistance, very high triglycerides and fatty liver as a result. Metreleptin was approved in the US in 2014 for generalised lipodystrophy and in the EU in 2018 for generalised and some partial lipodystrophy. It is a naturally occurring hormone, manufactured as a recombinant protein.

2How it's thought to work

Leptin crosses into the hypothalamus and acts on leptin receptors (LepRb), stimulating POMC neurons (which reduce appetite) and inhibiting NPY/AgRP neurons (which drive it) — the mirror image of ghrelin (#118).
Low leptin is read by the brain as starvation: appetite rises, metabolic rate, thyroid hormone, reproductive hormones and sympathetic tone fall. Replacement reverses these when leptin is truly low.
In lipodystrophy it also acts peripherally and centrally to lower triglycerides, reduce liver fat and improve insulin sensitivity, partly by reducing food intake and partly by direct metabolic signalling.
In common obesity, high leptin fails to suppress appetite ("leptin resistance"), proposed to involve impaired transport into the brain and SOCS3-mediated signalling blockade; this is why extra leptin does little.
After diet-induced weight loss, leptin falls disproportionately and drives the familiar hunger and reduced energy expenditure; restoring leptin to pre-diet levels reverses much of this in small studies (Rosenbaum 2005, J Clin Invest).
Leptin released by fat tissue in proportion to how much of it there is, read by receptors in the hypothalamus. It is the signal that the store is full. In common obesity the signal is present but acted on weakly, which is what leptin resistance describes.Schematic — not to scale

3What the research shows

Graded A/B

Lipodystrophy (approved indication)

The pivotal evidence is a long-running open-label NIH study (begun 2000) in patients with generalised and partial lipodystrophy: metreleptin reduced HbA1c by roughly 2 percentage points and triglycerides by around 30–60%, reduced liver fat and liver enzymes, and reduced need for insulin and other diabetes medicines (Oral 2002, NEJM; Brown 2018, J Clin Endocrinol Metab for long-term data). Approval rested mainly on this open-label, single-arm evidence because the disease is too rare for large ; small controlled sub-studies and a 2018 EMA assessment support it. [4][5]

Congenital leptin deficiency

Case series of children and adults with LEP mutations show dramatic, sustained weight loss, normalised appetite and onset of puberty with replacement (Farooqi 1999 and 2002, NEJM/J Clin Invest). Tiny numbers, but an unambiguous effect in a condition that is otherwise untreatable. [3]
Graded A (negative/minimal)

Common obesity

A dose-ranging RCT in 73 lean and obese adults found only modest, dose-dependent weight loss at the highest dose (around 7 kg over 24 weeks at 0.3 mg/kg vs 1.3 kg with placebo) with frequent injection-site reactions (Heymsfield 1999, JAMA). Subsequent studies, including pegylated leptin, were unimpressive. Leptin is not an obesity drug for people with normal or high leptin. [2]

Weight-loss maintenance

Small, mechanistically elegant studies show that low-dose leptin given after a 10% diet-induced weight loss reverses the drop in energy expenditure, thyroid hormone and sympathetic tone, and normalises brain responses to food (Rosenbaum 2005, J Clin Invest; Rosenbaum 2008, J Clin Invest). Not developed into a product. [6]
Graded A (small)

Hypothalamic amenorrhoea

In women with exercise- or low-weight-related loss of periods, metreleptin restored LH pulsatility, ovulation in some, and improved bone markers over 3 months (Welt 2004, NEJM; Chou 2011, PNAS). Not an approved use. [7][8]
Graded B/C

Type 1 diabetes, NASH, anorexia nervosa

Small pilots and rodent work; a pilot in anorexia nervosa reported improved mood and activity-drive with short-term metreleptin (2020–2023, small open series). Early-stage.

4Reported side effects and interactions

Literature-reported

Literature (approved use). injection-site reactions, headache, hypoglycaemia (in patients also on insulin or sulfonylureas), weight loss, abdominal pain, fatigue. Two boxed warnings in the US label: (1) development of anti-metreleptin neutralising antibodies, which can cancel the drug's effect and, in some cases, neutralise the patient's own leptin, with severe infections and worsening metabolic control reported; (2) T-cell lymphoma, reported in a small number of patients with acquired generalised lipodystrophy, a condition that itself carries lymphoma risk — causality is unresolved. Hypersensitivity reactions including anaphylaxis have occurred. Autoimmune disease flares (autoimmune hepatitis, glomerulonephritis) are described.

Community-reported

essentially no community use outside prescription, given the price and restricted distribution; occasional reports from people using it for fat loss describe only injection-site reactions and no benefit, consistent with the trials.

Theoretical. immune-stimulating and pro-proliferative actions of leptin on T cells and some cancers; pregnancy data very limited.

Interactions. insulin and sulfonylureas (hypoglycaemia — doses often need cutting substantially as sensitivity returns); may alter metabolism of CYP450-substrate drugs as inflammation and metabolic state change — narrow-margin drugs are monitored; hormonal contraceptives (efficacy may change; label advises monitoring).

Markers researchers commonly monitor

These follow the label and the lipodystrophy trial protocols:

MarkerWhy it's watched
HbA1c, fasting glucose and home glucosethe primary efficacy measure, and the main safety one for anyone also on insulin.
Fasting triglycerides and full lipid paneltriglycerides often fall dramatically; the second key efficacy marker.
Liver enzymes (ALT/AST) and liver fat imagingfatty liver improves; autoimmune hepatitis is a described adverse event.
Anti-metreleptin antibodies and neutralising activityon clinician request if efficacy is lost or infections increase.
CBC with differentialfor the lymphoma and infection signals, and general safety.
Fasting leptin level (before starting)confirms genuine deficiency; a normal or high level predicts little benefit.
Reproductive hormones (LH, FSH, oestradiol/testosterone)restored in deficiency states.
Body weight and food intakeweight loss is expected and can be excessive in thin patients.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

The approved product is a single-dose vial containing 11.3 mg of metreleptin, with 2.2 ml of water for injection to give 5 mg/ml. With the vial can be kept refrigerated and used over up to 3 days; with sterile water it is used once. Doses are small volumes of a concentrated protein, so draw-up accuracy matters; the label uses mg and the syringe reads ml, which is a common source of error. Do not shake.

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6Commonly studied alongside

Insulin and other diabetes medicines (doses fall as metreleptin works); GLP-1 agonists such as semaglutide (#3) and setmelanotide (which acts downstream of leptin on the MC4R pathway) in obesity research; ghrelin (#118) as its physiological opposite; amylin analogues (pramlintide) in a combination obesity programme that was abandoned.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

RegionStatus (checked —)
United StatesFDA-approved (Myalept, 2014) for complications of leptin deficiency in congenital or acquired generalised lipodystrophy; available only through the Myalept REMS programme; explicitly not approved for partial lipodystrophy, HIV-related lipodystrophy or general obesity
European UnionEMA-authorised (Myalepta, 2018) for generalised lipodystrophy from age 2 and partial lipodystrophy from age 12 with specified metabolic criteria; orphan medicine
United KingdomMHRA-licensed (Myalepta); prescription-only via specialist centres
AustraliaNot registered with the TGA as of review; access via special schemes †
South AfricaNot registered †
SportNot specifically listed by WADA; check current list †

8Open questions

  • Why neutralising antibodies develop in some patients and how to predict them.
  • Whether the lymphoma signal is caused by the drug or the underlying disease.
  • Whether low-dose leptin after dieting can prevent weight regain in ordinary obesity at an acceptable cost and risk.
  • Role in anorexia nervosa and hypothalamic amenorrhoea, where small trials are promising but unapproved.

9References

  1. 1Zhang Y et al. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature. PubMed · DOI
  2. 2Heymsfield SB et al. (1999). Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. PubMed · DOI
  3. 3Farooqi IS et al. (1999). Effects of recombinant leptin therapy in a child with congenital leptin deficiency. NEJM. PubMed · DOI
  4. 4Oral EA et al. (2002). Leptin-replacement therapy for lipodystrophy. NEJM. PubMed · DOI
  5. 5Brown RJ et al. (2018). Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. J Clin Endocrinol Metab (or Endocrine; verify). PubMed · DOI
  6. 6Rosenbaum M et al. (2005). Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. PubMed · DOI
  7. 7Welt CK et al. (2004). Recombinant human leptin in women with hypothalamic amenorrhea. NEJM. PubMed · DOI
  8. 8Chou SH et al. (2011). Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci USA. PubMed · DOI
  9. 9Amryt / Chiesi. Myalept / Myalepta prescribing information and EMA EPAR (current label). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

26 Oct 2026Profile published — awaiting medical review

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