715-P: Tirzepatide as Monotherapy Improved Markers of Beta-Cell Function and Insulin Sensitivity in People with Type 2 Diabetes (SURPASS-1)

Tirzepatide (TZP) , a novel dual GIP/GLP-1 receptor agonist, led to greater HbA1c, fasting serum glucose and body weight reductions vs. placebo (PBO) in people with early T2D (baseline mean T2D duration 4.7 y and 54% no prior diabetes medications) from the 40-wk SURPASS-1 trial. In a Phase 2b trial, TZP also improved β-cell function and insulin sensitivity (IS) vs. PBO and selective GLP-1 receptor agonist, dulaglutide 1.5 mg. Similarly, in SURPASS-1, TZP improved β-cell function, as indicated by a 75-80% increase in HOMA2-B, and insulin resistance, as indicated by a 2-12% decrease in fasting insulin and 8-20% decrease in HOMA2-IR. In this analysis, we aimed to explore changes in additional biomarkers of β-cell function and IS after TZP monotherapy (5, and 15 mg) . At 40 wks, proinsulin/C-peptide ratios, a marker of insulin processing, β-cell stress and β-cell function improved with decrease by 47-49% with TZP vs. -0.1% with PBO (p<0.001, all doses) (Table) . Fasting proinsulin decreased by 49-55% with TZP vs. no change with PBO (p<0.001, all doses) . Decreases in fasting C-peptide by 3-9% with TZP did not differ vs. PBO. TZP vs. PBO improved biomarkers of IS evidenced by increases in adiponectin (16-23% vs. -0.2%; p≤0.028, all doses) and IGFBP-2 (38-70% vs. 4.1%; p<0.001, all doses) . As a monotherapy for early T2D, TZP achieved significant improvement in markers of β-cell function and IS. Disclosure C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.Mao: Employee; Eli Lilly and Company. V.Thieu: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company