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

Abstract

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<0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. In conclusion, TZP induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight loss independent effects across the different trials. Disclosure I. Lingvay: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Mannkind, TARGET PharmaSolutions; Valeritas;; Altimmune; DataRevive; Click; Medscape Duke CRI; Janssen Pharma; Bayer; Intercept, Novo Nordisk, Sanofi, Zealand Pharma A/S. Consultant; Novo Nordisk. Research Support; NovoNordisk; Mylan; Merck, Sanofi. O. Mosenzon: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, BOL Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. Research Support; AstraZeneca, Novo Nordisk. Speaker's Bureau; AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk, Sanofi. K. Brown: Employee; Eli Lilly and Company. X. Cui: Employee; Eli Lilly and Company. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Patel: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company