Noboru Tamaki

Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) – receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes

To examine the effects of alogliptin, a dipeptidyl peptidase‐4 inhibitor, on glucose parameters, the advanced glycation end product (AGE)‐receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes patients.

One-year effectiveness and safety of open-label losartan/hydrochlorothiazide combination therapy in Japanese patients with hypertension uncontrolled with ARBs or ACE inhibitors

The long-term antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been appropriately evaluated in Japan. In this study, treated hypertensive patients taking angiotensin-receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) regimens not at blood pressure (BP) goals proposed by the Japanese Society of Hypertension (JSH) were switched to losartan/HCTZ combinations and followed for 1 year. Data analysis included 244 patients aged 64.5±10.7 years, 56% male, 27% with diabetes mellitus and 36% with dyslipidemia. Pre-switching BP 157±16/88±10 mm Hg promptly decreased and maintained a steady state, reaching 132±15/77±9 mm Hg (P<0.001) 1 year later. After 1 year of treatment, 50% of patients cleared the goals of the JSH guideline for systolic BP and 79% for diastolic BP. Patients with maximal doses of ARBs tended to show larger decreases in BP (159±11/90±10 to 128±10/75±8 mm Hg, P<0.001, n=32). Clinical and laboratory adverse events were reported for 29 patients (11%), but serious abnormalities were not observed. In particular, plasma levels of uric acid (UA) were well-maintained for 1 year, and significant decreases in UA were observed in patients with higher levels of UA (⩾7.0 mg dl−1). Losartan/HCTZ combinations showed strong and steady hypotensive abilities and acceptable safety and tolerability in patients currently not at BP goals with regimens including ARBs or ACEIs in Japan.

Comparison of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker or a thiazide diuretic, in elderly patients with hypertension

The blood pressure goals set for the treatment of hypertensive patients have been lowered in recent guidelines. To reduce blood pressure levels sufficiently, combination therapies are often needed, but there is little evidence about which combination should be chosen. The present study was carried out to compare the effects of combination therapies, including the angiotensin receptor blocker olmesartan and either a calcium channel blocker (CCB) or a thiazide diuretic, in elderly patients with hypertension. A total of 65 patients aged 65–85 years, with blood pressures of 140/90 mm Hg or higher for those taking antihypertensive medication or 160/100 mm Hg or higher for those not on medication, were randomly assigned to either the group treated with olmesartan plus a dihydropyridine CCB or the group treated with olmesartan plus a thiazide diuretic; 58 patients completed the treatment for 6 months. Systolic and diastolic blood pressures (SBP and DBP) were reduced during the treatment period in both the groups. The reductions in SBP at 1 and 6 months were significantly (P<0.05) greater in the CCB combination group than in the diuretic group (−29 vs. −18 mm Hg, respectively, at 1 month; −32 vs. −23 mm Hg, respectively, at 6 months). Despite greater reduction in SBP in the CCB group, the serum creatinine level and the estimated glomerular filtration rate (eGFR) remained unchanged, whereas in the diuretic group, creatinine was elevated (+0.06 mg per 100 ml, P<0.05) and eGFR was reduced (−4.5 ml min−1 per 1.73 m2). In addition, high-density lipoprotein cholesterol levels were reduced in the diuretic group (−5.0 mg per 100 ml, P<0.01). These results suggest that olmesartan plus a CCB is the preferable combination therapy in comparison with olmesartan plus a thiazide diuretic for elderly patients with hypertension.

Regional differences in hypertensive cardiovascular remodeling between fishing and farming communities in Japan.

BACKGROUND Effects of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) intake on the cardiovascular system have been reported, and thus we hypothesized that the prevalence of hypertensive cardiovascular remodeling would be lower in a fishing than a farming community. METHODS We recruited 263 essential hypertensives from a fishing and 333 from a farming village; all subjects were ≥40 years (mean 73 years; 42% men). They were cross-sectionally examined for serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), asymmetric dimethylarginine (ADMA) levels, left ventricular mass index (LVMI), and common-carotid artery (CCA) and internal-carotid artery (ICA) intima-media thickness (IMT). RESULTS Compared to the patients in the farming village, those in the fishing village had higher serum EPA and DHA levels (63.3 vs.70.9 µg/ml, 137.2 vs.157.8 µg/ml) and lower ADMA levels (0.49 vs.0.47 nmol/ml; all P < 0.05). LVMI and both CCA-IMT and ICA-IMT levels were lower in the fishing than the farming village (113.2 vs.121.6 g/m(2), 0.88 vs.0.94 mm, 1.10 vs.1.17 mm: all P < 0.01) even after adjustment for age, sex, body mass index (BMI), duration of hypertensive medication, number of antihypertensive medications, and 24-h systolic blood pressure (SBP) level. The differences in LVMI and IMT levels between these communities also remained unchanged (all P < 0.01) after additional adjustment for the regional differences in EPA, DHA, and ADMA levels. A multivariable linear regression analysis showed that the difference in place of residence was independently associated with LVMI as well as with both CCA-IMT and ICA-IMT levels (all P < 0.01). CONCLUSION The prevalence of cardiovascular remodeling was significantly lower in patients in the fishing community than in those in the farming community. Further investigations are required to explain the mechanisms underlying this association.

Synergistic effect of chronic kidney disease and high circulatory norepinephrine level on stroke risk in Japanese hypertensive patients.

OBJECTIVE Evidence is now available about the association between chronic kidney disease (CKD) and stroke. However, less is known about the underlying mechanisms, and there is currently no reliable marker for identifying stroke-prone high-risk patients among CKD patients. METHODS A total of 514 hypertensive patients aged >50 years (mean, 72.3 years; 37% men) underwent 24-h BP monitoring and measurement of circulatory high-sensitivity C-reactive protein (hs-CRP) and norepinephrine at baseline. CKD was defined as eGFR<60 ml/min/1.73 m(2) using the Cockcroft-Gault equation. RESULTS AND CONCLUSION During an average of 41 months (1751 person-years), there were 43 stroke events. Compared with hypertensive patients without CKD, those with CKD (n=225) had higher levels of sleep systolic BP (SBP) (125 mmHg vs. 129 mmHg), circulatory hs-CRP (0.12 mg/L vs. 0.20 mg/L) and norepinephrine (332.2 pg/ml vs. 372.8 pg/ml; all P<0.05). On multivariable analysis, the hazard ratio (HR) (95% CI) for stroke in CKD vs. non-CKD was 2.7 (1.2-6.9) (P<0.05). CKD, as well as the baseline presence of silent cerebral infarction, sleep SBP increase, and high hs-CRP level (highest quartile: ≥0.42 mg/L) were independently and additively associated with stroke events; above all, there was a synergistic effect of CKD and high norepinephrine level (highest quartile: ≥538 pg/ml) on stroke risk (all P<0.05). Among hypertensive patients with CKD, those within the highest quartiles of norepinephrine had a greater stroke risk compared to those who were in the lower quartiles of norepinephrine (HR (95% CI): 2.2 (1.0-4.5); P=0.045). In conclusion, CKD is an independent predictor of stroke in Japanese hypertensive patients; in particular, hypertensive patients with CKD and a high norepinephrine level have a synergistically augmented stroke risk.

Efficacy of eplerenone added to renin-angiotensin blockade in elderly hypertensive patients: the Jichi-Eplerenone Treatment (JET) study

Introduction: We assessed the additional effects of eplerenone to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on 24-h blood pressure (BP) level, fibrinolytic activity, and cardiovascular protection in elderly (>60 years) hypertensive patients. Materials and methods: In total, 20 patients (mean age 74 years, 25% men), whose BP was uncontrolled despite the use of anti-hypertensive drugs including ACEIs or ARBs (average 2.4 drugs), received eplerenone once daily (mean 37.5 mg) for 24 weeks. Results: Eplerenone treatment significantly reduced mean 24-h systolic/diastolic BP levels (143/80 mmHg to 132/74 mmHg, both p < 0.002). The reduction of 24-h systolic BP levels, especially night-time BP, was significantly associated with the reduction of atrial natriuretic peptide and brain natriuretic peptide levels (all p < 0.05). Furthermore, after eplerenone treatment, the mean plasminogen activator inhibitor-1 antigen level was significantly reduced (35 ng/ml to 25 ng/ml, p < 0.05), and the median level of plasma procollagen type III aminoterminal peptide and the urinary albumin excretion rate were also significantly reduced (0.8 U/ml to 0.6 U/ml, p < 0.003 and 53 mg/g·Cr to 23 mg/g·Cr, p < 0.05, respectively). During the intervention, eplerenone treatment was well tolerated with no reports of hyperkalaemia or hypotension. Conclusions: Addition of eplerenone to ACEIs or ARBs in elderly hypertensive patients offers significant benefits in terms of 24-h BP levels, fibrinolysis, and cardiovascular protection.

Association of cognitive dysfunction with cardiovascular disease events in elderly hypertensive patients.

Objectives: This study assesses whether presence of cognitive dysfunction can be a marker associated with the development of cardiovascular disease (CVD) events independent of ambulatory blood pressure (BP) or other indices of target organ damage (TOD) in elderly hypertensive patients. Methods: We recruited 585 hypertensive patients (mean age, 73 years; 41% men) who were ambulatory, lived independently, and were without clinically overt dementia. Cognitive function was assessed by Mini-Mental State Examination (MMSE) at baseline, and CVD events (coronary artery disease, stroke, congestive heart failure, and sudden death) were prospectively ascertained. Cognitive dysfunction was defined as the lowest quartile of MMSE scores (n = 183, median 24 points). Results: CVD events occurred in 42 people over an average of 2.8 years (1644 person-years). The prevalence of cognitive dysfunction was higher in patients with CVD events than those without (57 vs. 29%; both P <0.001) at baseline. Cognitive dysfunction was associated with CVD events, after adjustment for nocturnal SBP and evidence of TOD [i.e. albuminuria, cardiac hypertrophy, and carotid-artery intima–media thickness (IMT)], hazard ratio 2.5–2.9 (all P <0.01). Incorporation of MMSE in the risk model (including age, estimated glomerular filtration rate, and preexisting CVD) improved the C-statistics (from 0.691 to 0.741) and resulted in a net reclassification improvement of 17.6% (P = 0.02). In contrast, incorporation of albuminuria, cardiac hypertrophy, and high carotid-artery IMT added little further improvement in the risk prediction. Conclusion: Cognitive dysfunction is an independent marker associated with increased risk of CVD events in elderly hypertensive patients.

Three-Year Safety and Effectiveness of Fixed-Dose Losartan/Hydrochlorothiazide Combination Therapy in Japanese Patients with Hypertension Under Clinical Setting (PALM-1 Extension Study)

Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.

Differential blood pressure reductions by angiotensin receptor blocker plus calcium channel blocker or diuretic in elderly hypertension with or without obesity

We conducted the Miyazaki Olmesartan Therapy for Hypertension in the EldeRly (MOTHER) study, which suggested that there are preferable effects of an angiotensin receptor blocker (ARB), olmesartan, plus a calcium channel blocker (CCB) over the ARB plus a diuretic, in elderly patients with hypertension. In this subanalysis, we examined whether obesity influences the efficacies of these combination therapies. The study subjects were 58 hypertensive patients ages 65 to 85, who had been randomly assigned to either group treated with olmesartan plus a CCB or a diuretic and completed the treatment for 6 months. Systolic and diastolic blood pressures were reduced following these combination treatments in nonobese and obese patients. In the CCB combination, blood pressure reductions in nonobese patients were larger than in obese patients at 1 and 3 months, and serum creatinine remained unchanged despite the greater reduction of blood pressure. Meanwhile, such differences were not noted in the diuretic groups. Plasma aldosterone was significantly reduced in nonobese patients of two combination groups, but not in those with obesity. ARB plus CCB combination therapy might be preferably chosen for nonobese elderly patients, whereas the influence of obesity seems smaller in the efficacy of ARB plus a diuretic.

Diuretics enhance effects of increased dose of candesartan on ambulatory blood pressure reduction in Japanese patients with uncontrolled hypertension treated with medium-dose angiotensin II receptor blockers

Abstract Although blockade of the renin–angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly (p < 0.001). Attainment of the target office BP (p = 0.0014) and 24-h BP levels (p = 0.0296) also improved significantly. Subgroup analysis indicated that the reduction of 24-h systolic BP was larger in patients treated with diuretics than those without (p = 0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect.