Summary
Background
Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people
with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term
effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory
analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.
Methods
REWIND was a multicentre, randomised, double-blind, placebo-controlled trial 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 and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine
ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from
urine and serum values measured in local laboratories every 12 months. The primary
outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction,
non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including
a composite microvascular outcome), and safety outcomes of this trial have been reported
elsewhere. In this exploratory analysis, we investigate the renal component of the
composite microvascular outcome, defined as the first occurrence of new macroalbuminuria
(UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or
chronic renal replacement therapy. Analyses were by intention to treat. This trial
is registered with
ClinicalTrials.gov, number
NCT01394952.
Findings
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly
assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%)
had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m
2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820
person-years, the renal outcome developed in 848 (17·1%) participants at an incidence
rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants
at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio
[HR] 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria
(HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained
decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement
therapy.
Interpretation
Long-term use of dulaglutide was associated with reduced composite renal outcomes
in people with type 2 diabetes.
Funding
Eli Lilly and Company.
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© 2019 Elsevier Ltd. All rights reserved.