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Highlights from

EASD 2019

55th Annual Meeting of the European Association for the Study of Diabetes

Barcelona, Spain 16 - 20 September 2019

Dulaglutide reduces risk of CV and renal composite outcomes in patients with T2D

Take-home messages
  • The REWIND trial studied the effectiveness of once-weekly dulaglutide in 9,901 patients with T2D at moderate-to-high risk of CV events
  • Dulaglutide treatment resulted in a 12% lower risk of the MACE composite outcome compared with placebo
  • REWIND demonstrated that dulaglutide had a beneficial effect on renal outcome compared with placebo
"the REWIND trial showed that the benefit of the drug was […] almost identical in people with vs without a history of previous cardiovascular disease"

Professor Hertzel Gerstein, Endocrinologist, McMaster University, Canada

Patients with type 2 diabetes (T2D) have a two-fold higher chance of experiencing a cardiovascular (CV) event. Recent findings from REWIND, a trial designed to analyse the CV outcomes of patients with T2D being treated with the GLP-1 receptor agonist (GLP-1RA) dulaglutide, were presented at the EASD 2019 annual meeting by Professor Matthew Riddle, Professor of Medicine, Oregon Health and Science University, US and Professor Hertzel Gerstein, Endocrinologist and Population Health Institute Chair in Diabetes Research, McMaster University and Hamilton Health Sciences, Canada.

Study design
REWIND was a multicentre, randomised, double-blind, placebo-controlled, phase III trial studying the effect of dulaglutide compared with placebo on patients with T2D and moderate-to-high risk of CV disease. 9,901 participants across 24 countries were enrolled in the study, with an average age of 66 and of whom 46% were female. Eligible patients were either aged ≥50 with vascular disease, aged ≥55 with subclinical vascular disease, or aged ≥60 with two CV risk factors. Once-weekly subcutaneous dulaglutide or placebo was added to the patients’ existing treatment regimens.

Primary outcome: major adverse CV events (MACE: CV death, first occurrence of non-fatal myocardial infarction or non-fatal stroke).

Secondary outcomes included:

  • microvascular composite outcome
  • hospitalisation for unstable angina
  • hospitalisation or urgent visit for heart failure
  • the individual components of primary outcome
  • total mortality

An exploratory analysis examined the renal outcomes associated with dulaglutide treatment in this trial.

Main outcomes
Median follow-up time was 5.4 years (interquartile range 5.1-5.9), equating to 51,820 person-years. Patients at enrolment had a mean HbA1c of 7.3%, with a mean estimated glomerular filtration rate (eGFR) of 76.9 mL/min/1.73 m2. 22.2% of patients had an eGFR <60 mL/min/1.73 m2.

Cardiovascular outcomes
Over the course of the study, the MACE outcome occurred in 594 patients in the dulaglutide group (12.0%) and 663 patients in the placebo group (13.4%; HR 0.88; 95% CI 0.79-0.99; p=0.026). This reductive effect began within the first 12 months and continued throughout the whole study period. The results were similar, regardless of CV history:

  Individuals with MACE (%)    
  Dulaglutide Placebo HR (95% CI) p interaction
Overall 12.0% 13.4% 0.88 (0.79-0.99)  
Prior CV disease 17.9% 20.3% 0.87 (0.74-1.02) 0.97
No prior CV disease 8.9% 10.1% 0.87 (0.74-1.02)
Prior CV event 19.1% 23.4% 0.79 (0.66-0.96) 0.18
No prior CV event 10.2% 10.8% 0.93 (0.81-1.07)

These results are consistent with those from similar GLP-1RA CV outcomes trials. A recent meta-analysis of seven such studies revealed that GLP-1RAs reduce MACE by 13% (HR 0.87; 95% CI 0.80-0.96; p=0.011) with no significant heterogeneity between subgroups of patients with and without CV disease. The results from REWIND were also consistent across subgroups defined by sex, higher or lower BMI, and higher or lower HbA1c.

The incidence of the individual MACE components was lower with dulaglutide compared with placebo, with the largest risk reduction seen for non-fatal stroke (HR 0.76; 95% CI 0.61-0.95). No difference was seen for hospitalisation for heart failure or for all-cause death.

Renal outcomes
In an exploratory analysis, the microvascular renal composite of new macroalbuminuria, a ≥30% decrease in eGFR, or renal replacement therapy, was compared in the dulaglutide and placebo groups. New macroalbuminuria was defined as the first occurrence of a urine albumin: creatinine ratio of >33.9 mg/mmol. The risk of this composite outcome was seen to be relatively lower with dulaglutide than with placebo from the first renal measurement at 12 months, and this benefit was seen throughout the trial, with an event occurring in 17.1% and 19.6% of individuals by trial end in the treatment and control groups, respectively (HR 0.85; 95% CI 0.77-0.93; p=0.0004). This difference was largely driven by the new macroalbuminuria component (HR 0.77; 95% CI 0.68-0.87; p<0.0001). There was no significant difference in renal replacement therapy between the two groups. Dulaglutide did not demonstrate higher numbers of patients achieving an eGFR fall of ≥30% compared with placebo, but did show a statistical improvement in patients reaching greater eGFR targets:

  • ≥30% decline in eGFR: HR 0.89; 95% CI 0.78-1.01; p=0.066
  • ≥40% decline in eGFR: HR 0.70; 95% CI 0.57-0.85; p=0.0004
  • ≥50% decline in eGFR: HR 0.56; 95% CI 0.41-0.76; p=0.0002

Safety
47.4% of individuals receiving dulaglutide reported a gastrointestinal event during follow-up compared with 34.1% of individuals receiving placebo (p<0.0001), consistent with the expected tolerability of the GLP-1RA class. There was no difference in the incidence of other adverse events of special interest between the two groups.

Conclusions
REWIND demonstrated that dulaglutide can provide CV benefits for patients with T2D at moderate-to-high CV risk. The trial population is largely representative of patients seen in clinical practice, and as only 31.5% of the participants had CV disease prior to this study, REWIND is the largest primary prevention CV study with a GLP-1RA. The results thus suggest that earlier intervention can be advantageous in reducing CV comorbidities in patients with T2D. Furthermore, an exploratory analysis of the REWIND data showed long-term dulaglutide to have a beneficial effect on renal outcome in this population.

Based on the “Unique features and findings of the long-term REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial” session held on Thursday 19 September 2019 at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD), Barcelona, Spain, 16-20 September 2019:

Gerstein H C. Effect of dulaglutide on serious health outcomes (OP S39.1); Riddle M. New findings from the REWIND trial (OP S39.2).

BMI: body mass index; CI: confidence interval; CV: cardiovascular; eGFR: estimated glomerular filtration rate; GLP-1RA: GLP-1 receptor agonist; HR: hazard ratio; MACE: major adverse cardiovascular event; T2D: type 2 diabetes.

Top image: @ iStockPhoto: Kwangmoozaa

Article image: yodiyim

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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