SUN-233 - Improvement of Severe Hypertriglyceridemia with Semaglutide in A Patient with Type 2 Diabetes Mellitus and Mitochondrial Fusion Protein-Related Lipodystrophy- A Case Report

Introduction:
Management of severe hypertriglyceridemia in the setting of lipodystrophy and mitochondrial disease remains challenging, as triglyceride levels often respond poorly to conventional lipid-lowering therapies, including statins, fibrates, and omega-3 fatty acids. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated pleiotropic metabolic effects that extend beyond glucose regulation, with emerging evidence supporting potential benefits in lipid metabolism and adipose tissue dysfunction. However, evidence supporting their use in lipodystrophy-related hypertriglyceridemia remains limited.

Case Presentation:
We describe the case of a 46-year-old woman with Charcot-Marie-Tooth disease, longstanding hyperchylomicronemia, and type 2 diabetes mellitus who exhibited persistently severe hypertriglyceridemia despite various pharmacologic therapies and lifestyle modification. She had no known familial hypertriglyceridemia and no personal history of pancreatitis. Triglyceride levels peaked at approximately 2900 mg/dL in 2020 and remained markedly elevated despite treatment with high-intensity statins, fibrates, omega-3 fatty acids, and alirocumab, measuring 1531 mg/dL in 2022. In 2023, physical examination was remarkable for reduced subcutaneous fat in the face and extremities with relative central adiposity concerning for lipodystrophy, along with imaging evidence of hepatic steatosis. Pioglitazone was added, and a partial improvement in triglyceride levels to 685 mg/dL was noted. Given ongoing metabolic instability, the case was reviewed with investigators at the National Institutes of Health in January 2024, where she was diagnosed with mitochondrial fusion protein–related lipodystrophy, and initiation of semaglutide was recommended. Following semaglutide therapy at a dose of 1mg subcutaneously once weekly, triglyceride levels decreased from 682 mg/dL to 335 mg/dL, representing a 51% reduction within four months. This improvement was accompanied by better glycemic control and a reduced requirement for exogenous insulin.

Conclusion:
The clinical response observed in this patient highlights the potential role of GLP-1 receptor agonist therapy as an adjunctive approach in managing refractory hypertriglyceridemia associated with mitochondrial fusion protein-related lipodystrophy and type 2 diabetes mellitus. Further studies are needed to better define the role of GLP-1 receptor agonists in mitochondrial fusion protein lipodystrophy-related hypertriglyceridemia.

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