METRE-PL Data Shows Severe Metabolic Disease Burden in FPLD Despite Standard Therapy

Baseline data from METRE-PL, the first placebo-controlled clinical study to evaluate the therapeutic efficacy and safety of metreleptin in familial partial lipodystrophy (FPLD), identified a substantial metabolic disease burden in this patient population, including diabetes and hypertriglyceridemia, despite extensive use of antidiabetic and lipid-lowering therapies.

These data were presented at the Endocrine Society (ENDO) Annual Meeting 2026, with the ongoing global trial evaluating change from baseline in HbA1c and percent change in triglycerides (TG) at Month 6 in those with baseline HbA1c ≥7% and baseline TG ≥500 mg/dL, respectively. Safety is being assessed throughout the 12-month treatment period and during post-treatment follow-up.

Senior author and primary investigator Lindsay Fourman, MD, endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, spoke with HCPLive about the unmet need and multisystem metabolic dysfunction experienced by patients with FPLD.

“We've already tried all the usual conventional medications, and most patients are on multiple medications to treat diabetes and lipids prior to getting into the study, and despite this, like optimal medical therapy that we've tried, they still have such poorly controlled disease,” Fourman said.

Lipodystrophies constitute a group of rare, heterogeneous disorders characterized by partial or generalized deficiency of adipose tissue, while FPLD is a form of congenital lipodystrophy. The disease prevalence of FPLD has been estimated at around 1 in 100,000. Accumulating evidence in recent years has shown that a patient’s phenotype is not merely dependent on a specific genetic mutation, but is also defined by a combination of demographic (age, sex), environmental, and genetic factors.

Metreleptin is a recombinant analog of the human hormone leptin, functioning as replacement therapy in patients with leptin deficiency. By binding to leptin receptors in the hypothalamus, it mimics natural leptin signaling, which helps regulate appetite, restore energy balance, and improve metabolic processing of glucose and lipids.

In conditions like lipodystrophy, severe leptin deficiency leads to ectopic fat storage (lipotoxicity), insulin resistance, and hypertriglyceridemia. Metreleptin may reverse these metabolic complications by increasing insulin sensitivity, lowering HbA1c levels, and reducing circulating triglycerides.

The US Food and Drug Administration (FDA) approved metreleptin, alongside diet, for the treatment of metabolic complications of leptin deficiency in generalized lipodystrophy, but not partial lipodystrophy (PL). FPLD, a genetic form of PL, therefore does not have an FDA-approved therapy.

“While there is some data that it does help in these populations, there's never been a randomized study to demonstrate that, and so this is an important stepping stone towards demonstrating efficacy and safety, and potentially changing the way that we treat partial lipodystrophy,” said Fourman.

Fourman and colleagues are conducting the 12-month, randomized, multicenter, double-blind, placebo-controlled phase 3 study, with patients from 22 sites across 7 countries, randomized in a 1:1 ratio to receive metreleptin (maximum dose, 10 mg/day) or placebo.

METRE-PL includes 69 patients ≥12 years of age with an established diagnosis of FPLD and metabolic abnormalities (HbA1c ≥7% and/or fasting triglycerides (TG) ≥500 mg/dL) despite optimized and stable medical treatment. Key exclusion criteria included prior metreleptin treatment, leptin levels >20 ng/mL, acquired partial lipodystrophy, and HIV-associated lipodystrophy.

At baseline, 93% of patients had diabetes and 83% had hypertriglyceridemia. Pancreatitis and diabetic neuropathy each affected 29% of patients and were identified as the most common end-organ complications.

Among patients, mean HbA1c was 8.6% (±1.53; 4.9–12.9), and mean triglycerides were 696 mg/dL (±1001.1; 81–5487). Median leptin value was 8.3 ng/mL. In total, 96% of patients were taking ≥1 antidiabetic therapy and 91% were taking ≥1 lipid-lowering therapy.

Fourman told HCPLive that METRE-PL has just finished enrolling and that the final participant will complete the study this summer, with data expected in the fall.

Editor’s Note: Fourman reports relevant disclosures with Theratechnologies, Chiesi Farmaceutici, and Rhythm Pharmaceuticals.

References

1. Oral EA, Fourman LT, Montenegro RM Jr, et al. A 12-month randomized, multicenter, double-blind, placebo-controlled phase 3 study to evaluate the safety and efficacy of metreleptin in subjects with partial lipodystrophy: the METRE-PL study. Presented at: Endocrine Society Annual Meeting (ENDO 2026); June 14, 2026.

2. PubChem. Metreleptin. Nih.gov. Published 2026. Accessed June 24, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/Metreleptin

3. Aikaterini Kountouri, Emmanouil Korakas, Eirini Maratou, et al. Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center. International Journal of Molecular Sciences. 2023;24(15):12045-12045. doi:https://doi.org/10.3390/ijms241512045