Influence of treatment-time regimen of hypertension medications on ambulatory blood pressure in patients with type 2 diabetes

Resumo

The diagnosis of hypertension and clinical decisions regarding its treatment typically are based on a limited number of daytime clinic blood pressure (BP) measurements obtained in the physician¿s office. However, the correlation between BP level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinic BP measurements. In particular, independent prospective studies have reported that the asleep BP mean determined by ABPM is a better predictor of CVD events than the awake or 24h BP means. There is strong association between diabetes and increased risk of end-organ damage, stroke, and CVD morbidity and mortality. Non-dipping (<10% decline in the asleep relative to awake BP mean) and sleep-time hypertension, as determined by ABPM, are 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-reproducible, 24h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Generally, hypertensive patients, including those with diabetes, ingest all their BP-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and recently it was recently that routine ingestion of ¿1 hypertension medications at bedtime, compared to ingestion of all of them upon awakening, significantly reduces CVD events. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers better controls the asleep BP mean, with additional benefit, independent of medication terminal half-life, of converting the 24h BP profile into more normal dipper patterning. Accordingly, we investigated the: (i) influence of diabetes on the circadian BP pattern assessed by 48h ABPM to increase reproducibility of the results; and (ii) effects of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes. The sample represents a population of Spanish hypertensive patients, ¿18 years of age, and adhering to a routine of daytime activity alternating with nighttime sleep. Respecting the inclusion/exclusion criteria for this cross-sectional investigation, we identified 12765 hypertensive patients (6797 men/5968 women), 58.1±14.1 (mean±SD) years of age (range, 18 to 97 years), who completed the study and provided all required information and enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by 48h ABPM in primary care centers of Northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes, defined as fasting glucose ¿126 mg/dl on at least two clinical assessments ¿3 months apart, or glucose-lowering treatment. At the time of the study, 525/3314 patients with/without diabetes were untreated, and the remaining 2429/6497 patients with/without diabetes were ingesting BP-lowering medication. Among the 2429 treated participants with diabetes (1465 men/964 women, 65.9±10.6 years of age), 1176 (700 men/476 women) were ingesting all their BP-lowering medications in the morning upon awakening, while 1253 patients (765 men/488 women) were ingesting ¿1 hypertension medications at bedtime. Among the latter, 336 patients (177 men/159 women) were ingesting all BP-lowering medications at bedtime, while 917 patients (588 men/329 women) were ingesting the full daily dose of some hypertension medications upon awakening and some at bedtime. All hypertension medications were dosed once a day in their recommended therapeutic dose in Spain. For the present investigation, the protocol did not allow division of any of the prescribed once-a-day medications for ingestion as a split dose with half upon morning arising and the other half at bedtime. Thus, patients ingesting any medication at bedtime took the entire daily dose of the one (or more) medication(s) at this time and not a portion of one (or more) of the same medication(s) also in the morning. BP was automatically assessed every 20 minutes between 07:00 and 23:00h and every 30 minutes during the night for 48 consecutive hours. A 48h, instead of the most common 24h, monitoring was chosen to improve the reproducibility of results, because it was previously demonstrated the reproducibility of ABPM-derived parameters, including BP means and dipping classification, is highly dependent on duration of monitoring. Participants kept a diary listing the time of retiring to bed at night, awakening in the morning, consumption of meals, participation in exercise, and episodes of atypical physical activity, mood/emotional states, and other events that might affect BP. ABPM was considered controlled if the awake and asleep systolic (SBP)/diastolic (DBP) means were <135/85 and <120/70 mmHg, respectively. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of albuminuria, proteinuria, chronic kidney disease (CKD), 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<0.001), 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<0.001) 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<0.001) throughout the entire 24h in patients with diabetes, even after correcting for age. The prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1 vs. 45.9%; P<0.001). Largest difference between groups was in the prevalence of a 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<0.001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with diabetes; thus, among the uncontrolled hypertensive patients with diabetes, 89.2% had sleep-time hypertension. Our findings document a significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with diabetes. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was more than twice as prevalent in diabetes. Patients with diabetes also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. Collectively, these findings indicate type 2 diabetes should be included among the clinical conditions for which ABPM is mandatory for proper evaluation of CVD risk associated with alterations in the 24h BP pattern in those patients, as well as a means to establish the most adequate therapeutic scheme to increase CVD event-free survival. With regard to the second major objective of this dissertation, our cross-sectional study of a large sample of treated hypertensive patients with type 2 diabetes evaluated by 48h ABPM documents, first, lower prevalence of markers of CVD risk in those ingesting ¿1 BP-lowering medications at bedtime: they were less likely to have metabolic syndrome and CKD, and they also had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and LDL-cholesterol, plus higher eGFR and HDL-cholesterol compared to patients who ingested all hypertension medications upon awakening. Fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD were lowest in participants ingesting not just some, but all hypertension medications at bedtime. Our study also documents highly significant differences in circadian BP regulation between the treatment-time regimens. Patients with type 2 diabetes ingesting ¿1 hypertension medications at bedtime showed significantly lower asleep SBP and DBP means than those ingesting all medications upon awakening. Most important, the sleep-time relative SBP and DBP decline was significantly attenuated when all medications were ingested upon awakening (P< 0.001). Thus, the prevalence of non-dipping was significantly higher when all medications were ingested upon awakening (68.6%) than when ¿1 medications were ingested at bedtime (55.8%; P<0.001 between groups). Prevalence of non-dipping was even further attenuated, to 49.7%, among patients ingesting hypertension medications only at bedtime (Table 10). Moreover, prevalence of the riser BP pattern, associated with highest CVD risk, was very high, 23.6%, among those ingesting all medications upon awakening, lower in patients ingesting one or more medications at bedtime (20.0%), and lowest in those ingesting all medications at bedtime (12.2%; P<0.001 between groups). In conclusion, this large cross-sectional study on Spanish hypertensive patients with type 2 diabetes evaluated by 48h ABPM demonstrates significantly lower prevalence of markers of CVD risk, improved metabolic profile, lower asleep SBP mean, and attenuated prevalence of blunted nighttime BP decline when ¿1 hypertension medications were ingested at bedtime as compared to when all of them were ingested upon awakening. Most important, the prevalence of the riser BP pattern, associated with highest CVD risk among all possible circadian BP patterns, was twice as prevalent in patients ingesting all hypertension medications upon awakening than in those ingesting all of them at bedtime. Bedtime ingestion of all hypertension medications was also associated with significantly lower ambulatory SBP and PP and significantly higher prevalence of properly controlled ambulatory BP, which were achieved with a significantly lower number of hypertension medications, compared to the treatment regimen consisting of all medications ingested upon awakening. These collective findings indicate a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and to avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for type 2 diabetes.