Hertzel C Gerstein1, Helen M Colhoun2, Gilles R Dagenais3, Rafael Diaz4, Mark Lakshmanan5, Prem Pais6, Jeffrey Probstfield7, Fady T Botros5, Matthew C Riddle8, Lars Rydén9, Denis Xavier6, Charles Messan Atisso5, Leanne Dyal10, Stephanie Hall10, Purnima Rao-Melacini10, Gloria Wong10, Alvaro Avezum11, Jan Basile12, Namsik Chung13, Ignacio Conget14, William C Cushman15, Edward Franek16, Nicolae Hancu17, Markolf Hanefeld18, Shaun Holt19, Petr Jansky20, Matyas Keltai21, Fernando Lanas22, Lawrence A Leiter23, Patricio Lopez-Jaramillo24, Ernesto German Cardona Munoz25, Valdis Pirags26, Nana Pogosova27, Peter J Raubenheimer28, Jonathan E Shaw29, Wayne H-H Sheu30, Theodora Temelkova-Kurktschiev31. 1. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. Electronic address: gerstein@mcmaster.ca. 2. University of Edinburgh, Edinburgh, UK. 3. Institut Universitaire de Cardiologie et Pneumologie, Université Laval, Québec City, QC, Canada. 4. ECLA, Estudios Clínicos Latinoamérica, Rosario, Argentina. 5. Eli Lilly and Company, Indianapolis, IN, USA. 6. St John's Research Institute, Bangalore, India. 7. Department of Medicine, University of Washington, Seattle, WA, USA. 8. Department of Medicine, Oregon Health & Science University Portland, OR, USA. 9. Department of Medicine K2, Karolinska Institutet, Stockholm, Sweden. 10. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. 11. Instituto Dante Pazzanese de Cardiologia and University Santo Amaro, São Paulo, Brazil. 12. Medical University of South Carolina, Charleston, SC, USA. 13. Yonsei University Health System, Seoul, South Korea. 14. Endocrinology and Nutrition Department, Hospital Clínic i Universitari, Barcelona, Spain. 15. Memphis Veterans Affairs Medical Center, Memphis, TN, USA. 16. Mossakowski Medical Research Centre, Polish Academy of Sciences and Central Clinical Hospital MSWiA, Warsaw, Poland. 17. Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania. 18. Department of Internal Medicine, Dresden Technical University, Dresden, Germany. 19. Victoria University of Wellington, Wellington, New Zealand. 20. University Hospital Motol, Prague, Czech Republic. 21. Semmelweis University, Hungarian Institute of Cardiology, Budapest, Hungary. 22. Universidad de La Frontera, Temuco, Chile. 23. Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 24. Research Institute, FOSCAL and Medical School, Universidad de Santander UDES, Bucaramanga, Colombia. 25. Universidad de Guadalajara Centro Universitario de Ciencias de la Salud, Guadalajara, Mexico. 26. Latvijas Universitate, Riga, Latvia. 27. National Medical Research Center of Cardiology, Moscow, Russia. 28. University of Cape Town, Cape Town, South Africa. 29. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 30. Taichung Veterans General Hospital, Taichung, Taiwan. 31. Robert Koch Medical Centre, Sofia, Bulgaria.
Abstract
BACKGROUND:Two glucagon-likepeptide-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.
RCT Entities:
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.
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