Muh Geot Wong1, Vlado Perkovic2, John Chalmers1, Mark Woodward3, Qiang Li1, Mark E Cooper4, Pavel Hamet5, Stephen Harrap6, Simon Heller7, Stephen MacMahon8, Giuseppe Mancia9, Michel Marre10, David Matthews11, Bruce Neal12, Neil Poulter13, Anthony Rodgers1, Bryan Williams14, Sophia Zoungas15. 1. The George Institute for Global Health, University of Sydney, Sydney, Australia. 2. The George Institute for Global Health, University of Sydney, Sydney, Australia vperkovic@georgeinstitute.org.au. 3. The George Institute for Global Health, University of Sydney, Sydney, Australia The George Institute for Global Health, University of Oxford, Oxford, U.K. Department of Epidemiology, Johns Hopkins University, Baltimore, MD. 4. Baker IDI Heart and Diabetes Institute, Melbourne, Australia. 5. Centre hospitalier de l`Universite de Montreal, Montreal, Canada. 6. Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia. 7. University of Sheffield and Sheffield Teaching Hospitals, National Health Service Foundation Trust, Sheffield, U.K. 8. The George Institute for Global Health, University of Sydney, Sydney, Australia The George Institute for Global Health, University of Oxford, Oxford, U.K. 9. Policlinico di Monza and IRCCS Istituto Auxologico Italiano, University of Milano-Bicocca, Milan, Italy. 10. Hôpital Bichat-Claude Bernard and Université Paris 7, Paris, France. 11. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K. 12. The George Institute for Global Health, University of Sydney, Sydney, Australia International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, U.K. 13. International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, U.K. 14. Institute of Cardiovascular Science, University College, London, U.K. 15. The George Institute for Global Health, University of Sydney, Sydney, Australia School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia szoungas@georgeinstitute.org.au.
Abstract
OBJECTIVE: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes. RESEARCH DESIGN AND METHODS: Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes. RESULTS: A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26). CONCLUSIONS:Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure.
RCT Entities:
OBJECTIVE: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes. RESEARCH DESIGN AND METHODS: Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes. RESULTS: A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26). CONCLUSIONS: Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure.
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