Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are reported to prevent cardiovascular events by a mechanism possibly including diuresis and sodium excretion. In this respect, diuresis-induced compensatory upregulation of the renin-angiotensin-aldosterone (RAA) system should be clarified and we performed a randomized controlled trial using dapagliflozin, an SGLT2I. Hypertensive diabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomly assigned to a dapagliflozin group (DAPA) or a control group (CTRL) with the difference in the changes in plasma renin activity (PRA) after 24 weeks of the treatment as the primary outcome. PRA, plasma aldosterone concentration (PAC), age, sex, BMI, blood pressure, pulse rate, eGFRcys, and HbA1c were not different between the groups at baseline. After 24 weeks, the changes in the PRA from the baseline of the DAPA (n = 44) and CTRL (n = 39) groups were 6.30 ± 15.55 and 1.42 ± 11.43 ng/mL/h, respectively (p = 0.11) although the power of detection was too small. However, post hoc nonparametric analyses revealed that there was a definite increase in the PRA and PAC in the DAPA group (p < 0.0001 and p = 0.00025, respectively) but not in the CTRL group. The PRA in the DAPA group after 24 weeks treatment was significantly elevated compared to the CTRL group (p = 0.013) but not for the PAC. Accordingly, it would be suggested that dapagliflozin may not induce a profound increase, if any, in PAC after 24 weeks of treatment in hypertensive type 2 diabetic patients under RAA suppression.

The long-term coronary heart disease risk of previously obese patients with type 2 diabetes mellitus.

BACKGROUND: Obesity is associated with insulin resistance, development of diabetes, and coronary heart disease. There is limited information on the contribution of previous obesity on the risk of coronary heart disease. We aimed to examine the effect of previous history of obesity on the occurrence of coronary heart disease in patients with diabetes. METHODS: We carried out a retrospective chart analysis of 315 type 2 diabetic patients without obesity and without atherosclerotic cardiovascular events at their initial hospital visit (men/women 236/79; mean ± standard deviation; age 53.1 ± 6.6 years; maximal body mass index before enrollment (MAXBMI) 26.6 ± 3.4 kg/m2; decrease of the BMI at enrollment from MAXBMI (deltaBMI) 4.23 ± 2.62 kg/m2) to investigate the association of previous obesity (MAXBMI larger than 30 kg/m2) with the long-term incidence of cardiovascular events. Of 315 patients, forty-eight were previously obese. RESULTS: After median follow-up of 13.9 years, 48 patients developed coronary heart disease. The Kaplan-Meier analysis exhibited that coronary heart disease occurred more frequently in previously obese patients than in subjects in the reference category (22 kg/m2 < or = MAXBMI < 25 kg/m2) and that the effect lasted proportionally over follow-up periods. Multivariate Cox regression models showed that hazard ratios and corresponding 95% confidence intervals of coronary heart disease for patients with previous obesity compared with subjects in the reference category were 2.52 and 1.15 to 5.50 (p value = 0.020) after adjustment for age, sex, smoking status, systolic blood pressure, total cholesterol and HDL cholesterol. In this cohort, deltaBMI strongly correlated with MAXBMI and also behaved as a risk factor. The hazard ratios and 95% confidence intervals by the increment of one standard deviation of deltaBMI after adjustment for age, sex, smoking status, systolic blood pressure, total cholesterol and HDL cholesterol were 1.38 and 1.08 to 1.79 (p value = 0.013). CONCLUSIONS: Previous obesity and/or large body weight loss before admission might act as an increased risk for coronary heart disease.

Distribution of blood glucose and the correlation between blood glucose and hemoglobin A1c levels in diabetic outpatients.

PURPOSE OF THE STUDY: Tight glycemic control is important for the prevention of microvascular complications in diabetic patients. We examined the reliability of using blood glucose levels measured at various time-points relative to a meal as an index of glycemic control in Japanese diabetic outpatients. Basic procedures followed: We examined the correlation between the fasting blood glucose (FBG) level; the one-hour (1-h), two-hour (2-h), and three-hour (3-h) post breakfast blood glucose (PBBG) levels, the 1 h, 2 h, and 3 h post lunch blood glucose (PLBG) levels and the hemoglobin A1c (HbA1c) levels in Japanese diabetic outpatients. A total of 11451 patient-visits to the Marunouchi Hospital between January 2002 and December 2002 were included in the study. The main findings: The blood glucose levels measured at all of the above time-points were significantly correlated with the HbA1c level. As calculated using local polynomial regression fitting, the FPG, 1-h, 2-h, and 3-h PBBG levels that corresponded to an HbA1c level of 6.5% were 132 mg/dL, 174 mg/dL, 170 mg/dL, and 143 mg/dL, respectively. The FPG and 2-h PBBG levels exhibited a good sensitivity and specificity for predicting a glycemic control corresponding to an HbA1c<5.8%, while the FPG and 3-h PBBG levels exhibited fair sensitivity and specificity for predicting glycemic control corresponding to an HbA1c<6.5%. The principal conclusions: The FBG, 2-hPBBG, and 3-hPBBG levels can be used as rough estimates of glycemic control in Japanese diabetic outpatients.

Up-Titration Strategy After DPP-4 Inhibitor-Based Oral Therapy for Type 2 Diabetes: A Randomized Controlled Trial Shifting to a Single-Dose GLP-1 Enhancer Versus Adding a Variable Basal Insulin Algorithm.

INTRODUCTION: It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. METHODS: Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. RESULTS: HbA1c was significantly lower at week 24 (- 1.0 ± 0.9% in the IGlar group and - 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (- 2.9 ± 3.2% vs. - 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. - 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. CONCLUSION: For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial. TRIAL REGISTRATION: Trial Registry (UMIN-CTR) as UMIN000012224.

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

ApoE isoforms, treatment of diabetes and the risk of coronary heart disease.

AIM: To analyze the risk of coronary heart disease in patients with type 2 diabetes mellitus (T2DM) receiving standard medical treatment. METHODS: We performed a retrospective chart analysis of 269 middle-aged patients (age 45-64 years, mean age, 53.9 ± 5.5 years) with T2DM and without atherosclerotic cardiovascular events who underwent typing to determine their apolipoprotein E (apoE) isoforms. The apoE isoforms were determined using isoelectric focusing, followed by immunoblotting. We retrospectively evaluated the charts of the 269 patients, recorded between their first visit to the hospital (the study's start point, between 1987 and 1992) and the occurrence of an atherosclerotic cardiovascular event (the study's endpoint) or January 2004, whichever came first. The age-adjusted mean values and the prevalences of covariates were calculated to compare the laboratory data among the apoE phenotypes. To investigate the association of risk factors with the incidence of coronary heart disease during the follow-up period, monovariate and multivariate Cox regression models were used. RESULTS: At enrollment, the mean serum low density lipoprotein (LDL) cholesterol levels were lowest (2.92 ± 0.89 mmol/L) among the subjects with apoE2 (apoE2/2 or apoE2/3) and highest (3.52 ± 0.77 mmol/L) among the subjects with apoE4 (apoE3/4 or apoE4/4). No significant differences in mean age or the percentage of smokers were observed among the three groups. Furthermore, no significant differences were observed in the systolic and diastolic blood pressures, body mass index, HbA1c level or serum triglyceride levels among the three groups. There were 47 cases of coronary heart disease over 3285 person-years of follow-up. An age-adjusted multivariate Cox proportional model identified diabetic retinopathy (hazard ratio, 2.38, 95% CI: 1.28-4.43, P = 0.006), a high systolic blood pressure (hazard ratio, 1.04, 95% CI: 1.02-1.06, P < 0.001) and high HbA1c values (hazard ratio, 1.19, 95% CI: 1.02-1.38, P = 0.0029), but not the LDL cholesterol value at enrollment (hazard ratio, 1.01, 95% CI: 0.97-1.05, P = 0.77) nor the specific apoE isoform, as significant predictors of coronary heart disease. CONCLUSION: Under standard medical treatment of diabetes, including the control of LDL cholesterol levels, the apoE4 isoform was not associated with coronary heart disease among T2DM patients.

Use of insulin glargine in Japanese patients with type 1 diabetes.

OBJECTIVE: To evaluate the results of treatment with an insulin glargine-based regimen as compared with those of an NPH insulin-based regimen. METHODS: We reviewed the charts of 83 Japanese patients with Type 1 diabetes treated with insulin glargine for 12 months. PATIENTS: Median age, 56.9 years (range, 24.6-74.8 years), mean (+/-S.D.) body mass index, 21.2 (+/-2.2) kg/m2. RESULTS: The average HbA1c level of the cohort was 7.8 +/- 1.2% at baseline and 7.7 +/- 1.0% at the end of the 12-month treatment (P=0.34). The average insulin requirement per day in the cohort remained unchanged after the 12-month treatment (35.0 +/- 11.6 units/day versus 35.2 +/- 11.2 units/day (P=0.58). Of the 36 patients who were receiving twice or three times daily injections of NPH insulin, 30 could be switched to a single-daily injection of insulin glargine. The frequency of severe hypoglycemia with unconsciousness became lower after switching to the insulin glargine-based regimen than during treatment with the NPH-based regimen. The average ratio of the daily usage of insulin glargine to that of total insulin after 12 months was smaller than that reported from other countries (0.34 +/- 0.09). CONCLUSION: These results obtained from a larger number of patients as compared to previous Japanese studies confirm earlier reports that insulin glargine provides equivalent glycemic control to human NPH insulin, with a lower incidence of severe hypoglycemia. Thus, treatment with insulin glargine provides some benefits to Japanese patients with Type 1 diabetes.

Effects of chronic intake of vegetable protein added to animal or fish protein on renal hemodynamics.

BACKGROUND/AIMS: To examine whether chronic intake of vegetable protein added to animal protein diet affects renal hemodynamics or not, we studied effects of three kinds of diets containing various amounts of animal and vegetable protein with 1-week dietary program in each on renal hemodynamics. METHODS: The crossover design of different amounts of vegetable protein added to the constant amount of animal protein was applied to two groups of 7 healthy individuals after the control dietary program. Renal function and 24 hours' urinary albumin excretion rate (AER) were examined on every 7th day of three consecutive 1-week dietary programs. RESULTS: Glomerular filtration rate (GFR; sodium thiosulphate clearance) and renal plasma flow (RPF) significantly decreased after decreasing the intake of animal protein by one third with keeping the amount of vegetable protein constant. The results when substituting vegetable protein for some of the animal protein in the diet without changing the total amount of protein were identical. The filtration fraction and AER did not change over the study periods regardless of dietary composition. CONCLUSION: The lack of an effect a 1-week intake of vegetable protein added to animal protein on GFR and RPF suggests that vegetable protein may be excluded from lists of restriction in low protein diet therapy in patients with renal insufficiency.