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. Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation

Abstract

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 nonhypertensive 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 A1c 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 x 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 10000 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 mortality.