Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

Background:

• assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.

Methodology:

• multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries
  • men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1.5 mg) or placebo
  • all investigators and participants were masked to treatment assignment
  • primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population

Results:

• between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66.2 years [SD 6.5], median HbA1c 7.2% [IQR 6.6-8.1], 4589 [46.3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952)
• 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 (hazard ratio [HR] 0.88, 95% CI 0.79-0.99; p=0.026)
  • number needed to treat (NNT) = 71
• 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). 2347 (47.4%)
• participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34.1%) participants assigned to placebo (p<0.0001)

Study authors concluded that "..dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors."

Commentary:

• "The results for REWIND in terms of reducing the MACE (non-fatal MI, non-fatal stroke, or death from cardiovascular causes) is very similar to that seen in liraglutides cardiovascular safety trial (LEADER) (2):
  • comparing LEADER and REWIND
    • a primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority) where there was a 13% reduction in the MACE over a median of 3.8 years of follow-up
    • this is very similar to the 12% reduction in MACE in REWIND achieved over a median of 5.4 years but with a less emphatic P value of 0.026
    • the cardiovascular benefits seen in GLP-1 trials have become apparent 12-18 months into the trials and so the longer running of REWIND versus LEADER would, in simplistic terms, be expected to show more benefit in terms of MACE reduction
  • REWIND versus SUSTAIN-6
    • in SUSTAIN-6 there was a much more significant reduction in MACE for the active treatment arm versus placebo of 26% (p<0.001 for noninferiority, testing for superiority vs placebo not prespecified) with only a median study time of 2.1 years
    • REWIND low proportion of people (31.5%) with previous cardiovascular disease, a relatively high proportion of women (46.3%); in SUSTAIN-6 83.0% had cardiovascular disease and 41.1% women
• The results of REWIND have added to the evidence of benefit of reduction of cardiovascular risk with use of GLP-1s in patients with type 2 diabetes. The results seem, superficially at least, to be similar to those of LEADER; and did not show the same same level of MACE reduction seen in SUSTAIN-6 which occurred in a significantly shorter time-scale. However when comparing the study populations of REWIND and SUSTAIN-6, it must be noted that REWIND included a relatively low proportion of people with previous cardiovascular disease (31.5%) compared with the proportion in SUSTAIN-6 (83% with previous cardiovascular disease), and so direct comparison of the outcomes of these trials is not straightforward. " (2)

Reference:

• Gerstein HC et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-130.
• Personal Comment - Dr J McMorran, Editor in Chief, GPnotebook (17/11/19).