Rationale and design of the ADVANCE study: A randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with type 2 diabetes mellitus

Rationale Individuals with type 2 diabetes mellitus have an increased risk of vascular disease, which is reduced by lowering the blood pressure of patients with hypertension. However, the association between blood pressure and vascular risk appears to be continuous across a broad range of values of blood pressure, and it is likely that blood pressure-lowering will confer similar benefits in non-hypertensive individuals. Intensive glucose-lowering in these patients have also been shown to reduce microvascular disease, but the effects on macrovascular outcomes remain uncertain. Objectives To determine the effects on macrovascular and microvascular disease of first, lowering blood pressure using a very-low-dose angiotensin-converting enzyme (ACE) inhibitor-diuretic combination compared with placebo; and second, intensive glucose control targeting a glycated haemoglobin A_1c concentration of 6.5% or less compared with usual glucose control, in high-risk hypertensive and non-hypertensive individuals with type 2 diabetes. Design A 2 × 2 factorial randomised, controlled trial with a scheduled period of treatment and follow-up of 4.5 years. Setting The study will be conducted in approximately 200 centres in Australasia, Asia, Europe and North America. Participants The study will include 10 000 adults with type 2 diabetes at increased risk of vascular disease. Individuals will be eligible irrespective of baseline blood pressure, baseline glucose concentration or requirement for background ACE inhibitor treatment. Interventions After 6 weeks receiving the active perindopril-indapamide combination, eligible individuals will be randomly allocated to receive continued very-low-dose perindopril-indapamide combination or matching placebo; and to an intensive modified-release gliclazide-based glucose control regimen, or usual guidelines-based treatment. Study outcomes The primary outcomes are, first the composite of non-fatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. Secondary outcomes include cause-specific cardiovascular end-points in addition to dementia and all-cause mor-tality.