Three different glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to improve cardiovascular (CV) outcomes in people with type 2 diabetes at high CV risk with high HbA1c levels.
The REWIND trial assessed the effect of dulaglutide on major adverse CV events when added to existing anti-hyperglycaemic regimens in individuals with type 2 diabetes with and without previous CV disease and a wide range of glycaemic control.
Dulaglutide significantly improves the primary composite CV outcome compared with placebo.
Exploratory analyses suggest that dulaglutide also reduces the risk of total and ischaemic strokes.
Long-term use of dulaglutide is also associated with better renal outcomes.
Dulaglutide is a GLP-1 RA approved for the management of hyperglycaemia in people with type 2 diabetes. Clinical studies have shown that dulaglutide reduces blood glucose, blood pressure, weight and albuminuria, and may have other actions suggesting possible CV benefits. The fact that the CV effects of other GLP-1 RAs have been tested in middle-aged people with high HbA1c concentrations and a 4% or higher annual risk of CV events highlights the need to test the effect of dulaglutide on CV events in individuals with a broader CV risk and wider range of glycaemic control.
The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was designed to assess whether the addition of dulaglutide to the existing diabetes medication regimen of middle-aged and older people with type 2 diabetes safely reduces the incidence of CV events vs. placebo.
The long-term effects of dulaglutide on renal outcomes were also assessed in an exploratory analysis.
Multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries.
9901 participants at least 50 years with type 2 diabetes who had either a previous CV event or CV risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (n = 4949; 1.5 mg) or placebo (n = 4952).
Key inclusion criteria included HbA1C ≤9.5%, BMI >23 kg/m2, and age-related criteria (age ≥50 and CV disease, age ≥55 and subclinical CV disease, age ≥ 60 and 2 CV risk factors).
The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from CV causes (including unknown causes).
The renal component of the composite microvascular endpoint was defined as the first occurrence of new macroalbuminuria (UACR (urine albumin/creatinine ratio) >33.9 mg/mmol), a sustained decline in estimated glomerular filtration rate (eGFR) of 30% or more from baseline, or chronic renal replacement therapy.
During a median follow-up of 5.4 years (IQR 5.1–5.9), the primary composite outcome occurred in 594 (12.0%) participants at an incidence rate of 2.4 per 100 person-years in the dulaglutide group and in 663 (13.4%) participants at an incidence rate of 2.7 per 100 person-years in the placebo group (HR 0.88, 95% CI 0.79–0.99; P = 0.026).
All-cause mortality did not differ between groups (536 (10.8%) in the dulaglutide group vs 592 (12.0%) in the placebo group; HR 0.90, 95% CI 0.80–1.01; P = 0.067).
Exploratory renal analyses
At baseline, 791 (7.9%) participants had macroalbuminuria and mean eGFR was 76.9 mL/min/1.73 m² (SD 22.7).
During a median follow-up of 5.4 years (IQR 5.1–5.9) comprising 51,820 person-years, the renal endpoint developed in 848 (17.1%) participants at an incidence rate of 3.5 per 100 person-years in the dulaglutide group and in 970 (19.6%) participants at an incidence rate of 4.1 per 100 person-years in the placebo group (HR 0.85, 95% CI 0.77–0.93; P = 0.0004).
The clearest effect was for new macroalbuminuria (HR 0.77, 95% CI 0.68–0.87; P <0.0001), with HRs of 0.89 (0.78–1.01; P = 0.066) for sustained decline in eGFR of 30% or more and 0.75 (0.39–1.44; P = 0.39) for chronic renal replacement therapy.
Exploratory stroke analyses
Compared to placebo, dulaglutide reduced the risk of all stroke (HR 0.76; 95% CI 0.62–0.94; P = 0.010), nonfatal stroke (HR 0.76; 0.61–0.95; P = 0.017), and ischaemic stroke (HR 0.74; 0.59–0.94; P = 0.012).
Dulaglutide also reduced the risk of disabling stroke (HR 0.74; 95% CI 0.56–0.99; P = 0.042) vs placebo.
This long-duration randomised controlled trial of people with type 2 diabetes and only a 31.5% prevalence of previous CV disease showed that dulaglutide reduced the risk of CV events compared with placebo.
Long-term use of dulaglutide was associated with reduced composite renal endpoint in patients with type 2 diabetes.
Exploratory analyses suggest that dulaglutide also reduces the risk of stroke.
Key messages/Clinical Perspectives
The addition of dulaglutide might be considered for both primary and secondary CV prevention in middle-aged patients with type 2 diabetes and CV risk factors.
Future large prospective trials of the effects of dulaglutide on prespecified renal outcomes should be performed to better understand its effects on renal function in patients with preserved and reduced baseline renal function.