Five-Year REWIND Results Show Sustained Dulaglutide CV Benefits

Hertzel C. Gerstein, MD, MSc

Results from the REWIND trial—the longest ever study to assess cardiovascular outcomes in patients treated with a GLP-1 receptor agonist—show subcutaneous dulaglutide (Trulicity) is associated with a 12% decrease in cardiovascular events versus placebo in older patients with type 2 diabetes (T2D).

The findings from the five-plus year trial show the furthest real-world benefits of a cardiovascular risk-reducing agent in the field of diabetes.

Hertzel C. Gerstein, MD, MSc, director of the Division of Endocrinology & Metabolism and the Diabetes Care and Research Program at McMaster University, shared the cardiovascular outcome findings in a session at the American Diabetes Association (ADA) 2019 Scientific Sessions in San Francisco, CA. He and his colleagues had sought to assess the effect of dulaglutide on major adverse cardiovascular events (MACE) when added to T2D patients’ antihyperglycemic therapies.

The randomized, double-blind, multi-center trial recruited 9901 patients from 371 sites across 24 countries. Patients were recruited from August 2011 to August 2013, and were required to be at least 50 years old with T2D plus either a previous cardiovascular event or risk factors.

Mean patient age was 66.2 years, with women comprising 4589 (46.3%) participants. The median baseline hemoglobin A1c (HbA1c) level was 7.2%. Patients were randomized 1:1 to either subcutaneous dulaglutide injection (1.5 mg) or placebo. Investigators assessed for a primary outcome of first occurrence of composite endpoint of MACE—including non-fatal myocardial infarction (MI), non-fatal stroke, or death from cardiovascular causes.

Patients received physician follow-up at least every 6 months for incident cardiovascular and other serious outcomes. Median patient follow-up was 5.4 years.

The primary composite MACE outcome occurred in 594 (12.0%) dulaglutide-treated patients—an incidence rate of 2.4 per 100 person-years. The rates were significantly improved versus placebo, in which 663 (13.4%) patients reached the primary outcome for an incidence rate of 2.7 per 100 person-years (HR .88; 95% CI: .79 - .99; P= .026).

Gerstein noted the disparity between composite MACE rates in the treatment groups was apparent by 1 year of treatment, and only increased progressive and proportionally over the following four-plus years.

Among separate events versus placebo, dulaglutide reported no significant long-term benefit against nonfatal MI (HR .96; 95% CI: .79 — 1.16; P= .65), a minimal benefit against cardiovascular death (HR .91; 95% CI: .78 — 1.06; P= .21), and a major benefit against nonfatal stroke (HR .76; 95% CI: .61 - .95; P= .017).

Dulaglutide benefit for all-cause death versus placebo over five-plus years was 10% (HR .90; 95% CI: .80 — 1.01). Across 7 patient subgroups based on sex, age, and diabetes duration, dulaglutide was most beneficial for patients aged < 66 years (n= 263 [10.0%]; rate per 100 years: 1.9), females (n= 218 [9.5%]; rate per 100 years: 1.8), and patients with diabetes for < 5 years (n= 128 [10.4%]; rate per 100 years: 2.0). That said, P values were not adjusted for multiple testing, and were not significant.

A greater rate of dulaglutide-treated patients (n= 2347 [47.4%]) reported gastrointestinal adverse events during follow-up than those assigned to placebo (n= 1687 [34.1%]; P< .0001)

Equally telling of dulaglutide’s benefit was the supplemental findings showing treated patients’ lessened reliance on supplemental cardiovascular or T2D therapies. A lesser rate of dulaglutide patients were on metformin, SGLT-2 inhibitor, insulin, statin, sulfonylurea, and other common drugs than patients administered placebo.

Investigators concluded the wide, spanning data indicates dulaglutide’s potential as a glycemic control therapy in middle-aged and older patients with T2D, either with a previous cardiovascular disease or risk factors.

“When we actually tested the proponents of the primary outcome for any heterogeneity, there was none whatsoever, showing the results clearly apply across all the proponents,” Gerstein said.

The study, “Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial,” was published online in The Lancet.