Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes

Abstract

Objective: We prospectively investigated in hypertensive patients with type 2 diabetes if bedtime treatment with ≥1 hypertension medications exerts better blood pressure control and cardiovascular risk reduction than conventional therapy, in which all medications are ingested in the morning.

Research design and methods: We conducted a prospective, randomized, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean ± SD age 62.5 ± 10.8 years, randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. Ambulatory blood pressure was measured for 48 h at baseline and again annually or even more frequently (quarterly) after adjustments in treatment.

Results: After a median follow-up of 5.4 years, patients ingesting ≥1 hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 [95% CI 0.21-0.54]; P < 0.001). The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 [0.10-0.61]; P = 0.003). Patients treated at bedtime showed significantly lower sleep time blood pressure mean and higher prevalence of controlled ambulatory blood pressure (62.5 vs. 50.9%; P = 0.013). There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P < 0.001).

Conclusions: Among patients with diabetes, treatment with ≥1 hypertension medications at bedtime, compared with all medications upon waking, resulted in improved ambulatory blood pressure control and significantly reduced cardiovascular morbidity and mortality.

Trial registration: ClinicalTrials.gov NCT00295542.

Figures

Figure 1

Top: Kaplan-Meier survival curves as a function of time of day of hypertension treatment, i.e., for patients with type 2 diabetes ingesting either all their blood pressure–lowering medications upon awakening or ≥1 medications at bedtime. Bottom: Hazard ratios (95% CIs) of CVD events (adjusted by age and sex) as a function of time of day of hypertension treatment, i.e., for patients with type 2 diabetes ingesting either all their blood pressure–lowering medications upon awakening or ≥1 medications at bedtime. Total events include death (from all causes), cardiovascular events (myocardial infarction, angina pectoris, and coronary revascularization), cerebrovascular events (stroke and transient ischemic attack), heart failure, and other events (acute arterial occlusion of lower extremities and thrombotic occlusion of the retinal artery). Major events include cardiovascular deaths, myocardial infarction, ischemic stroke, and hemorrhagic stroke.

Figure 2

Hazard ratio of CVD events (adjusted by age, sex, and number of hypertension medications used for treatment) as a function of achieved asleep SBP mean (top) and daytime clinic SBP (bottom) at the time of the last ABPM evaluation. Studied population was divided into five classes of equal size (quintiles).