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Introduction: In the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial, weekly subcutaneous dulaglutide 1.5 mg, a glucagon-like peptide-1 receptor agonist, compared with matched placebo reduced MACE (cardiovascular [CV] death, non-fatal myocardial infarction or non-fatal stroke) (594 versus 663 events) in 9901 participants with type 2 diabetes at moderate CV risk [mean (SD) age 66.2 (6.5) years, 46.3% women, 31% with chronic CV disease and the others with CV risk factors] and followed for a median of 5.4 years. These findings, based on a time to first event analysis, do not reflect total CV event or mortality burden. Objective: To better reflect the burden of disease, the following outcomes were assessed: 1) total number of MACE or fatal events and 2) total number of CV (MACE, unstable angina, heart failure or revascularization) or fatal events in the REWIND participants. Methods: Incidence was estimated per 1000 person-years (py), and hazard ratios (HR) were calculated using conditional time gap and proportional means models. Results: A total of 1972 MACE outcomes or deaths and of 3673 CV outcomes or deaths occurred in the 9901 participants. Of the1128 all-cause deaths, 465 were non-CV. The incidence of total MACE or deaths was 35.8 in the dulaglutide group versus 40.3/1000 py in the placebo group [absolute reduction=4.5/1000 py; conditional time gap HR, 0.90 (95%CI, 0.82-0.98), P =0.020, and proportional means HR, 0.89 (95% CI, 0.80-0.98), P =0.022]. The incidence of total CV or fatal events on dulaglutide was 67.1 and 74.7/1000 py on placebo [absolute reduction=7.6/1000 py; conditional time gap HR, 0.93 (95% CI, 0.87-0.99), P =0.023, and proportional means HR, 0.90 (95% CI 0.82-0.99), P =0.028]. Similar effect sizes were noted for the first occurrence of MACE or deaths such that the absolute risk reduction was 4.1/ 1000 py. Conclusions: These findings suggest that weekly subcutaneous dulaglutide was associated with reduced total MACE, CV or fatal event burden in people with type 2 diabetes and moderate CV risk. This analysis illustrates the clinical relevance of assessing total events in addition to first events in clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique Identifier NCT01394952)

In the REWIND cardiovascular (CV) outcomes trial (CVOT), the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide reduced CV risk vs placebo in patients with type 2 diabetes (T2D) and elevated CV risk. The SUSTAIN 6 ([NCT01720446][1]) and PIONEER 6 ([NCT02692716][2]) CVOTs of the GLP-1RA