Shigeru Kageyama

Clinical Efficacy of Magnesium Supplementation in Patients with Type 2 Diabetes

Effects of magnesium (Mg) supplementation on nine mild type 2 diabetic patients with stable glycemic control were investigated. Water from a salt lake with a high natural Mg content (7.1%) (MAG21) was used for supplementation after dilution with distilled water to 100mg/100mL; 300mL/day was given for 30 days. Fasting serum immunoreactive insulin level decreased significantly, as did HOMA□R (both p < 0.05). There was also a marked decrease of the mean triglyceride level after supplementation. The patients with hypertension showed significant reduction of systolic (p < 0.01), diastolic (p = 0.0038), and mean (p < 0.01) blood pressure. The salt lake water supplement, MAG21, exerted clinical benefit as a Mg supplement in patients with mild type 2 diabetes mellitus.

Efficacy and safety of the selective aldosterone blocker eplerenone in Japanese patients with hypertension: a randomized, double-blind, placebo-controlled, dose-ranging study.

Approximately 40% of Japanese patients with essential hypertension, including low‐renin hypertension, are inadequately managed. Low‐renin hypertension generally responds poorly to angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers, but may respond more optimally to diuretics, calcium channel blockers, and aldosterone blockers. This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐ranging study evaluated the efficacy and safety of the selective aldosterone blocker eplerenone in 193 Japanese patients with essential hypertension. Although not a study inclusion criterion, baseline active plasma renin levels were consistently low (5.7–10.1 mU/L); most patients met the criteria for low‐renin hypertension (≤42.5 mU/L; normal range, 7–76 mU/L). Patients received placebo or eplerenone 50, 100, or 200 mg once daily for 8 weeks. Systolic blood pressure decreased significantly (−6.8 to −10.6 mm Hg vs. −2.1 mm Hg; p≤0.0245 vs. placebo) at all eplerenone doses; diastolic pressure decreased significantly at 100 and 200 mg doses (−6.9 to −7.5 mm Hg vs. −3.0 mm Hg; p≤0.0022 vs. placebo). Eplerenone offers significant blood pressure reduction with good tolerability in Japanese patients with hypertension, including those with low‐renin hypertension.

Comparison of the Effects of Acarbose and Voglibose in Healthy Subjects

Acarbose and voglibose are alpha-glucosidase inhibitors. Although the pharmacologic effects and incidence of abdominal adverse events associated with the two drugs have been reported to differ, no study has directly compared acarbose and voglibose. To compare the pharmacologic effects and gastrointestinal adverse events associated with the two drugs, a randomized, placebo-controlled, double-masked, fivefold crossover study was performed in 20 healthy male subjects. To assess the pharmacologic effects, plasma immunoreactive insulin (IRI), plasma glucose, and 24-hour urinary connecting-peptide immunoreactivity (CPR) excretion were measured. Although the postprandial increase in plasma glucose level was reduced significantly with both acarbose and voglibose, the rate of reduction was small. The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of plasma IRI after meals decreased significantly with all treatments except voglibose 0.3 mg compared with placebo. Overall, the Cmax and AUC of plasma IRI decreased more when subjects received acarbose than voglibose. Urinary CPR excretion decreased by 30.6% and 41.7%, respectively, in subjects who received acarbose 50 mg or 100 mg compared with the previous day when no drug was given, whereas the urinary CPR excretion did not decrease significantly with voglibose. There was no significant difference in the frequency of gastrointestinal adverse events between groups, including the placebo group. One-day administration of acarbose and voglibose at currently recommended clinical doses demonstrated that acarbose was more effective in sparing endogenous insulin secretion than was voglibose.

CD40 ligand immunotherapy in cancer: An efficient approach

Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system.

Interactions between Serum Vitamin D Levels and Vitamin D Receptor Gene FokI Polymorphisms for Renal Function in Patients with Type 2 Diabetes

Background We aimed to examine associations among serum 25-hydroxyvitamin D (25OHD) levels, 1,25-dihyroxyvitamin D (1,25OHD) levels, vitamin D receptor (VDR) polymorphisms, and renal function based on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. Methods In a cross-sectional study of 410 patients, chronic kidney disease (CKD) stage assessed by eGFR was compared with 25OHD, 1,25OHD, and VDR FokI (rs10735810) polymorphisms by an ordered logistic regression model adjusted for the following confounders: disease duration, calendar month, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers or statins, and serum calcium, phosphate, and intact parathyroid hormone levels. Results 1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations; peak levels were seen from May to October and the lowest levels were seen from December to February. These findings were evident in patients with CKD stage 3∼5 but not stage 1∼2. eGFR was in direct proportion to both 25OHD and 1,25OHD levels (P<0.0001), but it had stronger linearity with 1,25OHD (r = 0.73) than 25OHD (r = 0.22) levels. Using multivariate analysis, 1,25OHD levels (P<0.001), but not 25OHD levels, were negatively associated with CKD stage. Although FokI polymorphisms by themselves showed no significant associations with CKD stage, a significant interaction between 1,25OHD and FokITT was observed (P = 0.008). The positive association between 1,25OHD and eGFR was steeper in FokICT and CC polymorphisms (r = 0.74) than FokITT polymorphisms (r = 0.65). Conclusions These results suggest that higher 1,25OHD levels may be associated with better CKD stages in patients with type 2 diabetes and that this association was modified by FokI polymorphisms.

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study

AIMS Ipragliflozin is a novel and highly selective sodium-glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM. METHODS In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50mg or 100mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days -1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0-3h (AUC0-3h) and 0-24h (AUC0-24h). Pharmacokinetic characteristics included AUC0-24h, maximum ipragliflozin concentration (Cmax), and time to maximum plasma ipragliflozin concentration (tmax). RESULTS Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC0-3h and AUC0-24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC0-24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0-24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group. CONCLUSIONS Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.

Delapril versus manidipine in hypertensive therapy to halt the type-2-diabetes-mellitus-associated nephropathy

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

Effect of Antihypertensive Treatment on Cardiovascular Events in Elderly Hypertensive Patients: Japan's Benidipine Research on Anti-Hypertensive Effects in the Elderly (J-BRAVE)

The achievement rate of blood pressure (BP) target and the relationship between on-treatment BP and development of cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) were investigated in a total of 8,897 patients in the Japans Benidipine Research on Antihypertensive Effects in the Elderly (J-BRAVE) study, a prospective, 3-year observational study of a calcium channel blocker-based treatment in hypertensive patients aged ≥65 years as a post-marketing surveillance. Blood pressure decreased significantly from 164.8 ± 14.1/88.2 ± 10.3 mmHg to 137.0 ± 13.5/75.6 ± 9.5 mmHg and the percentage of patients who achieved BP <140/90 mmHg was 57.2% after 3 years. The incidence of cardiovascular events was 7.54/1,000 patient-years. Subgroups of patients stratified by on-treatment systolic blood pressure (SBP) were analyzed. Baseline BP, body mass index (BMI), the dose of benidipine, the mean number of anti-hypertensive drugs, and the incidence of cardiovascular events were higher in patients with on-treatment SBP ≥160 mmHg than in those with an SBP of <130 mmHg. In patients aged 65 to 74 years (n = 5,092) and patients aged ≥75 years (n = 3,805), the percentages of patients who achieved the BP target of <140/90 mmHg were 57.5% and 56.6% after 3 years, respectively, and the incidence of cardiovascular events was higher in patients with on-treatment SBP ≥160 mmHg in both age subgroups. The results of the J-BRAVE study show that on-treatment SBP ≥160 mmHg is associated with a higher incidence of cardiovascular events in elderly hypertensive patients.

Efficacy and safety of repaglinide vs nateglinide for treatment of Japanese patients with type 2 diabetes mellitus

Aims/Introduction:  Repaglinide is a short‐acting insulin secretagogue. We assessed the efficacy and safety of repaglinide in comparison with nateglinide in Japanese patients with type 2 diabetes previously treated with diet and exercise.

Hypertension management in diabetic patients: prescribing trends from 1999 to 2005 in three Japanese university hospitals

In hypertensive patients with diabetes, antihypertensive therapy is important in reducing the risk of macro‐ and microvascular complications. In contrast to the guidelines issued by the American Diabetes Association (ADA) in and after 2002, the guidelines issued by the Japanese Society of Hypertension (JSH) in 2000 and 2004 maintained the traditional view that β‐blockers and thiazides should be rated as second‐line drugs. However, both sets of guidelines recommended angiotensin converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as first‐line agents for such patients.