Shigehiro Katayama

Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes

BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).

Rationale, study design and implementation of the COLM study : the combination of OLMesartan and calcium channel blocker or diuretic in high-risk elderly hypertensive patients

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being <140 mm Hg for systolic BP and <90 mm Hg for diastolic BP. Safety and tolerability will also be investigated. A total of more than 4000 patients were recruited and will be followed up for at least 3 years.

Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: Reduction of MRNA levels for interleukin-1β, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor α (PPARα) in primary endothelial cells

We examined the effects of four 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (pravastatin, simvastatin, fluvastatin, and cerivastatin) on the production and expression of inflammatory cytokines and on enzyme expression involving prostaglandin and superoxide production in cultured human umbilical vein endothelial cells (HUVEC). All HMG-CoA reductase inhibitors significantly reduced interleukin-1beta and -6 mRNA expression and their protein levels in the culture medium, and also inhibited cyclooxygenase-2 mRNA expression and their protein levels. And these drugs induced peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma mRNA expression and their protein levels in HUVEC and hepatocyte. Moreover, the mRNA levels of p22phox, a 22-kD subunit and the protein levels of p47phox, a 47-kD subunit of nicotine adenine dinucleotide phosphate (NADPH) oxidase, was decreased by treatment with either simvastatin, fluvastatin or cerivastatin, and this effect was reversed by mevalonate, geranylgeraniol, farnesol, and cholesterol. The changes induced by HMG-CoA reductase inhibitors might be due to regulation of cellular cholesterol content level, cellular cholesterol metabolic pathway, and cellular PPARalpha activity, which was related with inflammation. This unique anti-inflammatory effect in addition to its hypolipidemic action, may be beneficial in preventing the vascular complications that are induced by hyperlipidemia.

Noninvasive Evaluation of Kidney Hypoxia and Fibrosis Using Magnetic Resonance Imaging

Interstitial fibrosis and hypoxia accelerate the progression of CKD, but clinical tools to quantitate these factors in patients are lacking. Here, we evaluated the use of two magnetic resonance imaging (MRI) techniques, diffusion-weighted (DW)-MRI and blood oxygen level-dependent (BOLD)-MRI, to assess kidney fibrosis and hypoxia of the cortex in 142 patients with either diabetic nephropathy (n = 43), CKD without diabetes (n = 76), or acute kidney injury (AKI) (n = 23). Apparent diffusion coefficient (ADC) values of DW-MRI correlated with estimated glomerular filtration rates (eGFR) in the diabetic nephropathy and CKD groups (r(2) = 0.56 and r(2) = 0.46, respectively). Although the T2* values of BOLD-MRI and eGFR displayed good correlation in the CKD group (r(2) = 0.38), we did not observe a significant correlation between these values in the diabetic nephropathy group, suggesting that factors other than tubulointerstitial alteration determine the degree of hypoxia in the renal cortex. In the AKI group, neither the T2* nor ADC values correlated with eGFR. Renal biopsies from patients with CKD demonstrated that the T2* and ADC MRI values correlated with renal pathology. Taken together, ADC and T2* values appear to serve as accurate indices for evaluating renal tubulointerstitial alterations and parenchymal hypoxia, respectively, in the cortex. Functional MRI can thus contribute to multilateral, noninvasive, in vivo assessment of kidney function.

Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

Diabetic nephropathy has developed into a worldwide epidemic and is responsible for the majority of end-stage renal disease in most countries. Antihypertensive treatment slows the progression of the disease. In addition, blockade of the renin–angiotensin system reduces the degree of albuminuria and angiotensin II receptor blockers (ARBs) have been shown to delay the progression from microalbuminuria to overt proteinuria in patients with diabetes. However, few studies have examined whether the initial stage of diabetic nephropathy (i.e. the development of microalbuminuria) in patients with type 2 diabetes can be slowed or prevented by ARB treatment. The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study is a placebo-controlled, multicentre, double-blind, parallel group study investigating the effect of the ARB, olmesartan medoxomil, on the incidence of microalbuminuria. A total of 4400 type 2 diabetes patients with normoalbuminuria will be randomized to treatment with 40 mg of olmesartan medoxomil once daily or placebo. Goal blood pressure will be 130/80 mmHg. The primary endpoint of the study is the occurrence of microalbuminuria. In ROADMAP, we will also assess as secondary endpoints the effects of olmesartan on fatal and non-fatal cardiovascular events in patients with diabetes. In addition, within subgroups of the ROADMAP patients, the effects of olmesartan on retinopathy and other microvascular circulations will be analysed. The study is expected to last a median of 5 years. The ROADMAP study will answer the question whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease.

Effect of Captopril on Glucose Concentration: Possible Role of Augmented Postprandial Forearm Blood Flow

The goal of this study was to evaluate the effects of captopril on plasma glucose concentration. The daily profiles of the plasma glucose levels were determined in 12 non-insulin-dependent diabetic normotensive subjects, treated with or without captopril at a dose of 25 mg 3 times/day. Forearm blood flow was also measured by strain-gauge plethysmography. Administration of captopril improved the daily profile of the plasma glucose level. Postprandial forearm blood flow was also augmented 2 h after a meal. These results suggest that angiotensin-converting enzyme inhibitors may improve glucose metabolism in diabetic subjects, possibly through enhancement of blood flow to skeletal muscle.

Serum Level of Triglycerides Is a Potent Risk Factor Comparable to LDL Cholesterol for Coronary Heart Disease in Japanese Patients with Type 2 Diabetes: Subanalysis of the Japan Diabetes Complications Study (JDCS)

CONTEXT Risk factors for cardiovascular complications in Japanese patients with diabetes have not been fully elucidated. OBJECTIVE Our objective was to determine incidence of and risk factors for coronary heart disease (CHD) and stroke in Japanese diabetic patients. DESIGN AND SETTINGS We conducted a prospective study at 59 hospitals throughout Japan. PATIENTS Patients included 940 men and 831 women with type 2 diabetes (mean age, 58.2 yr) without a history of cardiovascular complications who were followed for a median of 7.86 yr. INTERVENTION This was an observational study. MAIN OUTCOME MEASURES Incidence of CHD and stroke was evaluated. RESULTS Incidences of CHD and stroke per 1000 person-years were 9.59 and 7.45, respectively, whereas those of myocardial and brain infarctions were 3.84 and 6.29, respectively. Multivariate Cox analysis revealed that the serum log-transformed triglyceride level was a potent and independent predictor of CHD [hazard ratio (HR) = 1.54; 95% confidence interval (CI) = 1.22-1.94 per 1 sd increase), comparable to low-density lipoprotein (LDL) cholesterol (HR = 1.49; 95% CI = 1.25-1.78 per 1 sd increase). Triglycerides and LDL cholesterol linearly and continuously increased CHD risk, and subjects in the top third for both had markedly high risks of CHD, and their effects were possibly additive. However, serum triglycerides worked independently of blood pressure levels. Systolic blood pressure was the only significant predictor for stroke except for age (HR = 1.31; 95% CI = 1.04-1.65, per 1 sd increase). CONCLUSIONS In Japanese patients with type 2 diabetes, the serum triglyceride level was a leading predictor of CHD, comparable to LDL cholesterol. Because the serum triglyceride level is not a leading predictor of CHD in diabetic subjects in Western countries, ethnic group-specific strategies for prevention of diabetic macroangiopathy may be indicated.

Bezafibrate has an antioxidant effect: Peroxisome proliferator-activated receptor α is associated with Cu2+, Zn2+-superoxide dismutase in the liver

Administration of bezafibrate in rats significantly reduced the levels of plasma thiobarbituric acid-reactive substances (TBARS) in comparison with those obtained in rats fed a soy or lard chow. Moreover, an elevation of in vitro conjugated diene production and linoleic acid levels in the high-density lipoproteins and low-density lipoproteins induced by a soy or lard chow, was reduced by bezafibrate administration. In addition, the liver Cu2+, Zn2+-superoxide dismutase (SOD) gene expression showed a significant positive correlation with the liver peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA level (R=0.769, p<0.0001). This unique characteristic of bezafibrate, which possesses both a hypolipidemic effect and antioxidant activity, may be beneficial in preventing vascular complications in hyperlipidemia.

Phenotype and Genotype Characteristics of Age-related Macular Degeneration in a Japanese Population

PURPOSE To describe phenotype and genotype characteristics of age-related macular degeneration (AMD) in Japanese patients. DESIGN A case-control study. PARTICIPANTS A total of 550 case-control samples composed of 408 consecutive AMD cases and 142 controls. METHODS Clinical information assessing age, gender, affected eyes, fundus features, and fluorescein/indocyanine green angiograms were systematically evaluated. Four single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the complement factor H (CFH) gene, 1 SNP (rs11200638) in the high-temperature requirement factor A1 (HTRA1) gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were assessed using TaqMan technology. MAIN OUTCOME MEASURES The clinical phenotype information and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS Of Japanese patients with neovascular AMD (nAMD), 219 (58.7%) had typical nAMD and 154 (41.3%) had polypoidal choroidal vasculopathy (PCV). The frequency of bilateral exudative involvement was similar between typical nAMD (15.5%) and PCV (13.6%) (P = 0.613). Significant soft drusen were observed in the fellow eyes of 88 (47.6%) of 185 patients with unilateral typical nAMD and in 25 (18.8%) of 133 patients with unilateral PCV (P = 1.24x10(-7)). A serous pigment epithelium detachment was seen in 55 (25.1%) of 219 patients with typical nAMD and in 64 (41.6%) of 154 patients with PCV. A significant association was noted in CFH-rs800292, CFH-rs1410996, CFH-rs2274700, and HTRA1-rs11200638 with AMD development (P = 2.36x10(-5), 7.18x10(-5), 7.18x10(-5), 2.70x10(-7), respectively; population attributable risk = 57.3%, 57.8%, 57.8%, and 58.9%, respectively). We estimated the highest-risk group to have an approximately 70-fold greater risk of nAMD compared with the lowest-risk group when analyzing a combination of 4 SNPs in the CFH and HTRA1 genes. CONCLUSIONS The Japanese AMD phenotype is characterized by a higher frequency of PCV, male predominance, and lower frequency of bilateral presentation compared with Caucasian AMD. Genotype analyses demonstrate a significant population attributable risk for SNPs in the CFH and HTRA1 genes and demonstrate joint effects for both genes. Gene variants in both CFH and HTRA1 contribute significantly to the AMD phenotype in a Japanese population.

Complement Factor H and High-Temperature Requirement A-1 Genotypes and Treatment Response of Age-related Macular Degeneration

PURPOSE To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. DESIGN Prospective, case-control study. PARTICIPANTS One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. METHODS The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. MAIN OUTCOME MEASURES The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9 × 10⁻², 7.0 × 10⁻⁴, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12 × 10⁻²). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58 × 10⁻³). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700 (P = 8.50 × 10⁻³). CONCLUSIONS The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.