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 m2 (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.
Bibliographical noteFunding Information:
HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk, and Sanofi; honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, Kowa, and Cirius. HMC reports research grants from Eli Lilly, AstraZeneca, Regeneron, Pfizer, Roche, Sanofi, and Novo Nordisk; honoraria for speaking from Eli Lilly and Regeneron; consulting fees from Eli Lilly, Novartis, Regeneron, Sanofi, and Novo Nordisk; and shares in Bayer and Roche. RD reports research grants from the Population Health Research Institute, Duke Clinical Research Institute, Montreal Health Innovations Coordinating Center, CPC Clinical Research, DalCor, Amgen, Lepetit, and Cirius; honoraria for speaking from Sanofi; and consulting fees from Sanofi and Cirius. MCR reports grants to his institution from Eli Lilly, AstraZeneca, and Novo Nordisk; honoraria for consulting from Adocia, DalCor, GlaxoSmithKline, and Theracos; and honoraria for speaking from Sanofi. LR reports grants from the Swedish Heart Lung Foundation, Stockholms Läns Landsting, and Boehringer Ingelheim, and fees for consulting and speaking from Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck, and Bayer. ML is employed by Eli Lilly, owns stock, and has a patent pending, FTB is employed by Eli Lilly and has a patent pending. CMA is employed by Eli Lilly and owns stock. DX reports grants from Cadila, Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis, Pfizer, Bristol-Myers Squibb, the UK Medical Research Council, and the Wellcome Trust. JB reports consulting fees from Eli Lilly, ReCor, and Medtronic. WCC reports grants from Eli Lilly. EF reports consulting and speaking fees from AstraZeneca, Boehringer Ingelheim, Bioton, Mundipharma, MSD, Novartis, Novo Nordisk, and Servier. MH reports honoraria for speaking from Sanofi, Novo Nordisk, Amgen, MSD, and AstraZeneca. FL reports grants from the Population Health Research Institute. LAL reports grants from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Novo Nordisk, Sanofi, and GSK; honoraria for speaking from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, and Sanofi; and consulting fees from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. JES reports grants from Eli Lilly, and consulting fees or speaking honoraria from AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi, Mylan, Boehringer Ingelheim, Merck Sharp and Dohme, and Abbott. TT-K reports consulting fees from Bayer, AstraZeneca, and Hamilton Health Sciences. All other authors declare no competing interests.
The trial was sponsored and funded by Eli Lilly and Company led by an international steering committee coordinated by the Population Health Research Institute in Hamilton, Canada, which also did all data analyses. Site management and data collection were provided by ICON Clinical Research. Scientists employed by the funder were on the steering committee and contributed to trial design, trial implementation, and data interpretation. All authors and the sponsor jointly made the decision to submit for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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