There is strong association between diabetes and increased risk of end-organ damage, stroke, and cardiovascular disease (CVD) morbidity and mortality. Non-dipping (<10% decline in the asleep relative to awake blood pressure [BP] mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and consistently associated with increased CVD risk. The reported prevalence of non-dipping in diabetes is highly variable, probably due to differences in the study groups (normotensive subjects, untreated hypertensives, treated hypertensives), relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Accordingly, we evaluated the influence of diabetes on the circadian BP pattern by 48-h ABPM (rather than for 24 h to increase reproducibility of results) during which participants maintained a diary listing times of going to bed at night and awakening in the morning. This cross-sectional study involved 12 765 hypertensive patients (6797 men/5968 women), 58.1 ± 14.1 (mean ± SD) yrs of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes. At the time of study, 525/3314 patients with/without diabetes were untreated for hypertension, and the remaining 2429/6497 patients with/without diabetes were treated. Hypertension was defined as awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85 mm Hg, or asleep SBP/DBP mean ≥120/70 mm Hg, or BP-lowering treatment. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of microalbuminuria, proteinuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, and/or obesity, plus higher glucose, creatinine, uric acid, and triglycerides, but lower cholesterol and estimated glomerular filtration rate. In patients with diabetes, ambulatory SBP was significantly elevated (p < .001), mainly during the hours of nighttime sleep and initial hours after morning awakening, independent of presence/absence of BP-lowering treatment. Ambulatory DBP, however, was significantly higher (p < .001) in patients without diabetes, mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p < .001) throughout the entire 24 h in patients with diabetes, even after correcting for age. Prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1% vs. 45.9%; p < .001). Largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 8.1% in patients with and without diabetes, respectively; p < .001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients...

Abstract-Patients with resistant hypertension present high prevalence of a non-dipper blood pressure pattern. Recent results indicate that non-dipping is related partly to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. Accordingly, we investigated the impact of treatment time on the blood pressure pattern in 700 patients with resistant hypertension on the basis of clinic measurements who were studied by 48-hour ambulatory monitoring. Among them, 299 patients received all their medication on awakening, and 401 were taking Ն1 antihypertensive drug at bedtime. The percentage of patients with controlled ambulatory blood pressure was double in patients taking 1 drug at bedtime (Pϭ0.008). Among the 578 patients with true resistant hypertension, subjects receiving 1 drug at bedtime showed a significant reduction in the 24-hour mean of systolic and diastolic blood pressure (3.1 and 1.6 mm Hg, respectively; PϽ0.011). This reduction was much more prominent during nighttime (5.1 and 3.0 mm Hg; PϽ0.001). Accordingly, the diurnal/nocturnal blood pressure ratio was significantly increased by 2.7 and the prevalence on non-dipping reduced (56.9 versus 81.9%; PϽ0.001) in patients taking 1 drug at bedtime. Compared with patients receiving all drugs on awakening, subjects with 1 drug at bedtime also showed significant reductions in the average values of glucose, cholesterol, fibrinogen, and urinary albumin excretion (PϽ0.011). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest-activity cycle of each patient to improve control and to avoid the non-dipper pattern associated to higher cardiovascular risk. Key Words: blood pressure monitoring, ambulatory Ⅲ circadian rhythm H ypertension has been defined as resistant to treatment, or refractory, when a therapeutic plan that has included attention to lifestyle measures and the prescription of Ն3 antihypertensive drugs in adequate doses has failed to lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) sufficiently. 1,2 Patients with resistant hypertension are at a greater risk for stroke, renal insufficiency, and morbid cardiovascular events than patients whose blood pressure (BP) is well controlled by medical therapy. 3 Indeed, in patients with resistant hypertension, poor BP control may engender a consistent amount of target organ damage, and this, in turn, may become a cause of resistance to treatment. 4 It has also been reported that most patients receiving antihypertensive therapy show a "white-coat effect" that could cause an overestimation of their real BP. 4,5 The impact of this effect on the occurrence of resistant hypertension seems to be highly variable among different studies, ranging from 20% up to 43% of the patients. 6,7 Ambulatory BP monitoring (ABPM) is the only method to differentiate "isolated office resistant hypertension" from "true resistant hypertension." [5][6][7] It has thus been suggested that ABPM should be performed as an...

Administration of valsartan at bedtime as opposed to upon wakening improves the sleep-time relative blood pressure (BP) decline towards a more normal dipper pattern without loss of 24-h efficacy. Amlodipine, however, has been shown to be effective in reducing BP throughout the day and night, independent of dosing time. A large proportion of hypertensive subjects cannot be properly controlled with a single medication. However, no study has yet investigated the potential differing effects of combination therapy depending of the time-of-day of administration. Accordingly, the authors investigated the administration-time-dependent BP-lowering efficacy of valsartan/amlodipine combination. The authors studied 203 hypertensive subjects (92 men/111 women), 56.7 +/- 12.5 yrs of age, randomized to receive valsartan (160 mg/day) and amlodipine (5 mg/day) in one of the following four therapeutic schemes: both medications on awakening, both at bedtime, either one administered on awakening and the other at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after 12 wks of treatment. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. BP-lowering efficacy (quantified in terms of reduction of the 48-h mean of systolic/diastolic BP) was highest when both hypertension medications were ingested at bedtime, as compared to any one of the three other tested therapeutic schemes (17.4/13.4 mm Hg reduction with both medications on awakening; 15.1/9.6 mm Hg with valsartan on awakening and amlodipine at bedtime; 18.2/12.3 mm Hg with valsartan at bedtime and amlodipine on awakening; 24.7/13.5 mm Hg with both medications at bedtime; p < .018 between groups). The sleep-time relative BP decline was significantly increased towards a more normal dipper pattern only when both medications were jointly ingested at bedtime (p < .001). Bedtime dosing of the combination of the two medications also resulted in the largest percentage of controlled subjects among all the assessed therapeutic schemes (p = .003 between groups). In subjects requiring combination therapy to achieve proper BP control, the association of amlodipine and valsartan efficiently reduces BP for the entire 24 h independent of dosing time. However, the greater proportion of controlled patients, improved efficacy on lowering asleep BP mean, and increased sleep-time relative BP decline suggest valsartan/amlodipine combination therapy should be preferably administered at bedtime.

Torasemide is a high-ceiling loop diuretic frequently used in the treatment of congestive heart failure, renal failure, and hypertension. Low doses of torasemide (2.5 to 5 mg/day) do not elevate 24 h natriuresis, and they constitute effective monotherapy for mild-to-moderate uncomplicated essential hypertension according to results based on clinic blood pressure (BP). However, there has yet to be a proper evaluation of its 24 h efficacy or potential dependency of effects according to the circadian time of treatment. Accordingly, this trial investigated the administration time-dependent efficacy of torasemide in uncomplicated essential hypertensive patients. We studied a total of 113 grade 1 and 2 hypertensive patients, 51.7+/-10.6 yrs of age, randomly assigned to receive torasemide (5 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after six weeks of treatment. The efficacy of torasemide was significantly greater with bedtime dosing (i.e., 14.8 and 9.5 mmHg reduction in the 24 h mean systolic and diastolic BP, respectively) as compared with morning dosing upon awakening (i.e., 6.4 and 3.4 mmHg reduction in mean systolic and diastolic BP; p<0.001 between the two treatment-time groups). The percentage of patients with controlled ambulatory BP after treatment was also higher after bedtime treatment (64 vs. 23%; p<0.001). Safety and tolerability were comparable between the two treatment-time groups. A dose of 5 mg/day torasemide is more effective for BP reduction for uncomplicated essential hypertensive patients when ingested at bedtime than in the morning upon arising. The difference in antihypertensive efficacy as a function of the circadian dosing-time of torasemide here documented should be taken into account when prescribing this loop diuretic to treat essential hypertensive patients.