924-P: Exploring Potential Mediators of the Cardiovascular Benefit of Dulaglutide in REWIND
Authors: COLHOUN HELEN M. , HASENOUR CLINTON , RIDDLE MATTHEW C. , BRANCH KELLEY , KONIG MANIGE , ATISSO CHARLES , LAKSHMANAN MARK , MODY REEMA , GERSTEIN HERTZEL C. 
Published: June 2020

The REWIND trial showed that relative to placebo (PL), once weekly dulaglutide (DU) 1.5 mg reduced the incidence of a major adverse cardiovascular (CV) event (MACE; nonfatal myocardial infarction, nonfatal stroke, or CV death) in patients with T2D with and without established CV disease (hazard ratio (HR) 0.88, 95% CI [0.79, 0.99]; p=0.026). DU also significantly reduced A1C, body weight (BW), and systolic blood pressure (SBP) (Table). In this post-hoc assessment, a mediation analysis was used to estimate the degree to which the effect of DU on these risk factors could statistically account for its effect on MACE. Data were analyzed from 9901 patients who had 1257 first MACE events over 5.4 median yrs of observation. Those risk factors for which the updated mean on follow-up was significantly related to MACE were added to a separate Cox model that included DU allocation, the baseline [BL] value of the measurement and the updated mean of the variable as time dependent covariates. Only A1C satisfied this condition (Table), suggesting that BW and SBP did not mediate the effect of DU on MACE in this study population. The effect size of DU on the MACE outcome was attenuated by 36.1% after accounting for its effect on A1C (Table).
In conclusion, the results suggest most of the CV benefit of DU on MACE is not attributable to the A1C, BW, or SBP-lowering effects of DU.

Disclosure
H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. C. Hasenour: Employee; Self; Eli Lilly and Company. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K. Branch: Consultant; Self; Bayer AG. Research Support; Self; Bayer AG, Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.