All individuals provided written informed consent. exclusion criteria included the following: (1) type 1 diabetes; (2) history of myocardial infarction or coronary artery bypass grafting within 3 months before consent; (3) percutaneous coronary treatment, carotid artery or peripheral artery revascularization within 6 months; (4) stroke or transient ischemic assault within 1 year; (5) unstable angina pectoris or heart failure of New York Heart Association practical class III or IV; (6) rapidly progressive renal disease within 3 months before consent; (7) severe orthostatic hypotension; and (8) a serum potassium level ?3.5 or ?5.5?mEq?lC1. With this analysis, we included individuals with hypertension defined as a BP ?130/80?mm?Hg or treatment with any anti-hypertensive providers during the run-in period according to the Japan Society of Hypertension Recommendations (2009).17 Definitions of study outcomes The effectiveness measure was the time to the 1st event of the primary composite outcome of doubling of SCr, end-stage renal disease (SCr 5?mg?dlC1, dialysis, transplantation), and all-cause death. SCr was measured at a central laboratory in Japan (SRL, Tokyo, Japan). The secondary composite results included the following: (1) a composite end point of 1st event of cardiovascular death, nonfatal stroke except for transient ischemic attacks, non-fatal myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, revascularization of the coronary, carotid, or peripheral arteries, or lower extremity amputation; (2) switch in proteinuria; (3) rate of decline of the estimated glomerular filtration rate (eGFR) using the Japanese equation and the changes of diet in renal disease (MDRD) equation for estimating the GFR in Japanese and Chinese individuals, respectively.18, 19 Statistical analysis The Cox regression model was applied to estimate the HR between treatment organizations with the 95% CI for the renal and cardiovascular composite event rates.20 The covariates in the model were (1) UACR and SCr at baseline and regions (Japan/Hong Kong) for the renal Vericiguat composite event rate, and (2) baseline UACR, history of cardiovascular disease, and age for the cardiovascular composite event rate. The KaplanCMeier method was used to estimate the cumulative event rate in each treatment group stratified by the use of an ACEI.21 The linear mixed-effects model was used to compare the pattern in the percent change of the urinary protein:creatinine percentage (UPCR) and that of eGFR between the treatment and placebo organizations. Severe adverse events and discontinuation of the study drug due to adverse events were summarized. All statistical checks were two sided with 0.05 arranged as the significance level. Statistical analyses were performed using the Statistical Analysis System version 9.2 (SAS Institute, Cary, NC, USA). Results Individuals Among the 566 type 2 diabetic patients with overt nephropathy randomized in the ORIENT, 563 individuals (363 Japanese and 200 Chinese) experienced hypertension. Of these, 280 received olmesartan and 283 received placebo in addition to standard antihypertensive therapy (Table 1). Of the 563 individuals with hypertension, 414 (73.1%) were treated with ACEIs that were continued at the same dose throughout the study period of 3.2 (0.6) years (mean (s.d.)). The percentage of individuals receiving olmesartan was related in the ACEI-treated (205/414) and non-ACEI-treated organizations (75/149), at 50%. Table 1 Baseline characteristics of type 2 diabetic patients with hypertension and overt nephropathy treated with antihypertensive medicines including ACEI randomized to receive either olmesartan or placebo treatment for any mean period of 3.2 years (%). aMedian (interquartile range). bThe value for HbA1c (%) is definitely estimated as an National Glycohemoglobin Standardization System (NGSP) equivalent value (%) calculated from the method HbA1c (%)=HbA1c (Japan Diabetes Society (JDS))(%)+0.4%, considering the relational expression of.SI has received consultancy charges, lecture charges and study grants from Daiichi-Sankyo, Novartis, Astellas, MSD and Pfizer. females and 1.2C2.5?mg?dlC1 in males (normal range 1.0?mg?dlC1). The major exclusion criteria included the following: (1) type 1 diabetes; (2) history of myocardial infarction or coronary artery bypass grafting within 3 months before consent; (3) percutaneous coronary treatment, carotid artery or peripheral artery revascularization within 6 months; (4) stroke or transient ischemic assault within 1 year; (5) unstable angina pectoris or heart failure of New York Heart Association practical class III or IV; (6) rapidly progressive renal disease within 3 months before consent; (7) severe orthostatic hypotension; and (8) a serum potassium level ?3.5 or ?5.5?mEq?lC1. With this analysis, we included individuals with hypertension defined as a BP ?130/80?mm?Hg or treatment with any anti-hypertensive providers during the run-in period according to the Japan Society of Hypertension Recommendations (2009).17 Definitions of study outcomes The effectiveness measure was the time to the 1st event of the primary composite outcome of doubling of SCr, end-stage renal disease (SCr 5?mg?dlC1, dialysis, transplantation), and all-cause death. SCr was measured at a central laboratory in Japan (SRL, Tokyo, Japan). The secondary composite results included the following: (1) a composite end point of 1st event of cardiovascular death, nonfatal stroke except for transient ischemic attacks, non-fatal myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, revascularization of the coronary, carotid, or peripheral arteries, or lower extremity amputation; (2) switch in proteinuria; (3) rate of decline of the estimated glomerular filtration rate (eGFR) using the Japanese equation and the changes of diet in renal disease (MDRD) equation for estimating the GFR in Japanese and Chinese individuals, respectively.18, 19 Statistical analysis The Cox regression model was applied to estimate the HR between treatment organizations with the 95% CI for the renal and cardiovascular composite event rates.20 The covariates in the model were (1) UACR and SCr at baseline and regions (Japan/Hong Kong) for the renal composite event rate, and (2) baseline UACR, history of cardiovascular disease, and age for the cardiovascular composite event rate. The KaplanCMeier method was used to estimate the cumulative event rate in each treatment group stratified by the use of an ACEI.21 The linear mixed-effects model was used to compare the pattern in the percent change of the urinary protein:creatinine percentage (UPCR) and that of eGFR between the treatment and placebo organizations. Serious adverse events and discontinuation of the study drug due to adverse events were summarized. All statistical checks were two sided with 0.05 arranged as the significance level. Statistical analyses were performed using the Statistical Analysis System version 9.2 (SAS Institute, Cary, NC, USA). Results Individuals Among the 566 type 2 diabetic patients with overt nephropathy randomized in the ORIENT, 563 individuals (363 Japanese and 200 Chinese) experienced hypertension. Of these, 280 received olmesartan and 283 received placebo in addition to standard antihypertensive therapy (Table 1). Of the 563 individuals with hypertension, 414 (73.1%) were treated with ACEIs that were continued at the same dose throughout the study period of 3.2 (0.6) years (mean (s.d.)). The percentage of individuals receiving olmesartan was related in the ACEI-treated (205/414) and non-ACEI-treated organizations (75/149), at 50%. Table 1 Baseline characteristics of type 2 diabetic patients with hypertension and overt nephropathy treated with antihypertensive medicines including ACEI randomized to receive either olmesartan or placebo treatment for any mean period of 3.2 years (%). aMedian (interquartile range). Mouse monoclonal to Epha10 bThe value for HbA1c (%) is definitely estimated as an National Glycohemoglobin Standardization System (NGSP) equivalent value (%) calculated from the method HbA1c (%)=HbA1c (Japan Diabetes Society (JDS))(%)+0.4%, considering the relational expression of HbA1c (JDS)(%) measured by the previous Japanese standard compound and measurement methods. Blood pressure In the olmesartan group, the imply BP fell from 141.9/77.8?mm?Hg at baseline to 137.6/75.1?mm?Hg at week 12 and 131.9/72.2?mm?Hg at week 144. The respective values were 140.9/77.2, 140.4/76.6 and 136.6/73.6?mm?Hg in Vericiguat the placebo group (Number 1a). There was a greater reduction in time-averaged systolic and diastolic BP (SBP and DBP) in the olmesartan group compared with the placebo group (SBP, 2.8?mm?Hg; DBP, 1.6?mm?Hg, ?7.120?ml?minC1 per 1.73 m2 per year; 15 (5.3%)). The respective rates Vericiguat were 11.7% 7.2% in the ACEI-treated individuals and 2.7% 0% in the non-ACEI-treated individuals (Table 3). None of the individuals required acute dialysis in the.