Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND

Abstract

Background: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.

Methods: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model.

Results: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).

Conclusions: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://ichgcp.net/clinical-trials-registry/NCT01394952.

Keywords: Cardiovascular; Diabetes; Dulaglutide; Glucagon-like peptide-1; Mediators.

Conflict of interest statement

MK and RM are employees and shareholders of Eli Lilly and Company. CMA and MCL are former employees and shareholders of Eli Lilly and Company. MCR reports grants to his institution from Eli Lilly and Company, AstraZeneca, and Novo Nordisk; honoraria for consulting from Adocia, DalCor, GlaxoSmithKline, and Theracos; and honoraria for speaking from Sanofi. HMC reports research grants from Eli Lilly and Company, AstraZeneca, Regeneron, Pfizer, Roche, Sanofi, and Novo Nordisk; honoraria for speaking from Eli Lilly and Company and Regeneron; consulting fees from Eli Lilly and Company, Novartis, Regeneron, Sanofi, and Novo Nordisk; and shares in Bayer and Roche. KRB reports research grants to his institution from Bayer, Eli Lilly and Company, and Sanofi; and consulting fees from Bayer, Janssen, and Sana. SR is an employee of Eli Lilly and Company. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly and Company, AstraZeneca, Merck, Novo Nordisk, and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novo Nordisk, Janssen, Sanofi, Kowa, and Cirius.

© 2021. The Author(s).

Figures

Fig. 1

Effects of treatment on potential mediators over time up to 6 years: dulaglutide versus placebo. Dulaglutide significantly reduced HbA1c, body weight, WHR, SBP, LDL, and UACR over time from baseline compared to placebo. HbA1c hemoglobin A1c, LDL low density lipoprotein, LSM least squares mean, SBP systolic blood pressure, SE standard error, UACR urine albumin creatinine ratio, WHR waist-to-hip ratio