GLP-1 receptor agonist lowers MACE in broad range of persons with T2DM
The data of the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial show that dulaglutide, an injectable glucagon-like peptide-1 receptor agonist (GLP-1RA), demonstrates superiority in the reduction of cardiovascular events for a broad range of people living with type 2 diabetes (T2DM). The data were presented at the American Diabetes Association’s (ADA’s) 79th Scientific Sessions. The study confirmed a CV benefit, without unexpected side effects or an increase in hypoglycemia.
The REWIND trial is the first study to include a majority of participants (69%) with no history of cardiovascular disease (CVD) at enrolment. The REWIND trial had a median follow-up period of more than five years, the longest for a CV outcome trial of a GLP-1RA.
This international, double-blind randomized controlled trial enrolled 9,901 people, age 50 and older with T2DM from 24 countries at 371 care centres. The study evaluated whether weekly subcutaneous injections of 1.5 mg dulaglutide could reduce major adverse cardiovascular events (MACE) compared to placebo, when added to the anti-hyperglycemic regimen. A wide spectrum of participants similar to those seen in a community practice were studied. Many with guideline-recommended glucose levels. Participants had a mean A1C level of 7.3% (with half having a level below 7.2%) at the beginning of the study, 46% were women, and 69% of participants did not have prior CVD. All participants had CV risk factors. Researchers randomly assigned participants to receive either the placebo or dulaglutide for up to eight years, and the average follow-up duration was 5.4 years.
REWIND’s primary CV outcome was the first occurrence of MACE, the composite of CV death or non-fatal myocardial infarction or non-fatal stroke. A significant 12% reduction in MACE was observed with dulaglutide vs. placebo (HR=0.88, 95% CI: 0.79-0.99), which was sustained throughout the duration of the trial. This risk reduction was consistent in subgroups based on having established CVD (HR=0.87, 95% CI: 0.74-1.02) or not (HR=0.87, 95% CI: 0.74-1.02), having baseline A1c ≥7.2% (HR=0.86, 95% CI: 0.74-1.00) or <7.2% (HR=0.90, 95% CI: 0.76-1.06) and in women (HR=0.90, 95% CI: 0.76-1.06) and men (HR=0.90, 95% CI: 0.79-1.04). All three MACE components contributed to the significant reduction dulaglutide provided, including CV death (HR=0.91, 95% CI: 0.78-1.06), non-fatal heart attack (HR=0.96, 95% CI: 0.79-1.16) and non-fatal stroke (HR=0.76, 95% CI: 0.61-0.95).
A composite clinical microvascular outcome (as a secondary outcome) comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality, was also significantly reduced (HR=0.87, 95% CI: 0.79-0.95). Analysis of the renal outcomes suggests long-term dulaglutide use was associated with reduced progression of renal disease in people with T2DM. Moreover, A1c was reduced in the dulaglutide group by 0.46%, while the placebo group showed an increase of 0.16%. Participants receiving dulaglutide lost on average 2.95 kg and those in the placebo group 1.49 kg.
Dulaglutide was also evaluated in the AWARD-7 study, in people with T2DM and moderate-to-severe chronic kidney disease (CKD) and A1c of 7.5% - 10.5%. Patients were randomized to dulaglutide 1.5 mg or 0.75 mg, or to insulin glargine. Data of AWARD-7 were also presented at the ADA congress, and showed that those treated with dulaglutide 1.5 mg once weekly had a reduction of clinical events associated with end-stage kidney disease (ESKD) including dialysis and with a kidney transplant. Moreover, a slower rate of kidney function decline was seen, compared to people who used insulin or a lower dose of dulaglutide.
The REWIND data were simultaneously published in The Lancet.