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

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 <or=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.

Trial registration: ClinicalTrials.gov NCT00145925.

Figure 1

Relative effects of routine blood pressure–lowering and intensive glucose control strategy on all prespecified renal events. The effects of treatment (HRs) were estimated from unadjusted Cox proportional hazards models that used all available data at 4.3 years of follow-up. The diamonds incorporate the point estimates, represented by the vertical dashed lines, and the 95% CIs of the overall effects within categories; for subcategories, black squares represent point estimates (with the area of each square proportional to the inverse variance of each estimate), and horizontal lines represent 95% CIs. The HRs and relative risk reductions are given for intensive glucose control compared with standard glucose control in the blood pressure–lowering arm and for perindopril-indapamide (Per-Ind) compared with placebo in the glucose-lowering arm.

Figure 2

Combined effects of routine blood pressure–lowering and intensive glucose control strategy on the incidence of death from any cause. Incidence of death from any cause is presented as the annual event rate (percent) by the four randomized treatment groups: intensive glucose control and perindopril-indapamide (Per-Ind), standard glucose control and perindopril-indapamide, intensive glucose control and placebo, and standard glucose control and placebo. The effects of treatment (HRs and P values) were estimated from unadjusted Cox proportional hazards models that used all available data at 4.3 years of follow-up. The diamond incorporates the point estimate, represented by the vertical dashed line and the 95% CI of the overall effect. The HRs and relative risk reductions (RRRs) are given for intensive glucose control compared with standard glucose control in the blood pressure (BP)-lowering arm and for perindopril-indapamide compared with placebo in the glucose-lowering arm.