Tirzepatide for Congenital Generalized Lipodystrophy

This correspondence details the use of tirzepatide, a once-weekly dual GLP-1/GIP agonist, in two patients with congenital generalized lipodystrophy type 1 (AGPAT2 variant). Congenital generalized lipodystrophy results in extreme insulin resistance, hepatic steatosis, and hypertriglyceridemia due to near-total adipose tissue deficiency and leptin deficiency. The FDA-approved treatment is metreleptin, but it requires daily painful injections that patients often discontinue.

A 23-year-old Black man with severe insulin resistance (HbA1c: 14.7%) and low leptin (0.5 ng/mL) had previously refused all treatments due to injection pain. He agreed to tirzepatide monotherapy, with a rapid dose escalation from 2.5 mg to 15 mg within four weeks. His glucose levels normalized only at the 15 mg dose, and upon reducing the dose to 7.5 mg (due to unavailability), his glucose worsened. Resuming 15 mg tirzepatide restored normoglycemia, confirming a dose-dependent effect.

A 64-year-old Black woman receiving insulin detemir, insulin lispro, and metreleptin sought an alternative to reduce injection burden. Gradual tirzepatide titration allowed discontinuation of all insulin therapy, with stable glucose control (99% within target range) at 15 mg weekly. However, she discontinued tirzepatide due to diarrhea.

This correspondence details the use of tirzepatide, a once-weekly dual GLP-1/GIP agonist, in two patients with congenital generalized lipodystrophy type 1 (AGPAT2 variant). Congenital generalized lipodystrophy results in extreme insulin resistance, hepatic steatosis, and hypertriglyceridemia due to near-total adipose tissue deficiency and leptin deficiency. The FDA-approved treatment is metreleptin, but it requires daily painful injections that patients often discontinue.

A 23-year-old Black man with severe insulin resistance (HbA1c: 14.7%) and low leptin (0.5 ng/mL) had previously refused all treatments due to injection pain. He agreed to tirzepatide monotherapy, with a rapid dose escalation from 2.5 mg to 15 mg within four weeks. His glucose levels normalized only at the 15 mg dose, and upon reducing the dose to 7.5 mg (due to unavailability), his glucose worsened. Resuming 15 mg tirzepatide restored normoglycemia, confirming a dose-dependent effect.

A 64-year-old Black woman receiving insulin detemir, insulin lispro, and metreleptin sought an alternative to reduce injection burden. Gradual tirzepatide titration allowed discontinuation of all insulin therapy, with stable glucose control (99% within target range) at 15 mg weekly. However, she discontinued tirzepatide due to diarrhea.