Yoichiro Hirakawa

Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes

BACKGROUND In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up. METHODS We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. RESULTS The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively. CONCLUSIONS The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).

Glucose tolerance status and risk of dementia in the community The Hisayama Study

Objective: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. Methods: A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. Results: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L. Conclusions: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

Midlife and Late-Life Blood Pressure and Dementia in Japanese Elderly: The Hisayama Study

The associations between blood pressure and dementia have been inconclusive. We followed up a total of 668 community-dwelling Japanese individuals without dementia, aged 65 to 79 years, for 17 years and examined the associations of late-life and midlife hypertension with the risk of vascular dementia and Alzheimer disease using the Cox proportional hazards model. During the follow-up, 76 subjects experienced vascular dementia and 123 developed Alzheimer disease. The age- and sex-adjusted incidence of vascular dementia significantly increased with elevated late-life blood pressure levels (normal: 2.3, prehypertension: 8.4, stage 1 hypertension: 12.6, and stage 2 hypertension: 18.9 per 1000 person-years; P trend<0.001), whereas no such association was observed for Alzheimer disease (P trend=0.88). After adjusting for potential confounding factors, subjects with prehypertension and stage 1 or stage 2 hypertension had 3.0-fold, 4.5-fold, and 5.6-fold greater risk of vascular dementia, respectively, compared with subjects with normal blood pressure. Likewise, there was a positive association of midlife blood pressure levels with the risk of vascular dementia but not with the risk of Alzheimer disease. Compared with those without hypertension in both midlife and late life, subjects with midlife hypertension had an ≈5-fold greater risk of vascular dementia, regardless of late-life blood pressure levels. Our findings suggest that midlife hypertension and late-life hypertension are significant risk factors for the late-life onset of vascular dementia but not for that of Alzheimer disease in a general Japanese population. Midlife hypertension is especially strongly associated with a greater risk of vascular dementia, regardless of late-life blood pressure levels.

Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese Half-Century Data From the Hisayama Study (1961–2009)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors. # Clinical Perspective {#article-title-30}Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial

BACKGROUND High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079). METHODS INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150-220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2-7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. FINDINGS We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05-1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14-2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14-1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13-1·88; ptrend=0·0044). INTERPRETATION Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. FUNDING National Health and Medical Research Council of Australia.

Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial

OBJECTIVE There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

Impact of Sleep Duration on Obesity and the Glycemic Level in Patients With Type 2 Diabetes The Fukuoka Diabetes Registry

OBJECTIVE Few studies are currently available regarding the influence of sleep duration on glycemic control in diabetic patients. The objective of the current study was to examine the relationship between sleep duration, obesity, and the glycemic level in type 2 diabetic patients. RESEARCH DESIGN AND METHODS A total of 4,870 Japanese type 2 diabetic patients aged ≥20 years were divided into six groups according to their self-reported sleep duration: less than 4.5 h, 4.5–5.4 h, 5.5–6.4 h, 6.5–7.4 h, 7.5–8.4 h, and more than 8.5 h. The associations of sleep duration with obesity and the HbA1c levels were examined in a cross-sectional manner. RESULTS The HbA1c levels showed a quadratic association with sleep duration; namely, a shorter or longer sleep duration was associated with a higher level compared with a sleep duration of 6.5–7.4 h (P for quadratic trend <0.001). This association remained significant after adjusting for potential confounders, including the total energy intake and depressive symptoms. Furthermore, additional adjustments for obesity, which also showed a U-shaped relationship with sleep duration, did not attenuate the U-shaped sleep-HbA1c association. A significant interaction between sleep duration and age or the use of insulin was observed for the HbA1c levels. CONCLUSIONS Sleep duration was shown to have U-shaped associations with obesity and the HbA1c levels in type 2 diabetic patients, independent of potential confounders, and therefore may be an important modifiable factor for the clinical management of patients with type 2 diabetes.

Brachial-ankle pulse wave velocity predicts the development of cardiovascular disease in a general Japanese population: the Hisayama Study.

Objective: We examined the relationship between brachial-ankle pulse wave velocity and the development of cardiovascular disease in a general Japanese population. Methods: A total of 2916 community-dwelling Japanese individuals without history of cardiovascular disease aged at least 40 years were followed up for an average of 7.1 years, and the relationship between brachial-ankle pulse wave velocity and the cardiovascular risk was estimated using the Cox proportional hazards model. To compare the accuracy of the risk assessment for cardiovascular events between the models adjusted for known cardiovascular risk factors with and without brachial-ankle pulse wave velocity, the area under the receiver-operating characteristic curve and net reclassification improvement were computed. Results: During the follow-up period, 126 patients experienced cardiovascular events. Age and sex-adjusted incidence rates of cardiovascular disease increased linearly with elevating brachial-ankle pulse wave velocity levels (P for trend <0.001). After adjusting for confounding factors, every 20% increment in brachial-ankle pulse wave velocity was associated with a 1.30-fold [95% confidential interval (CI) 1.10–1.53] greater cardiovascular risk. When brachial-ankle pulse wave velocity was incorporated into a model with known cardiovascular risk factors, the area under the receiver-operating characteristic curve was significantly increased (0.776 vs. 0.760; P = 0.01), and the net reclassification improvement was 0.085 (P = 0.008). Conclusions: Our findings suggest that brachial-ankle pulse wave velocity is a significant predictive factor for cardiovascular disease in the general Japanese population and that information on brachial-ankle pulse wave velocity substantially improves cardiovascular risk assessment beyond that achieved by a model based on potential risk factors in general practice.

Association of alzheimer disease pathology with abnormal lipid metabolism: the hisayama study

Objective: The relationship between lipid profiles and Alzheimer disease (AD) pathology at the population level is unclear. We searched for evidence of AD-related pathologic risk of abnormal lipid metabolism. Methods: This study included brain specimens from a series of 147 autopsies performed between 1998 and 2003 of residents in Hisayama town, Japan (76 men and 71 women), who underwent clinical examinations in 1988. Lipid profiles, such as total cholesterol (TC), triglycerides, and high-density lipoprotein cholesterol (HDLC), were measured in 1988. Low-density lipoprotein cholesterol (LDLC) was calculated using the Friedewald formula. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimers Disease guidelines (CERAD) and neurofibrillary tangles (NFTs) were assessed according to Braak stage. Associations between each lipid profile and AD pathology were examined by analysis of covariance and logistic regression analyses. Results: Adjusted means of TC, LDLC, TC/HDLC, LDLC/HDLC, and non-HDLC (defined as TC–HDLC) were significantly higher in subjects with NPs, even in sparse to moderate stages (CERAD = 1 or 2), compared to subjects without NPs in multivariate models including APOE ε4 carrier and other confounding factors. The subjects in the highest quartiles of these lipid profiles had significantly higher risks of NPs compared to subjects in the lower respective quartiles, which may suggest a threshold effect. Conversely, there was no relationship between any lipid profile and NFTs. Conclusion: The results of this study suggest that dyslipidemia increases the risk of plaque-type pathology.

Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: The Hisayama Study

OBJECTIVE We examined the association between the ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) or the docosahexaenoic acid (DHA)/AA and the development of cardiovascular disease in a general Japanese population. METHODS A total of 3103 community-dwelling Japanese individuals aged ≥40 years were followed up for an average of 5.1 years. Serum EPA/AA ratios were categorized into quartiles. The risk estimates were computed using a Cox proportional hazards model. RESULTS During the follow-up period, 127 subjects experienced cardiovascular events. Age- and sex-adjusted incidence rates of cardiovascular disease increased with lower serum EPA/AA ratios in individuals with high-sensitivity C-reactive protein (HS-CRP) of ≥1.0 mg/L (p for trend = 0.006), whereas no clear association was observed in those with HS-CRP of <1.0 mg/L (p for trend = 0.27). The multivariable-adjusted risk of cardiovascular disease increased significantly, by 1.52 times (95% confidence interval 1.12-2.04) per 0.20 decrement in serum EPA/AA ratio in subjects with HS-CRP of ≥1.0 mg/L. A lower serum EPA/AA ratio was significantly associated with an increased risk of coronary heart disease, but there was no evidence of an association with stroke. The magnitude of the influence of the serum EPA/AA ratio on the cardiovascular risk increased significantly with elevating HS-CRP levels taken as a continuous variable (p for heterogeneity = 0.007). However, no such association was observed for DHA/AA ratio. CONCLUSION Our findings suggest that a lower serum EPA/AA ratio is associated with a greater risk of cardiovascular disease, especially coronary heart disease, among subjects with higher HS-CRP levels in the general Japanese population.