Lindsay Fourman, MD, is an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School

Lindsay Fourman, MD

When to Add GLP-1 Receptor Agonists to Metreleptin in Lipodystrophy, With Lindsay Fourman, MD

"If a patient is on metreleptin and you're looking to add another agent, a GLP-1 receptor agonist might be a good option,” Lindsay Fourman, MD, endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told 

The comments come alongside new real-world data presented at 

Endocrine Society (ENDO) Annual Meeting 2026

, showing that nearly 1 in 5 adults receiving sustained metreleptin therapy for lipodystrophy subsequently initiated sustained GLP-1 receptor agonist therapy. While the descriptive analysis did not assess efficacy, it highlights growing clinical adoption of the combination and the need for prospective studies.

Metreleptin is approved by the US Food and Drug Administration (FDA) as leptin replacement therapy for complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

Since lipodystrophy is associated with severe insulin resistance, diabetes, hypertriglyceridemia, and ectopic fat accumulation, investigators have begun exploring GLP-1 receptor agonists as adjunctive therapy. Early retrospective and preclinical data suggest these agents may improve metabolic outcomes, supporting interest in combination treatment with metreleptin, although the available evidence remains limited and largely observational.

While the rationale for combination therapy includes potential metabolic benefits, clinicians should consider patients’ baseline health status, including pancreatitis risk and elevated triglyceride levels.

“In terms of who you'd hesitate with, there is this kind of cloud around the question of pancreatitis. A lot of data speaks against it now, so we're not so worried about pancreatitis with GLP-1s, but it is a little bit of a hesitation. If a patient just had pancreatitis, I would give it some time for resolution of that episode before starting. I might wait 6 months or something. I also try to get triglycerides down because that can be the trigger for pancreatitis.”

Once a GLP-1 receptor agonist has been initiated in a patient receiving metreleptin therapy, Fourman emphasized the importance of ongoing monitoring. Since metreleptin has been associated with hypoglycemia, blood glucose should be closely tracked, and she recommended the use of a continuous glucose monitor during titration for safety.

Ultimately, Fourman noted that case series suggest GLP-1 receptor agonist monotherapy in lipodystrophy may reduce HbA1c by about 1 to 2%, while combination therapy with metreleptin has been associated with reductions of 2 to 3% or greater in some cases, suggesting a response that may be more synergistic than simply additive. However, she emphasized that additional data are needed before the combination can be incorporated into routine clinical practice.

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

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.

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

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Real-world data highlight GLP-1 receptor agonist use with metreleptin in lipodystrophy and clinician guidance on timing and safety monitoring.

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

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 

, 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 

 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.”

Metreleptin (Myalept) is a recombinant analog of human leptin approved by the 

 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.

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 

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 (

 = .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.

Lindsay Fourman, MD, discusses early real-world data exploring the use of GLP-1 receptor agonists alongside metreleptin in lipodystrophy.

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

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 

 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.

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.

PubChem. Metreleptin. Nih.gov. Published 2026. Accessed June 24, 2026. 

https://pubchem.ncbi.nlm.nih.gov/compound/Metreleptin

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

First placebo-controlled phase 3 METRE-PL data show prevalent metabolic burden in familial partial lipodystrophy (FPLD) despite standard therapy.


Lindsay Fourman, MD

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