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.

Baker Heart and Diabetes Institute Melbourne VIC Australia

Department of Internal Medicine Dresden Technical University Dresden Germany

Department of Medicine K2 Karolinska Institutet Stockholm Sweden

Department of Medicine Oregon Health and Science University Portland OR USA

Department of Medicine University of Washington Seattle WA USA

ECLA Estudios Clínicos Latinoamérica Rosario Argentina

Eli Lilly and Company Indianapolis IN USA

Endocrinology and Nutrition Department Hospital Clínic i Universitari Barcelona Spain

Institut Universitaire de Cardiologie et Pneumologie Université Laval Québec City QC Canada

Instituto Dante Pazzanese de Cardiologia and University Santo Amaro São Paulo Brazil

Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca Romania

Latvijas Universitate Riga Latvia

Li Ka Shing Knowledge Institute St Michael's Hospital University of Toronto Toronto ON Canada

Medical University of South Carolina Charleston SC USA

Memphis Veterans Affairs Medical Center Memphis TN USA

Mossakowski Medical Research Centre Polish Academy of Sciences and Central Clinical Hospital MSWiA Warsaw Poland

National Medical Research Center of Cardiology Moscow Russia

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton ON Canada

Research Institute FOSCAL and Medical School Universidad de Santander UDES Bucaramanga Colombia

Robert Koch Medical Centre Sofia Bulgaria

Semmelweis University Hungarian Institute of Cardiology Budapest Hungary

St John's Research Institute Bangalore India

Taichung Veterans General Hospital Taichung Taiwan

Universidad de Guadalajara Centro Universitario de Ciencias de la Salud Guadalajara Mexico

Universidad de La Frontera Temuco Chile

University Hospital Motol Prague Czech Republic

University of Cape Town Cape Town South Africa

University of Edinburgh Edinburgh UK

Victoria University of Wellington Wellington New Zealand

Yonsei University Health System Seoul South Korea

Lancet. 2019 Jul 13;394(10193):95-97. doi: 10.1016/S0140-6736(19)31267-X. PubMed

Lancet. 2020 Feb 22;395(10224):559. doi: 10.1016/S0140-6736(19)32550-4. PubMed

References provided by Crossref.org

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

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ClinicalTrials.gov
NCT01394952