865-P: Metformin Reduces Insulin Dose and Visceral Fat Accumulation, and Increases GDF15 without Reducing Insulin Resistance in Adults with Type 1 Diabetes—A 26-Week, Randomized, Double-Blind Placebo-Controlled Trial (INTIMET)

Insulin resistance is a cardiovascular (CV) risk factor in type 1 diabetes (T1D). The effect of metformin on liver and muscle insulin resistance has not been studied in adults with T1D. We recruited 40 adults with T1D (HbA1c 7.5±0.9% [58±10mmol/mol], diabetes duration 22.9±8.9 years, age 37.4±8.8 years, 60% male, BMI 26.4±3.8 kg/m²). Twenty age, gender and BMI matched controls without diabetes were studied at baseline only. Subjects with T1D were randomized to metformin XR 1500mg daily or placebo for 26 weeks. At baseline and end of treatment, subjects completed two-step hyperinsulinemic-euglycemic clamps with 6,6-²H₂ glucose to measure insulin sensitivity at liver (endogenous glucose production during low dose insulin infusion; EGP) and muscle (glucose infusion rate during high dose insulin infusion; GIR). Arterial stiffness (augmentation index; AIx), body composition (DXA, MRI), continuous glucose monitoring (CGM) and growth differentiation factor 15 (GDF15) were measured. Adults with T1D displayed insulin resistance in muscle (GIR 29% lower) and liver (EGP 64% higher). After 26 weeks, metformin reduced total daily insulin dose (estimated treatment difference [ETD] -6.5 units/day [95% CI -11.4 to -1.7]; p=0.009) and visceral fat (p=0.04), and increased serum GDF15 levels (ETD 382 pg/mL [59 to 704]; p<0.001). Metformin did not improve EGP, GIR, AIx, body composition, HbA1c or CGM time in range vs placebo. Metformin reduced insulin dose and visceral fat, and increased GDF15, without improving insulin resistance. This insulin dose difference was previously associated with a 6% CV risk difference. This study: 1) Implicates insulin resistance-independent actions of metformin; 2) Highlights reducing insulin dose as a possible mediator of metformin’s cardioprotection; and 3) Postulates that metformin’s effects in adults with T1D may involve GDF15.