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Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

Abstract In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re‐categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re‐categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P‐interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

| INTRODUCTION
In the cardiovascular (CV) outcomes trial "Researching cardiovascular Events with a Weekly Incretin in Diabetes" (REWIND; NCT01394952), the glucagon-like peptide-1 receptor agonist (GLP-1 RA) dulaglutide reduced CV risk versus placebo in patients with type 2 diabetes. 1 This result was seen in the overall trial population, and in both the "established CV disease" (CVD) and "CV risk factor" subgroups. 1 In REWIND (9901 patients), a comparatively high proportion of patients were included in the CV risk factor subgroup compared with other GLP-1 RA CV outcomes trials. However, the criteria for established CVD are not consistent across trials. The "Semaglutide in Subjects with Type 2 Diabetes 6" (SUSTAIN 6; NCT01720446) and the "Peptide Innovation for Early Diabetes Treatment 6" (PIONEER 6; NCT02692716) trials of semaglutide 2,3 used a broader definition than REWIND for established CVD. 1 Key differences in CVD criteria between the trials included patients with chronic kidney disease, chronic heart failure (HF), prior Note: Patients needed to meet one or more of the established CVD criteria to be in the established CVD subgroup, and one or more of the CV risk factors criteria to be in the CV risk factors subgroup. Patients could not be in both groups. Differences in criteria between trials are in bold. Abbreviations: CV, cardiovascular; CVD, cardiovascular disease; ECG, electrocardiogram; MI, myocardial infarction; NYHA, New York Heart Association.  A limitation of the present analysis is that, with different inclusion criteria between the trials, definitive re-categorization of SUSTAIN 6 and PIONEER 6 patients was difficult to achieve.

Endpoint CV risk group P-interaction
In conclusion, the results of this analysis suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum, consistent with the GLP-1 RA metaanalysis and dulaglutide results from REWIND.

ACKNOWLEDGMENTS
The authors are grateful to Emre Yildirim, Novo Nordisk, for review of and input to the manuscript. Writing assistance was provided by Alice Therapeutics, PhaseBio and Stability Health, and his effort here is also supported by grants from the National Institutes of Health (UL1TR002489, P30DK124723).

AUTHOR CONTRIBUTIONS
S.R. performed the statistical analyses. All authors were responsible for the content and editorial decisions, were involved at all stages of manuscript development, and approved the final version. S.V. is the guarantor of the article, had full access to all data presented and takes responsibility for its integrity and analysis.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author.