Tirzepatide Could Replace Daily Hormone Shots for Rare Genetic Fat Disorder

A once-weekly injection of tirzepatide could replace daily hormone shots for patients with congenital generalized lipodystrophy (CGL), a rare genetic disorder leaving patients with nearly zero fat tissue, according to a new study.1

Current standard-of-care for CGL centers around daily injections of metreleptin, a synthetic form of naturally occurring leptin approved by the US Food and Drug Administration (FDA), but issues in daily use, including a substantial price tag and severe pain stemming from lack of fat, can make administration difficult for patients with the rare disorder.

“Leptin is an important hormone, made only by fat tissue, that is an important regulator of metabolism, so leptin therapy made intuitive sense in patients with CGL,” said senior author Christopher Buettner, MD, PhD, chief of endocrinology, metabolism, and nutrition at Rutgers Robert Wood Johnson Medical School.2 “The hormone GLP1, which is mimicked by tirzepatide, is not made in adipose tissue, and while tirzepatide is an insulin sensitizer, we did not expect it would have such potency in patients with CGL.”

Affecting only a few thousand globally, CGL is a rare autosomal recessive disorder characterized by an absence of adipose tissue beginning at birth. This absence of tissue, and a resultant leptin deficiency, can result in severe metabolic disease and diabetes due to insulin resistance. Individuals with CGL experience greater degrees of hepatic steatosis and hypertriglyceridemia than people with partial lipodystrophy.3

“These patients are severely ill and face markedly reduced life expectancy due to profound insulin resistance,” Buettner added.2

In this study, Buettner and colleagues investigated tirzepatide, a dual GLP-1/GIP agonist FDA-cleared as an adjunct to diet and exercise for both type 2 diabetes and chronic weight management, on CGL, given the drug’s beneficial effect on insulin resistance.1 The team also pointed to the potential of once-weekly administration of tirzepatide to reduce pain linked to CGL treatment, and its cost, citing its affordability versus metreleptin.

The study reported on 2 patients with CGL type 1 due to a variant in AGPAT2, a highly prevalent variant among people of African descent. The first, a 23-year-old Black man (body mass index [BMI], 23), presented with a low plasma leptin level (0.5 ng/mL), a high glycated hemoglobin level (14.7%), an elevated triglyceride level (238 mg/dL), and an elevated C-peptide level (7.06 ng/mL).

At 21 years old, this patient was hospitalized for hyperglycemia without diabetic ketoacidosis and restarted insulin and metreleptin after previous intermittent treatment. In the years since discharge, all treatments were declined owing to the pain of injections. The patient agreed to once-weekly tirzepatide monotherapy, receiving 2.5 mg, 5 mg, 7.5 mg, and 15 mg over 4 weeks.

Upon analysis, treatment with the 2.5 mg, 5 mg, and 7.5 mg tirzepatide doses did not decrease glucose levels, but insulin sensitivity improved, based on decreasing C-peptide levels. Increasing the dose to 15 mg per week led to glucose levels normalizing rapidly within the target range. Reducing the dose to 7.5 mg, based on commercial unavailability, increased glucose levels, but a return to the 15 mg weekly dose normalized glucose levels.

Overall, Buettner and colleagues identified a dose-dependent effect, with 3 weeks of 15 mg tirzepatide treatment improving the patient’s average glucose level from 252 mg/dL to 128 mg/dL, with the percentage of glucose levels in the target range increasing from 8% to 93%.

The second patient, a 64-year-old woman, achieved well-controlled glucose levels with metreleptin, insulin detemir, and insulin lispro, but sought alternative therapy to reduce injection burden. Investigators initiated tirzepatide and tapered the patient’s insulin regimen as the dose increased to 15 mg per week when all insulin therapy ceased.

After a single week of tirzepatide 15 mg monotherapy, the average glucose level was 129 mg/dL and 99% of glucose values were within the target range, without additional insulin therapy. However, Buettner and colleagues noted the patient stopped tirzepatide therapy after experiencing diarrhea, which resolved within 1 week.

“The surprise here was that when we stopped leptin and gave tirzepatide, the patient was very well-controlled, probably better than while she was taking leptin,” Buettner concluded.2

Based on these care reports, once-weekly tirzepatide monotherapy achieved glycemic control without the need for additional insulin therapy, but Buettner and colleagues called for further trials to assess the long-term efficacy and safety in CGL and other leptin-deficient conditions.1

References

1. Ten S, Bhangoo A, Buettner C. Tirzepatide for Congenital Generalized Lipodystrophy. The New England Journal of Medicine. January 29, 2025. Accessed February 1, 2025. https://www.nejm.org/doi/full/10.1056/NEJMc2413871.
2. RutgersU. A weekly injection could replace painful daily treatment for rare fat disorder. EurekAlert! January 29, 2025. Accessed January 31, 2025. https://www.eurekalert.org/news-releases/1071960.
3. Quinn K, Chauhan S, Purcell SM. Lipodystrophies. [Updated 2023 Jun 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459180/