Tirzepatide for treatment of familial partial lipodystrophy

Project Summary Specific deficiency of fat tissue, or lipodystrophy, leads to progressive metabolic and endocrine disorders such as high triglyceride levels, insulin resistance, and ectopic steatosis especially in the liver. If the fat loss is generalized, patients also display leptin deficiency. Familial partial lipodystrophy (FPLD) is a primary cause of lipodystrophy syndromes in many affected individuals. In this form of lipodystrophy, fat loss is partial – affecting the limbs and the subcutaneous compartment of the trunk while adipose tissue in the face and neck as well as visceral fat depots are preserved and undergo compensatory hypertrophy. While these hypertrophic depots also display inflammation and scarring and would become insulin resistant over time, these depots preserve some ability to produce and secrete leptin. Consequently, patients with FPLD tend to have normal or even elevated endogenous leptin levels, which may be associated with decreased efficacy of exogenous leptin replacement therapy. Thus, although metreleptin is approved as therapy for generalized lipodystrophy, FPLD patients represent a high unmet medical need because there is no FDA-approved therapy for FPLD in the US. Nevertheless, because patients with FPLD have markedly increased appetite, this disease is characterized by a mismatch between their large caloric intake in the face of limited adipocyte storage capacity. We propose to test the hypothesis that patients with FPLD would derive clinical benefit if treated with a drug that decreased food intake. Tirzepatide is a dual incretin (activating receptors for both GLP1 and GIP) that induces an unprecedented magnitude of weight loss in patients with obesity and overweight status. In addition, tirzepatide is reported to enhance glucose-stimulated insulin secretion, enhance storage of triglyceride in white adipose tissue, and increase insulin sensitivity in skeletal muscle. These pleiotropic pharmacologic activities offer potential benefit for patients with FPLD. This application proposes a prospective randomized clinical trial testing the efficacy of tirzepatide in improving body weight and fat mass, adipocyte inflammation, metabolic perturbations such as hyperglycemia and dyslipdemia, hepatic steaotosis and hepatic stiffness (fibrosis). We will also collect information on important safety parameters and some parameters of patient reported outcomes. This rigorously designed trial offers potential to address the unmet medical need of patients with familial partial lipodystrophy and will shed light on pathophysiology of familial partial lipodystrophy as well as novel insights on the crosstalk among gut hormones (GLP1 and GIP), adipose tissue, and appetite regulation by the brain.