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Contribution to Literature:

The REWIND trial showed that dulaglutide is superior to placebo in improving glycemic control and reducing cardiovascular (CV) events in patients with type 2 diabetes and higher CV risk.

Description:

The goal of the trial was to assess the cardiovascular (CV) safety of dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in patients with type 2 diabetes mellitus at higher risk for CV events.

Study Design:

Patients were randomized in a 1:1 fashion to either dulaglutide 1.5 mg once weekly (n=4,949) or matching placebo (n=4,952). Both medications were administered as a subcutaneous injection.

• Total screened: 12,133

• Total number of enrollees: 9,901

• Duration of follow-up: 5.4 years

• Mean patient age: 66.2 years

• Percentage female: 46.3%

Inclusion criteria:

• Type 2 diabetes

• Hemoglobin A1c ≤9.5%

• Stable doses of two oral glucose-lowering drugs

• If age ≥50 years, then had to have concomitant vascular disease (a previous myocardial infarction [MI], ischemic stroke, revascularization, hospital admission for unstable angina, or imaging evidence of myocardial ischemia)

• If age ≥55 years, then had to have concomitant myocardial ischemia; coronary, carotid, or lower extremity artery stenosis exceeding 50%; left ventricular hypertrophy; estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; or albuminuria

• If age ≥60 years, then had to have at least two of the following: tobacco use, dyslipidemia, hypertension, or abdominal obesity

Exclusion criteria:

• eGFR <15 mL/min/1.73 m²

• Cancer in the previous 5 years

• Severe hypoglycemia in the previous year

• Life expectancy less than 1 year

• Coronary or cerebrovascular event within the previous 2 months

• Planned revascularization

Other salient features/characteristics:

• Established CV disease: 31.5%

• Previous heart failure: 8.5%

• Duration of diabetes: 10.5 years

• Baseline hemoglobin A1c: 7.4%

• Metformin: 81.2%, insulin: 24%

Principal Findings:

The primary outcome, CV death, MI, or stroke for dulaglutide vs placebo, was 12.0% vs 13.4% (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.79-0.99, P=0.026 for superiority)

• CV death for dulaglutide vs placebo: 6.4% vs 7.0% (P=0.21)

• Nonfatal MI for dulaglutide vs placebo: 4.1% vs 4.3% (P=0.65)

• Nonfatal stroke for dulaglutide vs placebo: 2.7% vs 3.5% (P=0.017)

Secondary outcomes, for dulaglutide vs placebo:

• All-cause mortality: 10.8% vs 12.0% (P=0.067)

• Chronic heart failure hospitalization/urgent visit: 4.3% vs 4.6% (P=0.46)

• Composite microvascular outcome (eye or kidney): 18.4% vs 20.6% (P=0.002)

• Severe hypoglycemic event: 1.3% vs 1.5% (P=0.38)

• Acute pancreatitis: 0.5% vs 0.3% (P=0.11); pancreatic cancer: 0.4% vs 0.2% (P=0.22)

• Median reduction in hemoglobin A1c: 0.61%

Renal outcomes, for dulaglutide vs placebo:

• Composite renal outcome (new macroalbuminuria, sustained decline in eGFR ≥30% chronic renal replacement therapy): 17.1% vs 19.6% (HR 0.85, 95% CI 0.77-0.93, P=0.0004)

• New macroalbuminuria: 8.9% vs 11.3% (P<0.0001)

• Sustained decline in eGFR ≥50%: 1.2% vs 2.2% (P=0.0002)

Interpretation:

The results of this trial indicate that once-weekly dulaglutide administered via subcutaneous injection is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. There was also a significant reduction in nonfatal strokes. In addition, the drug had a moderate effect on the composite renal outcome, and reduced new macroalbuminuria in this patient population. These are really important findings and suggest that dulaglutide may need to be considered for the management of type 2 diabetes in similar high-risk patients going forward.

Dulaglutide is a novel drug for the treatment of type 2 diabetes and functions as a GLP-1 agonist. These drugs reduce hyperglycemia in patients with type 2 diabetes and are also known to cause slight reductions in weight and blood pressure. However, pulse can increase with the use of these agents, but in this trial, suggests no adverse CV consequences.

Similar results have been noted with other GLP-1 agents as well. The renal benefits noted in this trial are similar to those noted with SGLT-2 inhibitors, and may be due to a combination of better glycemic and blood pressure control, although other undefined mechanisms are also likely to be responsible.

References

Gerstein HC, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394: 121-130.

Gerstein HC, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019; 394: 131-138.

Verma S, et al. Is it time to REWIND the cardiorenal clock in diabetes? Lancet 2019; 394: 95-97.

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