Metabolic Improvements with Tirzepatide in Lipodystrophy: A Novel Option?

Objective: Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal fat distribution, with near-total (generalized lipodystrophy, GL) or partial (partial lipodystrophy, PL; e.g. familial partial lipodystrophy, FPLD) absence of adipocyte mass leading to a decreased ability to store lipids safely. Excess lipids are more likely to be stored in non-adipose tissues, which leads to the metabolic manifestations. We have recently shown that glucagon-like peptide-1 agonists are associated with metabolic improvements in FPLD. Here we hypothesize that tirzepatide, a dual incretin, may also lead to metabolic improvement in patients with lipodystrophy. Research Design and Methods: Observational cohort of patients with lipodystrophy who received tirzepatide clinically were tracked in the context of ongoing natural history studies. Results: Seventeen patients received tirzepatide, 14 with FPLD (ages within 30-74 years; 12 female 2 male). After a median 8.7 months of follow-up, BMI (medianΔ -1.7; range -5.9 to 0.9 kg/m2; p=0.008), HbA1c (medianΔ -1.1%; range -6.3 to -0.1%; p<0.001), triglycerides [medianΔ -65 mg/dL (-0.73 mmol/L); range -3820 to 43 mg/dL (-43.2 to 0.49 mmol/L); p=0.003] and total daily insulin requirements (medianΔ -109; range -315 to 0 units/day; p=0.002) were significantly reduced. Three additional patients with rarer forms of lipodystrophy, also with robust response to tirzepatide, are also discussed (atypical partial lipodystrophy, n=1; acquired GL; n=2; ages within 35-64 years; all female). Side effects were limited to benign gastrointestinal symptoms. Conclusions: Tirzepatide may be an effective treatment for patients with lipodystrophy.