To evaluate among individuals with diabetes whether major microvascular and macrovascular events are reduced by: (1) blood pressure lowering with a perindopril/indapamide combination compared with placebo; (2) intensive glucose control (targeting a haemoglobin A1c level of ≤6.5%) with a gliclazide MR-based regimen, compared with usual care.
Participants with diabetes aged 55 years and older with at least one additional vascular risk factor were randomly assigned, using a 2 × 2 factorial design, to additional blood pressure lowering versus placebo and intensive versus standard glucose control. The primary outcomes were macrovascular (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) and microvascular (new or worsening nephropathy or retinopathy) events jointly and separately.
A total of 11 140 participants were randomly assigned to the blood pressure and glucose-lowering arms, which ended after 4.3 and 5.5 years, respectively. The effects of the two interventions were independent and additive on prespecified endpoints. Compared with placebo, additional blood pressure lowering of 5.6/2.2 mmHg was associated with reductions of 9% in the primary endpoint (P = 0.041), 18% in cardiovascular death (P = 0.027), 14% in total mortality (P = 0.025), and 21% in total renal events (P < 0.01). Compared with standard glucose control, intensive control (mean in-trial 0.67 percentage point reduction in haemoglobin A1c level) was associated with reductions of 10% in the primary endpoint (P = 0.013), 14% in major microvascular events (P = 0.01) and 11% in total renal events (P < 0.001).
Additional blood pressure lowering and intensive glucose control, as achieved in ADVANCE, produce independent benefits and, when combined, substantially reduced cardiovascular mortality and all-cause mortality and improved renal outcomes.