Glucagon-like peptide 1 receptor agonists (GLP-1 RA) reduce cardiovascular (CV) events in patients with type 2 diabetes and established CV disease or who are at CV risk. The mechanisms are not fully elucidated. Retardation of atherosclerosis may be important for the long-term impact of GLP-1 RA, possibly due to their beneficial effects on atherosclerotic plaque volume and composition. A composite outcome reflecting this would include all ischemic CV events or revascularization. Available pieces of evidence showing that GLP-1 RA may favorably affect atherosclerosis include reduced carotid intima-media thickness (cIMT) with liraglutide (1) and a reduced risk of nonfatal myocardial infarction (MI), stroke, or revascularization with semaglutide (2).
The Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) study, which investigated the effect of dulaglutide versus placebo on CV events in patients with type 2 diabetes, stands out among GLP-1 RA trials because of its long follow-up, and 69% of the participants did not have a previous CV event (3). This makes it suitable for testing the hypothesis that dulaglutide reduces a clinical outcome reflecting atherosclerosis progression in type 2 diabetes (3).
Briefly, REWIND was a multicenter, double-blind trial that randomized 9,901 patients with type 2 diabetes and high CV risk or previous CV events to either dulaglutide (1.5 mg/week subcutaneously; n = 4,949) or placebo (n = 4,952) (3). During a median follow-up of 5.4 years, dulaglutide significantly reduced the primary composite outcome, which comprised nonfatal MI, nonfatal stroke, and death from CV or unknown causes (hazard ratio [HR] 0.88; 95% CI 0.79–0.99; P = 0.026). The present post hoc analysis assessed the dulaglutide- and atherosclerosis-related outcomes, including a composite of the first for CV death, nonfatal MI, nonfatal ischemic stroke, and any revascularization, including coronary, peripheral, or carotid. Cox proportional hazards models were used to estimate the effect of randomized treatment. The effect in selected subgroups was estimated by including each subgroup and an interaction term in the model for the atherosclerosis-related primary outcome. The composite of any component of the atherosclerosis-related primary end point and non-CV death was considered an atherosclerosis-related secondary end point.
Mean age of the participants was 66.2 years, 4,589 were female, and 69% were free from previous CV events. The atherosclerosis-related primary end point occurred in 799 (16.1%) dulaglutide patients and 870 (17.6%) placebo patients (incidence rates: 3.25/100 person-years vs. 3.58/100 person-years; HR 0.91; 95% CI 0.83–1.00; P = 0.05) during a median follow-up of 5.4 years (Fig. 1), irrespective of sex, BMI (lower or higher than 32 kg/m2), previous CV disease status, and diabetes duration (<5, 5–10, and >10 years). The incidence of atherosclerosis-related secondary outcome was also lower in the dulaglutide group (HR 0.91; 95% CI 0.83–0.99; P = 0.03).
Our findings, although of borderline significance, support the hypothesis that dulaglutide retards progression of atherosclerosis.
In a large meta-analysis of 119 randomized controlled trials involving 100,667 patients, Willeit et al. (4) reported that interventions reducing cIMT progression were associated with a lower risk of the combined CV end point (MI, stroke, revascularization procedures, or fatal CV disease). Every 10-μm/year reduction resulted in a relative risk for the primary end point of 0.91 (95% CI 0.87–0.94), with no significant heterogeneity (4). The present investigation resulted in the same point estimate (HR 0.91), supporting the hypothesis that dulaglutide reduces the risk of this clinical outcome by reducing atherosclerosis progression. Dulaglutide was also associated with a lower risk of the secondary end point, including non-CV death.
The mechanism behind the potentially beneficial effect on progression of atherosclerosis may partly be mediated by an impact on metabolic factors such as the lipid profile and glycemia. GLP-1 RA may also have a direct effect on atherosclerotic plaque development, as suggested by the findings of Rizzo et al. (1), which showed a reduction of cIMT with liraglutide. Contributory factors may be improved endothelial function, as reported in experimental studies with GLP-1 infused in humans with type 2 diabetes (5), and inflammatory deactivation.
In conclusion, dulaglutide was associated with a 9% reduced index of atherosclerosis in patients with type 2 diabetes and established CV disease or various levels of CV risk. This finding supports the hypothesis that dulaglutide retards the progression of atherosclerosis, but mechanistic studies directly measuring surrogates of atherosclerosis progression are needed to assess causality.
Article Information
Funding. The REWIND trial was funded by Eli Lilly and Company.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. G.F., H.C.G., and L.R. are responsible for conceptualization and manuscript drafting. L.G.M. contributed to discussion and revision. F.K. and C.R. performed data analysis. H.C.G. and L.R. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
