Heart and death risks in people with type 2 diabetes and heart risk factors treated with dulaglutide in the REWIND trial

People with diabetes continue to be at high risk for cardiovascular (CV) events and premature death despite the use of established cardioprotective therapies. Large randomized placebo-controlled CV outcomes trials have therefore been conducted to assess the effects of glucose-lowering drugs on the hazard of major adverse CV events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke or death from CV causes. Seven such trials using glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have now been published. Four of them reported a reduced hazard of MACE [1–4], and a meta-analysis of these plus three additional trials whose results were neutral [5–7], reported a statistically significant hazard ratio of 0.88 for this outcome [8]. One of these trials was the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial, in which the addition of a once-weekly subcutaneous injection of dulaglutide (1.5 mg) significantly reduced the hazard of MACE by 12% in 9901 individuals with type 2 diabetes with either chronic CV disease or CV risk factors [4]. It also clearly demonstrated similar effect sizes in the subgroups with (31.5% of participants) and without (68.5% of participants) known CV disease.

These 7 CV outcomes trials all reported time-to-occurrence of the first MACE. Limiting the analysis to time-to-the first event precludes relevant clinical information pertaining to the total event burden experienced by participants [9–16]. To assess the impact of dulaglutide on total major events in the REWIND trial, we compared the composite of total number of MACE or non-CV deaths and the composite of total number of expanded MACE (MACE, heart failure, unstable angina or revascularization) or non-CV deaths between participants randomized to the GLP-1 RA and those randomized to placebo.

In this post hoc analysis of data from the REWIND trial, participants randomized to a once-weekly subcutaneous injection of dulaglutide 1.5 mg had a reduced total number of CV or fatal outcomes in addition to the number of first CV or fatal events compared with participants randomized to placebo. Moreover, the reduction in absolute numbers of events was greater for expanded MACE or non-CV deaths than for MACE or non-CV deaths in the dulaglutide treatment group.

The pre-specified primary analyses of all CV outcomes trials with GLP-1 receptor agonists, including REWIND, focused on estimating a participant’s risk of experiencing the first primary CV outcome, MACE after randomization. The reported HRs therefore reflect differences in the time from randomization to the first outcome in people who were randomly assigned to the active versus control therapy. The previously reported HR of 0.88 for dulaglutide versus placebo in the REWIND trial means that on average at any time-point after randomization, people who had been randomly assigned to dulaglutide were 12% less likely to have experienced a first post-randomization MACE than people who had been randomized to placebo [4]. Although this provides important information regarding the therapeutic effect of dulaglutide, patients and health care providers are also interested in knowing the total burden of serious CV events, and deaths from any cause in participants treated with dulaglutide. The estimated HR of about 0.9 for the burden of total MACE or non-CV death therefore focuses on events and not participants. It means that at any time-point after randomization, there were 10% fewer events in people randomly assigned to dulaglutide versus placebo. In the participants with a placebo-group MACE or non-CV death rate of 40.3 per 1000 py, this 10% difference would be consistent with 108 fewer MACE or non-CV deaths, and 179 fewer expanded MACE or non-CV deaths (with a placebo rate of 74.7 per 1000 py) in the dulaglutide group during the 5.4-year follow-up. If the results of this post hoc analysis are replicated, we hypothesize that the number of events avoided would be higher in individuals with event rates higher than those reported in Table 2.

The inclusion of non-CV death within the primary analyses presented here represents a conservative approach to estimating the effect of dulaglutide on the overall burden of CV disease as well as on the time to the first occurrence. First, death from any cause is clearly relevant to both participants and providers. Second, including all-cause deaths versus just CV deaths eliminates any misclassification of the cause of death (i.e. CV or non-CV death). Finally, it eliminates the possibility that a benefit of the drug on event burden would be negated by an increase in death, also referred to as the competing risk of death [21]. Whereas some investigators addressed this possibility in sensitivity analyses [13–15], we and others have integrated all-cause death into the main analyses of event burden [16]. Notably, the estimated HR of 0.88 for the time to the occurrence of the first MACE outcome or non-CV death was identical to the previously reported HR for the first occurrence of MACE alone [4]. However, the addition of non-CV deaths increases the event rates in both treatment groups compared with MACE alone and hence the number of people spared from experiencing an event. This is reflected in the absolute risk reduction which was 3.1 per 1000 py for the first occurrence of a MACE as previously reported (594 versus 663 events) [4], and 4.1 per 1000 py for the first occurrence of a MACE or non-CV death as noted in Additional file 1: Table S3 (789 versus 879 events).

The finding of a reduced burden of CV events in the REWIND trial is similar to the results of an analysis of event burden from the Liraglutide Effect and Action in Diabetes Evaluation of cardiovascular Results (LEADER) trial of another GLP-1 RA. In this analysis liraglutide was associated with a reduction of total (first and recurrent) MACE by 16% and of total CV events by 13% in 9340 participants followed for a median of 3.8 years [15]. Notably, inclusion of non-CV deaths in a sensitivity analysis did not alter their findings. The higher outcome reduction rates in the LEADER trial than in the REWIND mostly result in a higher risk population; indeed, 83% of the LEADER enrolled participants had a chronic CV disease compared with 31% of the REWIND enrolled participants.

Although the exact mechanism of the benefit of dulaglutide or other GLP-1 receptor agonists on CV disease reduction is unknown, possibilities include a decrease of risk factors such as high HbA1c, LDL-cholesterol, blood pressure and bodyweight as well as potential effects on the atherothrombotic process by improving endothelial and platelet functions [22] and attenuating the arterial plaque progression by reducing inflammation and vascular tone [23]. The fact that other GLP-1 receptor agonists such as liraglutide and semaglutide have qualitatively similar effects on CV events, metabolic and other indices overall and within sub-groups is consistent with general “class effect” of these drugs [24–26].

These analyses are limited by the fact that they were not pre-specified and causal conclusions should not be drawn. Strengths include the 5.4-year median follow-up period, the large number of participants from many countries with well characterized baseline clinical findings, the high proportion of enrolled women, and the inclusion of all deaths in the composite event as a measure of total event burden.

These findings suggest that dulaglutide reduced the event burden of CV or fatal outcomes in a population at moderate CV risk. The absolute reduction was greatest for the composite outcome that included an expanded definition of a MACE. Our study supports the clinical implication of assessing all CV events or deaths in addition to the first manifestation of the primary outcome of randomized trials to capture the impact of the pharmacological intervention on the burden of disease.

The authors thank the participants and the staff of the REWIND trial for their valuable contributions.

GRD and HCG wrote first draft and LD did the statistical analysis. All authors were involved in the REWIND trial. They reviewed the data and provided comments on the different versions. All authors read and approved the final manuscript.

The REWIND trial and this post hoc analysis were funded by Eli Lilly.

All the data for the present report came from the Population Health Institute (PHRI) in Hamilton, Canada. PHRI did also all data analysis for the REWIND trial. The REWIND main trial data are in references 4, 17 and 18. The REWIND data sharing policy is described in the Additional file. 1

Ethics review boards responsible for each of the 371 participating sites (24 countries) approved the protocol and each of the 9901 participants provided written informed consent.

Not applicable.

GRD received honoraria from BAYER for lectures. LR received research grants from Swedish Heart–Lung Foundation, Stockholm County council, Family Erling Perssons Foundation and Boehringer-Ingelheim and speaker honoraria from Bayer AG, Boehringer-Ingelheim, Eli Lilly and Novo Nordisk. LAL received research grants from, provided CME on behalf of and/or acted as an adviser to AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Lexicon, Merck, Novo Nordisk, Sanofi, and Servier. ML is employed by Eli Lilly. LD has no competing interests. JLP has no competing interests. CMA is employed by Eli Lilly. JES has received honoraria from AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Eli Lilly, Novo Nordisk and Boehringer Ingelheim. IC has received honoraria for lectures and consulting fees from Abbot, Medtronic, Bayer, GlaxoSmithKline, Eli Lilly, Novo Nordisk, Sanofi-Aventis, Novartis and MSD. WCCPLJ has received honoraria for speaking from Merck, Menarini, Sanofi, Abbott, WCC has received institutional grant support from Eli Lilly. FL has no competing interests. EGCM acted as an adviser for Servier and received honoraria from Menarini, Sanofi, MSD, Silanes, Novo, Stendhal, Boryun for lectures. VP has no competing interests. NP has no competing interests. JB received research grants from Eli Lilly, ReCor, and Ablative Solutions. He is a consultant for both Medtronic and Up-to-Date. WHHS provided CME and/or acted as an adviser to MSD, AstraZeneca, Boehringer Ingelheim, Tanabe, Takeda, Eli Lilly, Bayer’s, Novo Nordisk, and Sanofi. TTK has no competing interests. PJR has no competing interests. MK has no competing interests. SH has no competing interests. PP has no competing interest. HMC has received grants from Eli Lilly, AstraZeneca, Regeneron, Pfizer, Novo Nordisk, honoraria for speaker bureau from Eli Lilly and advisory panel from Sanofi Aventis and Novartis, and is shareholder Roche Pharma. MCR reports grant support through Oregon Health & Science University from Astra Zeneca, Eli Lilly, and Novo Nordisk, and honoraria for consulting from Adocia, AstraZeneca, Eli Lilly, GlaxoSmithKline, Intercept, Novo Nordisk, Sanofi, and Theracos. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, and Kowa.

Supplementary information accompanies this paper at 10.1186/s12933-020-01179-1.