Synergy Between Metreleptin and GLP-1 Receptor Agonists in Lipodystrophy Real-World Data Suggest

Metreleptin (Myalept) is a recombinant analog of human leptin approved by the US Food and Drug Administration (FDA) as replacement therapy, in conjunction with diet, for the treatment of complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

Lipodystrophy is a rare group of metabolic disorders characterized by partial or complete loss of subcutaneous adipose tissue. As a result of impaired fat storage capacity, patients develop ectopic fat deposition and, in many cases, relative leptin deficiency. This leads to severe metabolic complications, including marked insulin resistance, difficult-to-manage diabetes, hypertriglyceridemia, and an increased risk of cardiovascular disease.

A real-world analysis evaluating sustained GLP-1 receptor agonist (GLP-1RA) therapy initiated on a background of ongoing metreleptin treatment among adults with lipodystrophy was presented at the Endocrine Society (ENDO) Annual Meeting 2026, suggesting a rationale for the clinical combination.

“We've actually seen in some case series, and from some preliminary data, that there seems to be a potential synergy between metreleptin and GLP-1 receptor agonists,” Lindsay Fourman, MD, endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told HCPLive on site at the conference. “There are some animal data as well that show there are receptors in the brain where both GLP-1 and leptin signaling pathways overlap, so there is this potential kind of crosstalk or synergy between them.”

GLP-1 receptor agonists have been explored as a potential treatment option in partial lipodystrophy, with retrospective analyses suggesting improvements in weight and HbA1c, and potential benefit in addressing key metabolic disturbances associated with the disease. Similar metabolic improvements have also been observed in preclinical mouse models of generalized lipodystrophy.

“It seems like from some case series that the effect of a GLP-1 receptor agonist alone in lipodystrophy may be a reduction in HbA1c of about 1 to 2 percent,” Fourman said. “But the combination in some of the cases we've seen appears to be more in the range of 2 to 3 percent, and even higher in some instances. So it's not just an additive effect, but actually something that looks more like a synergistic response rather than simply layering the effects of each agent.”

Despite an emerging biologic rationale for combination therapy with metreleptin and GLP-1RA agents, clinical evidence remains limited.

To address this gap, Fourman and colleagues conducted a descriptive real-world analysis using Komodo Healthcare claims data from 2016 to 2025 among adults aged ≥20 years with lipodystrophy, defined by ≥4 claims for each medication of interest. The index date was defined as the last observed metreleptin claim for the monotherapy group and the last metreleptin claim prior to GLP-1RA initiation for the combination therapy group, to better align patients at a comparable stage of treatment. Metabolic comorbidities were identified using diagnosis codes. Between-group comparisons were performed using Fisher exact tests, with statistical significance defined as P <.05.

Among 125 adults with lipodystrophy receiving sustained metreleptin therapy, 22 (18%) subsequently initiated and maintained add-on GLP-1RA therapy. Those receiving combination therapy were older, with 45% aged 50 years or older compared with 22% among those on metreleptin monotherapy (P = .03). Sex distribution was similar, with women comprising 82% of the combination cohort and 85% of the monotherapy cohort. Baseline metabolic comorbidities were broadly comparable between groups, including diabetes (95% vs. 80%), dyslipidemia (91% vs. 83%), metabolic dysfunction-associated steatotic liver disease (59% vs. 51%), cardiovascular disease (36% vs. 34%), and prior pancreatitis (32% vs. 38%).

Overall, the findings suggest that while combination metreleptin and GLP-1RA therapy is being used in clinical practice, its use remains limited and largely exploratory. Fourman emphasized that prospective studies are needed to better define the safety, efficacy, and optimal patient selection for combination therapy in lipodystrophy.

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

References

1. Fourman T, Berria R, Zadeh E, et al. Real-World Prescribing Patterns of Combined Metreleptin and GLP-1 Receptor Agonist Therapy in Adults with Lipodystrophy. Poster presented at: Endocrine Society; June 13-17, 2026; Chicago, Ill.

2. Lebenthal Y, Halperin S, Interator H, Brener A, Brown R. American Diabetes Association. Published March 19, 2025. Accessed June 26, 2026. https://diabetesjournals.org/care/article/48/5/e71/158022/Oral-Glucagon-Like-Peptide-1-Analog-as-an-Adjuvant