716-P: Systolic Blood Pressure Reduction with Tirzepatide across SURPASS Program: A Mediation Analysis Using Weight Loss as a Factor

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes. Across the SURPASS 1-5 clinical studies, TZP 5, and 15 mg demonstrated significant improvements in HbA1c (-1.9 to -2.6%) , body weight (-6.6 to -13.9%) and systolic blood pressure (SBP) (-2.8 to -12.6 mmHg) at primary endpoint. Post-hoc mediation analyses were conducted to evaluate weight loss dependent (WL-D) and independent (WL-IND) effects of TZP on SBP reductions across 5 SURPASS studies. The difference in mean SBP change from baseline at 40-weeks (Total effect) between TZP and comparator group was -1.3 to -5.1 mmHg (TZP 5 mg) , -1.7 to -6.5 mmHg (TZP mg) and -3.1 to -11.5 mmHg (TZP 15 mg) . The contribution of WL-D and WL-IND effects on these treatment differences are presented below (Figure) . In SURPASS-4 study which enrolled patients with established cardiovascular disease, WL-IND effects explained 33% to 57% of difference in SBP change between TZP and insulin glargine groups, with the remainder of 67% to 43% of the effect being WL-D. In a pooled analysis of SURPASS 1-5 studies, there was a significant (p