Introduction

Angiotensin II receptor blockers (ARBs) are effective and well-tolerated antihypertensive agents that inhibit aldosterone production, vasoconstriction and sodium retention by blocking the renin–angiotensin–aldosterone system.1, 2, 3 Telmisartan is a highly selective ARB for the AT1 receptor and, as the elimination half-life of this agent is 24 h, once-daily administration of telmisartan is reported to reduce blood pressure (BP) for an entire 24 h.4, 5 Amlodipine, a calcium channel blocker (CCB), is another highly effective and long-acting antihypertensive agent that is widely used for hypertension treatment.6

The current guidelines indicate that treatment with two or more antihypertensive agents is necessary to achieve optimal BP for most hypertensive patients in order to reduce cardiovascular risk.1, 2 Moreover, the Anglo-Scandinavian Cardiac Outcomes Trials Blood Pressure Lowering Arm (ASCOT-BPLA)7 and Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)8 revealed the clinical benefits of combination therapy with renin–angiotensin–aldosterone system blockade and CCB.

Currently, a single-pill combination of ARB and CCB is available for once-daily administration to manage hypertension with better treatment adherence.9, 10 Telmisartan 40 mg+amlodipine 5 mg (T40/A5) fixed-dose combination (FDC) therapy is expected to achieve tight BP control because of the strong efficacy and long half-life of each agent.11 However, to our knowledge, no studies have been conducted that employed ambulatory BP monitoring (ABPM) in Japanese hypertensive patients to show that T40/A5 FDC therapy has lasting BP-lowering efficacy. In addition, there are no data available regarding whether the administration time (morning or evening) of T40/A5 FDC influences its BP-lowering effects in Japanese patients who had uncontrolled hypertension while taking amlodipine. However, Hermida et al.12 reported that telmisartan monotherapy with bedtime administration could achieve significantly better nocturnal BP regulation compared with morning administration. The aims of this study were (1) to evaluate the 24-h efficacy of T40/A5 FDC therapy in the control of hypertension by performing ABPM on the participants and (2) to conduct a preliminary investigation of differences owing to administration time in Japanese patients whose hypertension was not controlled by 5 mg of amlodipine per day.

Methods

Study subjects and study design

Figure 1 shows the study design. In this randomized clinical trial, we initially recruited patients who had been taking 5 mg of amlodipine/day for >4 weeks. Written informed consent was obtained from all of the participants. Patients taking other CCBs or ARBs were excluded, and there was no change to the other antihypertensive agents throughout the observation period. After a screening period of >2 weeks, subjects with a clinical systolic BP (SBP) of 140 mm Hg, a clinical diastolic BP (DBP) of 90 mm Hg, or both were enrolled in this study. We then switched the patients from 5 mg of amlodipine per day to T40/A5 FDC therapy. The subjects were randomly assigned to either a morning (n=22) or an evening (n=22) administration group. At baseline and 8 weeks after randomization, we evaluated the clinical BP, ABPM and various laboratory values.

Figure 1
figure 1

Study design.

We assessed changes from baseline in the 24 h, daytime, nighttime and early morning BP after 8 weeks of treatment and changes from baseline in the clinical BP and laboratory values after 8 weeks of treatment. We also performed comparisons of the above assessments between the morning and evening administration groups. The Clinical Investigations Ethics Committee of Osaka University Hospital approved the study protocol. The study was performed in adherence with the principles of the Declaration of Helsinki and according to Good Clinical Practice standards.

BP measurements

Conventional BP was measured by trained observers with an electronic sphygmomanometer. Following guidelines for the management of hypertension, clinical BP was measured at least two times in a sitting position after 5 min of rest, and we adopted the average of two readings as the clinical BP if the difference in measured values was <5 mm Hg. When the difference in measured values was 5 mm Hg, additional measurements were conducted to obtain stable BP readings and we adopted the average of the two stable readings as the clinical BP.

Ambulatory BP monitoring

Ambulatory BP was evaluated with portable monitors (FB-270 device; Fukuda Denshi Co. Ltd., Tokyo, Japan) at 30-min intervals from 0600 to 2300 hours and at 60-min intervals from 2300 to 0600 hours. From the ABPM value, we calculated the 24-h mean BP, daytime (0900 to 2100 hours) mean BP, nighttime (0100 to 0600 hours) mean BP, and early morning (2 h after rising) mean BP.13

Clinical evaluations

The estimated glomerular filtration ratio (eGFR) was calculated with the following equation: eGFR (ml min−1 1.73 m−2)=194 × creatinine−1.094 × age−0.287 ( × 0.739 if female).14 Patients with diabetes mellitus were diagnosed according to the diagnostic criteria of the American Diabetes Association: fasting plasma glucose (FPG) 126 mg dl−1, HbA1c 6.5%, 2-h value in oral glucose tolerance test 200 mg dl−1, random plasma glucose concentration 200 mg dl−1 in the presence of symptoms, or taking drugs for diabetes. Patients with considered to have hyperlipidemia if total cholesterol was 220 mg dl−1, low-density lipoprotein cholesterol was 140 mg dl−1, triglycerides were 150 mg dl−1, or they were taking drugs for hyperlipidemia. We evaluated insulin resistance by means of the HOMA-R (homeostasis model assessment ratio), which was calculated with the following equation: HOMA-R=FPG × fasting plasma insulin/405.

Metabolic syndrome was defined as the presence of two or more of the following abnormalities in addition to abnormally high waist circumference (85 cm for men and 90 cm for women): (1) triglycerides 150 mg dl−1 and/or high-density lipoprotein cholesterol <40 mg dl−1 or under treatment for dyslipidemia, (2) SBP 130 mm Hg and/or DBP 85 mm Hg or under treatment for hypertension, and (3) FPG 110 mg dl−1 or under treatment for diabetes mellitus.15 Potential metabolic syndrome was also defined as one of above abnormalities in addition to BMI 25.

Statistical analysis

Data were analyzed with SAS 9.3 (SAS, Cary, NC, USA) and are presented as the mean±s.d. Differences in patient characteristics and laboratory test results between the groups were analyzed with Fisher’s exact test and two-sample t-test. Differences in the clinical BP, clinical heart rate and ABPM values between the groups were analyzed with analysis of covariance. A value of P<0.05 was regarded as significant.

Results

Table 1 lists the baseline clinical characteristics of the participants in the present study. The mean age of the 44 subjects was 67.8±10.2 years. Although the subjects in the morning administration group had significantly higher triglyceride levels (193.5±145.1 vs. 109.2±59.0 mg dl−1, P=0.022) and significantly lower high-density lipoprotein cholesterol (50.5±13.4 vs. 72.9±21.5 mg dl−1, P<0.001) than subjects in the evening administration group, there were no significant differences in the other characteristics between the two groups.

Table 1 Patient characteristics

First, we analyzed the BP profile of the study subjects. Figure 2 shows a comparison of the 24-h BP profile for ABPM at baseline and at 8 weeks. The mean SBP at 8 weeks was significantly decreased compared with the mean SBP at baseline (121.8±13.2 vs. 130.5±11.4, 125.6±13.2 vs. 134.4±11.2, 116.1±16.2 vs. 123.5±13.6, and 127.4±14.5 vs. 135.2±12.0 mm Hg for 24 h, daytime, nighttime and early morning, respectively) (Table 2). The mean DBP at 8 weeks was also significantly decreased compared with the mean DBP at baseline (74.8±9.3 vs. 80.3±10.7, 77.1±9.0 vs. 83.0±10.1, 69.5±11.0 vs. 75.1±11.9, and 78.7±9.8 vs. 84.8±12.5 mm Hg for 24 h, daytime, nighttime and early morning, respectively) (Table 2). However, there were no significant differences in the mean BP change (24 h, daytime, nighttime and early morning) from baseline to 8 weeks between the subjects in the morning and evening administration groups (Table 2). Similarly, the clinical BP at 8 weeks was significantly diminished compared with the clinical BP at baseline (SBP: 135.7±15.0 vs. 150.2±10.4, DBP: 75.0±10.0 vs. 83.0±10.2 mm Hg). However, there was no significant difference in the change in clinical BP from baseline to 8 weeks between subjects in the morning and evening administration groups (Table 3). In addition, the time at which T40/A5 FDC therapy was administered (morning or evening) did not appear to make a difference in the clinical heart rate (Table 3) or mean heart rate as evaluated by ABPM (data not shown). To further investigate, we analyzed the effect of T40/A5 FDC on dipper and non-dipper type hypertension in the subjects. The mean nighttime BP at 8 weeks in subjects with dipper type hypertension did not significantly decrease compared with the mean BP at baseline and showed no excessive BP lowering; however, the daytime BP at 8 weeks in subjects with dipper type hypertension, and both the daytime and nighttime BP at 8 weeks in subjects with non-dipper type hypertension, was significantly decreased compared with the mean SBP at baseline. In our subjects, 18.2% changed from non-dipper to dipper type hypertension, 12.1% changed from dipper to non-dipper type hypertension, 30.3% remained in dipper type hypertension and 39.4% remained in non-dipper type hypertension. There were no significant differences between the subjects in the morning and evening administration groups (P=0.345).

Figure 2
figure 2

Twenty-four-hour profile of mean hourly blood pressure: baseline (gray) and 8 weeks (black).

Table 2 ABPM Value
Table 3 Clinic blood pressure and clinic heart rate

Table 4 contains comparisons of the laboratory test values measured at baseline and after 8 weeks of treatment. There were no significant changes in FPG, HOMA-R, HbA1c, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, eGFR, urinary albumin/creatinine ratio, serum noradrenaline, serum dopamine and urinary 8-OHdG in all subjects, subjects in the morning administration group or subjects in the evening administration group. However, subjects in the morning administration group had significantly lower serum adrenaline levels (27.6±20.4 vs. 34.8±22.5 mg dl−1, P=0.032) and subjects in the evening administration group had significantly lower fasting plasma insulin level (6.1±2.2 vs. 8.7±2.2 mg dl−1, P=0.025) at 8 weeks compared with baseline.

Table 4 Laboratory test

Finally, we compared BP profiles between subjects with or without metabolic syndrome or potential metabolic syndrome. There was no significant difference in the mean BP change (24 h, daytime, nighttime and early morning) from baseline to 8 weeks between subjects with or without metabolic syndrome (Table 5).

Table 5 ABPM Value (compared between subjects with and without metabolic syndrome)

Discussion

Although telmisartan is known to have long-lasting effects on lowering BP, previous reports have suggested that high-dose (80 mg per day) telmisartan monotherapy administered at bedtime may achieve significantly better nocturnal BP regulation than morning administration.12 Previous reports have shown that drug adherence rates are generally higher for morning administration than for evening administration.16 Although the present study was conducted in a university medical hospital and subjects showed good adherence to drug administration, such differences in adherence rate could influence the observed effect of T40/A5 FDC on the patients’ general clinical condition. In fact, in the present study we found that in patients whose hypertension was uncontrolled by 5 mg of amlodipine per day, T40/A5 FDC therapy achieved optimal mean BP during the day and night regardless of the time of administration. We also revealed that both morning administration and evening administration of T40/A5 FDC could safely reduce BP equally in subjects with dipper type and non-dipper type hypertension. In addition to both telmisartan and amlodipine having strong efficacy and a long half-life, these two agents likely have complementary effects on reducing BP; telmisartan inhibits vasoconstriction caused by angiotensin II, while amlodipine leads to vasodilation by blocking the transmembrane calcium influx into vascular smooth muscle cells. The 24-h BP profile as measured by ABPM is known to correlate with the development of cardiovascular disease and prognosis more accurately than office BP;17, 18, 19, 20 in addition, nighttime BP was recently shown to be a better predictor of outcome than other BP profiles evaluated by ABPM.21, 22 Our study suggests that T40/A5 FDC therapy may prevent cardiovascular disease and improve prognosis independent of the time of administration.

The relationship between metabolic syndrome and diurnal BP changes remains controversial, although pooled data suggest that patients with metabolic syndrome are more likely to have a nondipping pattern in their 24-h BP profile.23 Telmisartan is known to act as a partial agonist of peroxisome proliferator-activated receptor gamma, which regulates fatty acid storage and glucose metabolism, and it is reported to have positive effects on glucose and lipid metabolism.24, 25 Therefore, we investigated the changes in glucose and lipid metabolism after 8 weeks of treatment withT40/A5 and found that there were no significant changes. We also investigated whether there were significant differences in the efficacy of T40/A5 FDC therapy between patients with and without metabolic syndrome and found that T40/A5 FDC therapy was associated with optimal BP in patients with and without metabolic syndrome with no significant differences.

Morning administration of T40/A5 was associated with a significant reduction in serum adrenaline from baseline values, but evening administration had no impact on serum adrenaline. CCB causes reflex activation of the sympathetic nervous system and increases catecholamine.26, 27 On the other hand, activation of the AT1 receptor by angiotensin II could cause sympathetic overactivity28, 29 and, although the effects of ARBs on catecholamine secretion is still controversial, several studies have shown that renin–angiotensin–aldosterone system blockade by ARBs could decrease the excess sympathetic responses to chronic stress and reduce serum catecholamine.30 The elimination half-life of telmisartan is 24 h and that of amlodipine is 30–50 h;4, 5, 6 as we drew blood samples from all of our patients in the daytime, it is possible that only when T40/A5 was administered in the morning were blood concentrations of telmisartan high enough to reduce serum catecholamine levels at the time of the blood draw. However, further investigations are needed to clarify the mechanisms of action of T40/A5 therapy.

The present study has several limitations. First, the sample size was relatively small and the follow-up period was relatively short; larger and longer studies could better reflect the clinical efficacy or impact on prognosis of T40/A5 FDC therapy. Second, several study subjects had already taken various orally administered drugs for dyslipidemia and diabetes mellitus at baseline; these agents might have affected several parameters, such as glucose levels and lipid profile. Third, although all blood samples were obtained during the daytime, the time of blood sampling varied (morning or afternoon); therefore, the circadian variation in catecholamine might have affected our results. Finally, more-frequent BP measurement (for example, 15–20-min intervals) or 48-h periods of ABPM might have revealed the clinical effects of T40/A5 FDC therapy on the diurnal BP profile more accurately.

In conclusion, we showed that combination therapy with 40 mg of telmisartan and 5 mg of amlodipine significantly decreased the 24-h mean BP and clinical BP in patients whose hypertension was uncontrolled by 5 mg of amlodipine per day, independent of administration time (morning or evening).