Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes
New results from the ADVANCE trial
- Sophia Zoungas, MD, PHD1,2,
- Bastiaan E. de Galan, MD, PHD1,3,
- Toshiharu Ninomiya, MD, PHD1,
- Diederick Grobbee, MD, PHD4,
- Pavel Hamet, MD, PHD5,
- Simon Heller, MD6,
- Stephen MacMahon, DSC, PHD1,
- Michel Marre, MD, PHD7,
- Bruce Neal, MD, PHD1,
- Anushka Patel, MD, PHD1,
- Mark Woodward, PHD1,8,
- John Chalmers, MD, PHD1 and
- on behalf of the ADVANCE Collaborative Group*
- 1The George Institute for International Health, University of Sydney, Sydney, New South Wales, Australia;
- 2Monash University, Melbourne, Victoria, Australia;
- 3Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands;
- 4Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, the Netherlands;
- 5Centre Hospitalier de l'Université de Montreal and Université de Montreal, Montreal, Quebec, Canada;
- 6University of Sheffield and Sheffield Teaching Hospitals, National Health Service Foundation Trust, Sheffield, U.K.;
- 7Hôpital Bichat-Claude Bernard and Université Paris 7, Paris, France;
- 8Mount Sinai School of Medicine, New York, New York.
- Corresponding author: Sophia Zoungas, szoungas{at}george.org.au.
Abstract
OBJECTIVE To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes.
RESEARCH DESIGN AND METHODS This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR–based regimen (target A1C ≤6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models.
RESULTS There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12–50%, P = 0.005), new onset of macroalbuminuria by 54% (35–68%, P < 0.0001), and new onset of microalbuminuria by 26% (17–34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1–32%, P = 0.04).
CONCLUSIONS The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
Footnotes
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↵*All members of the ADVANCE Collaborative Group have been listed in full previously (8). Additional authors can be found in an online appendix.
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Clinical trial reg. no. NCT00145925, clinicaltrials.gov.
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This study was designed, conducted, analyzed, and interpreted by the investigators independently of all sponsors.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received May 26, 2009.
- Accepted July 27, 2009.
- © 2009 by the American Diabetes Association.
