Adding Dulaglutide, Liraglutide or Semaglutide (GLP-1 agonists) to existing treatment for type 2 diabetes has major cardiovascular benefits. Exenatide* and Lixisenatide were neutral for providing cardiovascular benefits.
Previous studies were done on GLP-1 agonists to establish a cardiovascular benefit in patients with type 2 diabetes. These studies showed noninferiority to placebo concerning reducing cardiovascular events. These studies used a population with a high HbA1C and a 4% higher risk of CV events. Therefore, the REWIND study wanted to test the effect of dulaglutide in a broader CV risk patient population and a wider range of HbA1c.
The objective of the REWIND study was to assess the reduction of cardiovascular outcomes by the addition of dulaglutide. It was a multicenter, randomized, double-blind, placebo-controlled trial. Nine thousand nine hundred one participants were randomized to 2 arms: dulaglutide 1.5 mg weekly vs. placebo. The mean age of participants was 66.2 years, and 46.3% were female. 31.5% of patients reported previous cardiovascular disease and 22.2% had an eGFR of less than 60 mL/min per 1.73m2. The median duration of diabetes was 9.5 years, and the median HbA1c was 7.2% (ranging from 6.6-8.1). GLP-1 agonist and DPP4 inhibitors were discontinued at the start of the study. The primary composite endpoint was the 1st occurrence of a cardiovascular event (nonfatal myocardial infarction, nonfatal stroke) or death. The secondary endpoints were microvascular outcomes (diabetic retinopathy, clinical proteinuria, a 30% decline in estimated glomerular filtration rate, or need for chronic renal replacement therapy), hospital admission secondary to unstable angina, heart failure requiring hospital admission or an urgent clinic visit, individual components of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke), and all-cause mortality. Participants were followed for 5.4 years. Cumulative risks were generated by Kaplan-Meier estimates along with the Cox hazard ratio (HR) that were used to determine outcomes. The log-rank test was used to assess adverse effects of interest, while the chi-square test was used to assess adverse events and serious adverse events.
Primary composite outcome occurred in 594 (12%) in the dulaglutide group and 663 (13·4%) participants in the placebo group (HR 0·88, 95% CI 0·79–0·99; p=0·026). The effects that were observed in the 3 components of the composite primary outcome were not significantly different (Pheterogeneity=0·89), with HRs of 0·91 (95% CI 0·78–1·06; p=0·21) for cardiovascular death, 0·96 (0·79–1·16; p=0·65) for non-fatal myocardial infarction, and 0·76 (0·61–0·95; p=0·017) for non-fatal stroke. The HR of the intervention on the primary outcome was similar in participants with and without previous CVD disease (pinteraction=0.97); in participants whose HbA1c was less than 7.2% or greater than or equal to 7.2% (pinteraction=0.75); and in participants analyzed according to age, sex, duration of diabetes, and BMI. The secondary composite endpoints compared to placebo had an (HR 0.87, 95% CI 0.79–0.95). This difference was characterized by fewer composite renal outcomes in the dulaglutide group than in the placebo group (HR 0.85, 95% CI 0.77–0.93). Dulaglutide did not significantly affect the incidence of all-cause mortality, heart failure, revascularization, hospital admissions, fractures, or cholelithiasis. Dulaglutide showed a 0.61% reduction in HbA1c (p<0.0001), a 1.46 kg reduction in body weight (p<0.0001), a 0.53 kg/m2 reduction in BMI (p<0.0001), a 1.70 mm Hg reduction in systolic blood pressure (p<0.0001), a 1.87 beats per min elevation in heart rate (p<0.0001). Additional benefits were a reduction in cholesterol, weight circumference, LDL, pulse pressure, and arterial blood pressure. The most reported adverse event was GI adverse events compared to placebo (P<0.0001).
This study showed that a weekly injection of 1.5 mg of dulaglutide reduced the risk of CV outcomes compared to placebo starting from the 1st year of therapy. Regarding the three composite primary outcomes, the biggest difference was seen in non-fatal strokes. This study suggested that dulaglutide has a renal protective effect. Therefore, more studies should be on establishing the renal benefit of GLP-1 agonists. Strengths of the study included a median follow-up of 5.4 years with a high proportion of women (46.3%), a low proportion of people with previous CVD (31.5%), and mean HBA1C of 7.3% or higher. One limitation was that 25% of the participants were not taking the drug at the time of their last visit. The participants took the study drug for more than 80% of the follow-up time. Dulaglutide could be considered for the management of glycemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
- The addition of dulaglutide reduces the likelihood of a cardiovascular outcome over at least five years with the most benefit being towards non-fatal strokes.
- Dulaglutide showed renal benefit compared to the placebo.
- This was the first study to establish the superiority of a GLP-1 agonist compared to placebo.
*based on CV morbidity and mortality outcomes, but not reduced risk of death from any cause.
Gerstein, Hertzel, et al. “Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): a Double-Blind, Randomised Placebo-Controlled Trial.” The Lancet, 13 July 2019.
Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy