Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus: The ADVANCE Trial

Study Questions:

Visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. To what degree do these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus?


ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) was a factorial randomized placebo-controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. This analysis included 8,811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation [SD]) and maximum SBP were determined during the first 24 months after randomization.


Mean age was 66 years, and 42% were female. Mean (1-SD) baseline SBP was 145(21) and diastolic BP 81(11) mm Hg; mean on-study SBP was 137(15) and DBP 11(5) mm Hg. The coefficient of variation % for SBP was 7.9(3.4) and maximum SBP 152(19) mm Hg. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both p < 0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99–2.39) for macrovascular events and 1.84 (1.19–2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios for the highest tenth were 3.64 (1.73–7.66) and 2.18 (1.04–4.58), respectively.


The authors concluded that visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus.


The magnitude of the increase in event rates with visit-to-visit variability in BP is impressive. But even more impressive and worrisome is the range of differences from the first to tenth decile in both the placebo and treatment groups, which were similar. In the active drug group, the first decile SD was 0.4 to 5.0, 5.1 and tenth 16.8 to 33.5 mm Hg. The ranges of maximum SBP in the active drug group were 91.0 to 127.0 in the first, and 173.0 to 247.0 mm Hg in the tenth decile. The clinical implications are highly relevant in regard to choice and frequency of drugs, as well as morning BP targets in hypertension.

Clinical Topics: Prevention, Vascular Medicine, Hypertension

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Blood Glucose, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Blood Pressure, Diabetic Angiopathies, Hypertension

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