For type 2 diabetes patients older than 50 years, adding the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide to routine medical management can improve cardiovascular (CV) and renal outcomes over 5 years while also reducing glucose, blood pressure, and weight, according to 2 new analyses of the REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial published in The Lancet.

In REWIND, investigators randomly assigned 9901 participants with a mean age of 66.2 years to receive dulaglutide (1.5 mg weekly, administered subcutaneously) or placebo for up to a median 5.4 years. Results showed that 12.0% of dulaglutide recipients vs 13.4% of placebo recipients experienced myocardial infarction, stroke, or CV-related death, at an incidence rate of 2.4 vs 2.7 per 100 person-years, respectively. Dulaglutide patients had a 12% lower risk for the CV end point, mostly driven by a decrease in stroke events, Hertzel C. Gerstein, MD, of McMaster University and Hamilton Health Sciences in Ontario, Canada, and colleagues reported. For patients with a previous CV event, 18 would need to be treated for up to 5 years to prevent 1 new occurrence. For patients with CV risk factors only, 60 would need to be treated to prevent 1 new event. The team found no difference in all-cause mortality between groups.

According to Dr Gerstein and the team, the findings “suggest that dulaglutide might be effective for both primary and secondary cardiovascular prevention in a high proportion of people with type 2 diabetes.”

Additionally, the investigators examined renal outcomes in an exploratory analysis. At baseline, mean estimated glomerular filtration rate (eGFR) was relatively high at 76.9 mL/min/1.73 m² and no patient had an eGFR less than 15 mL/min/1.73 m². Only 7.9% had macroalbuminuria.

During the more than 5 year follow-up, 17.1% of dulaglutide-treated patients vs 19.6% of placebo recipients experienced new macroalbuminuria (urinary albumin to creatinine ratio of more than 33.9 mg/mmoL), a sustained eGFR decline of 30% or more, or required long-term renal replacement therapy (RRT). The incidence rates were 3.5 vs 4.1 per 100 person-years, respectively. Dulaglutide-treated patients had 15%, 23%, 11%, and 25% decreased risks of the composite renal end point, new macroalbuminuria, eGFR decline of 30% of more, and RRT, respectively.

Consistent with results from prior studies of GLP-1 receptor agonists, reduced macroalbuminuria was the biggest driver of results. For each 31 treated patients, 1 renal event would be prevented.

According to Dr Gerstein’s group, “these exploratory analyses suggest that about 5 years’ exposure to dulaglutide might reduce progression of renal disease across a wide range of cardiovascular risk, renal function, and glycaemic control. Our findings also suggest that this reduction occurs for reasons that extend beyond the effect of dulaglutide on glucose and blood pressure and is independent of the use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers.”

With respect to adverse events, significantly more dulaglutide than placebo patients suffered a gastrointestinal event: 47.4% vs 34.1%. The groups did not differ significantly in serious renal and urinary adverse events.

In an accompanying editorial, Subodh Verma, MD, PhD, of St Michael’s Hospital in Ontario, Canada, and colleagues noted that although SGLT2 inhibitors and GLP-1 receptor agonists are recommended for patients with established atherosclerotic vascular disease, evidence from the DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 and REWIND trials shows that “SGLT2 inhibitors and GLP-1 receptor agonists afford cardiovascular superiority even in primary prevention; with SGLT2 inhibitors preventing heart failure and GLP-1 receptor agonists preventing atherosclerotic events, and both potentially affording renal protection.”

The REWIND trial was conducted at 371 sites in 24 countries. Unlike previous trials, REWIND had a long follow-up of 5.4 years, a high proportion of women (46.3%), and low median hemoglobin A1c at baseline of 7.2%. A major study limitation is that more than a quarter of participants were not taking dulaglutide at their final visit, although all took the drug for more than 80% of the follow-up time.

The studies were funded by Eli Lilly and Company, the producers of dulaglutide (Trulicity).

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References

  1. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. Published online June 10, 2019. doi:10.1016/S0140-6736(19)31150-X
  2. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. Published online June 10, 2019. doi:10.1016/S0140-6736(19)31149-3
  3. Verma S, Mazer CD, Perkovic V. Is it time to REWIND the cardiorenal clock in diabetes? Lancet. Published online June 10, 2019. doi:10.1016/S0140-6736(19)31267-X