SUN-699 - Tirzepatide in Congenital Generalized Lipodystrophy: A Case of Improved Glycemic Control in A Person with Severe Insulin Resistance

Background: Congenital generalized lipodystrophy (CGL) is a rare genetic disorder characterized by the absence of adipose tissue, severe insulin resistance, and early-onset diabetes mellitus. Glycemic control in this population remains suboptimal despite metreleptin and insulin therapies, and evidence supporting GLP-1 receptor agonists, including tirzepatide, is limited. According to current UK guidelines, only patients with elevated body mass indexes (BMI) are eligible for GLP-1RA prescriptions.

Clinical

Case: We report a 21-year-old woman with CGL due to a BSCL2 mutation, known to the UK’s National Severe Insulin Service. She developed severe insulin resistance and early-onset diabetes with limited response to basal insulin and multiple oral hypoglycemic agents, now demonstrating improvement following initiation of tirzepatide. Long-term complications included a low BMI (18 kg/m²), acanthosis nigricans, hepatic steatosis, hypertension, proteinuria, and hypertriglyceridemia (510 mg/dL; normal < 150 mg/dL). Psychological complications related to chronic disease further impaired adherence to dietary modification and glucose monitoring. At diagnosis at age 10, the patient had an HbA1c of 8.3% (normal < 5.7%). During adolescence, metreleptin therapy was initiated and titrated from 2.5 mg to 10 mg daily. Although appetite improved significantly, glycemic control remained sub-optimal. Escalating doses of metformin, sitagliptin, and insulin degludec resulted in slight improvements in blood glucose, though the HbA1c remained persistently elevated at 10.5%. Following a trial of an SGLT-2 inhibitor, dapagliflozin, hematocrit was elevated (58%; normal 36–46%), which improved after drug cessation. Tirzepatide was subsequently initiated, despite limited evidence in CGL. Thus far, glucose values have improved, with mean glucose decreasing from 250 mg/dL to 184 mg/dL (normal 70–180 mg/dL) and time in range increasing from 20% to 53%, as per continuous glucose monitoring data. Close monitoring of weight and signs of malnutrition is essential, yet challenging given her low baseline BMI.

Conclusion: This case demonstrates significant improvement in glycemic control with tirzepatide in a patient with congenital generalized lipodystrophy and severe insulin resistance, demonstrating its potential as an effective additional therapy in this patient.

References: Lebenthal Y, Halperin S, Interator H, Brener A, Brown RJ. Oral glucagon-like peptide-1 analog as an adjuvant therapy in generalized lipodystrophy. Diabetes Care. 2025;48(5):71–73. doi:10.2337/dc25-0272.

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