MON-734 TIrzepatide Reverses Insulin Resistance Independent of Weight Loss in Individuals Without Diabetes

Abstract Disclosure: T.L. McLaughlin: Lilly USA, LLC. J. Yang: None. N. Turk: None. C. Johnston: None. D. Perelman: None. A. Choi: None. H. Chen: None. Objective/Hypothesis: We hypothesized that tirzepatide (TIRZ) reduces insulin resistance independent of weight loss via beneficial GIP effects on adipose tissue. We compared the effects of tirzepatide vs. matched dietary weight loss on adipose tissue structure/function, in-vivo metabolic responses (insulin resistance and B-cell function), and body composition. Methods: Adults (TIR: n=19, diet: n=17) with BMI 27-39.9 and FBG <126 mg/dL were randomized to a 22-week trial of hypocaloric diet vs TIRZ with weight loss matching at wk 6. Adipose tissue biopsies at baseline, wk 6, and wk 22 were analyzed for adipose cell size, lipolysis, gene expression, differentiation, and fat storage. Insulin resistance was evaluated with gold-standard steady-state plasma glucose (SSPG) test and glucose tolerance/beta-cell function with OGTT. Body composition was assessed by DXA, and macronutrient intake by Cronometer app. Results: Weight loss was matched at 6 wks: TIRZ –3.80 kg, diet –4.00 kg; p=0.77. SSPG decreased significantly with TIRZ (–82+48 mg/dL) vs diet (–13+42 mg/dL; p=0.0001), as did 2-hour OGTT glucose (TIRZ –43+51 mg/dL, diet 11+40 mg/dL; p=0.0012). Basal lipolysis increased in both TIRZ (+2.44 mg/dL, p=0.0043) and diet (+2.81 mg/dL, p=0.00072). Insulin suppression of lipolysis improved with TIRZ (+3.74 mg/dL, p=0.036), no change in diet (+0.55 mg/dL, p=0.79). Metabolic flexibility (difference between isoproterenol stimulation and insulin suppression of lipolysis) improved in TIRZ (3.8 + 8.2, p=0.05) but not diet (0.45+ 2.7, p=0.79) at 6 wks. Total cholesterol dropped in TIRZ (–20.06 mg/dL, p=0.00047) no change in diet (–7.38 mg/dL, p=0.20). Fat mass loss was greater in diet (-2600.69g, p=0.0012) than TIRZ (-1630.87g, p=0.00003). Lean mass loss was greater in TIRZ (–1877.55g, p=0.0038), no change in diet (–781.33g, p=0.19). Lean/fat mass ratio decreased significantly in both groups at 22 but not 6 wks, with NS difference between treatment arms (p=0.28). Conclusions: TIRZ improves insulin sensitivity independent of weight loss. This metabolic effect is unique to the dual agonist TIRZ and has not been reported with single agonists for GLP1. This may be due to enhanced adipose insulin sensitivity as evidenced by differential changes in adipose cells. Presentation: Monday, July 14, 2025