Impact of febuxostat on visit-to-visit blood pressure variability: insights from the randomised PRIZE Study.

OBJECTIVES: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The aim of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomised trial setting. METHODS: This was a subanalysis of the PRIZE Study, a randomised trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured ≥3 times. BP and PR variabilities were assessed with SD and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities was adjusted with age, sex and baseline BP or PR, expressed with 95% CIs. RESULTS: A total of 472 patients were included into the present subanalysis. During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 (126.8-130.0) vs 130.7 (129.1-132.2) mm Hg, p=0.04) and CV of systolic BP (7.4 (6.7-8.0) vs 8.2 (7.6-8.8), p=0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 (4.93-6.97) vs 7.33 (6.32-8.33), p=0.04). CONCLUSION: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability in patients with hyperuricemia and carotid plaques. TRIAL REGISTRATION NUMBERS: University Hospital Medical Information Network Clinical Trial Registry (UMIN000012911 and UMIN000041322).

A randomized controlled trial of two diets enriched with protein or fat in patients with type 2 diabetes treated with dapagliflozin.

Sodium-glucose cotranspsorter-2 (SGLT2) inhibitors (SGLT2i) involve loss of skeletal muscle mass, potentially leading to inadequate HbA1c reduction in type 2 diabetes (T2DM), since muscle mass is related to insulin sensitivity. The benefit of protein-enriched diet for improving HbA1c in SGLT2i-treated T2DM patients remains unclear. We conducted a multicenter, double-blind, randomized, controlled, investigator-initiated clinical trial. 130 T2DM patients treated with dapagliflozin (5 mg) were randomized to isoenergic protein-rich formula diet (P-FD) or fat-rich FD (F-FD) (1:1 allocation) to replace one of three meals/day for 24 weeks. Primary outcome was change in HbA1c. Secondary outcomes were changes in serum insulin, body composition and other metabolic parameters. Although HbA1c decreased significantly in both groups [mean (95% confidence interval) - 0.7% (- 0.9 to - 0.5) in P-FD, - 0.6% (- 0.8 to - 0.5) in F-FD], change in HbA1c was not significantly different between the two groups (P = 0.4474). Fasting insulin and body fat mass decreased, while HDL-cholesterol increased significantly in P-FD, and these changes were significantly greater compared with F-FD (all, P < 0.05). In T2DM treated with dapagliflozin, protein-enriched diet does not contribute to HbA1c reduction, although it decreases serum insulin and body fat mass, and increases HDL-cholesterol compared with fat-enriched diet with identical calories and carbohydrate ratio.

Effects of Sodium Glucose Co-Transporter 2 Inhibitors in Type 1 Diabetes Mellitus on Body Composition and Glucose Variabilities: Single-Arm, Exploratory Trial.

INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus; they prevent cardiovascular events and reduce fat mass. However, little is known about the effects of SGLT2 inhibitors on type 1 diabetes mellitus as an adjuvant to insulin therapy. Therefore, we aimed to elucidate the effects of SGLT2 inhibitors on body composition of patients with type 1 diabetes mellitus and assess blood glucose variability. METHODS: A single-center, single-arm, prospective, interventional study was performed on Japanese patients with type 1 diabetes mellitus who were not administered SGLT2 inhibitors prior to this study. These patients were equipped with flash glucose monitoring (FGM) and administered ipragliflozin 50 mg daily. Body composition was evaluated using bioelectrical impedance analysis, and glycemic variabilities were assessed using FGM before and after SGLT2 inhibitor treatment. RESULTS: After 52 weeks of treatment, the total fat mass tended to be reduced (- 9.10% from baseline, P = 0.098). In addition, skeletal muscle mass also decreased (- 2.98% from baseline, P = 0.023). Although the basal insulin dose was reduced, SGLT2 inhibitors decreased HbA1c levels. FGM revealed that glycemic variabilities were also reduced, and time within the target glucose range increased (51.7% vs. 62.5%, P = 0.004). CONCLUSION: SGLT2 inhibitors have beneficial effects on glycemic variabilities and fat mass reductions in patients with type 1 diabetes mellitus. However, loss of skeletal muscle is a major concern; therefore, caution is required when using SGLT2 inhibitors in lean patients with type 1 diabetes mellitus. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000042407).

Comparison of Patient-Led and Physician-Led Insulin Titration in Japanese Type 2 Diabetes Mellitus Patients Based on Treatment Distress, Satisfaction, and Self-Efficacy: The COMMIT-Patient Study.

INTRODUCTION: In Japan, patient-led insulin titration is rare in type 2 diabetes mellitus (T2DM) patients. Few studies have compared the effects of patient-led versus physician-led insulin titration on patient-reported outcomes in Japanese T2DM patients. This study aimed to compare the effects of patient-led and physician-led insulin titration in Japanese insulin-naïve T2DM patients on safety, glycemic control, and patient-reported outcomes (emotional distress, treatment satisfaction, and self-efficacy). METHODS: Ultimately, 125 insulin-naïve Japanese T2DM patients were randomly assigned to either a patient-led insulin self-titration group or a physician-led insulin titration group and monitored for 24 weeks. The primary endpoint was a change in emotional distress as measured using the Problem Areas in Diabetes scale (PAID). Secondary endpoints included treatment satisfaction, as measured with the Diabetes Treatment Satisfaction Questionnaire (DTSQ), self-efficacy as measured using the Insulin Therapy Self-Efficacy Scale (ITSS), glycated hemoglobin (HbA1c) levels, fasting plasma glucose levels, body weight, insulin daily dose, and frequency of hypoglycemia. RESULTS: There was no significant difference between the groups in PAID and DTSQ scores. The results for the primary endpoint should be interpreted taking account that the sample size for the power calculation was not reached. ITSS scores were significantly higher in the patient-led self-titration group. HbA1c and fasting plasma glucose levels were significantly decreased in both groups, but the decrease was significantly larger in the patient-led self-titration group. Although the insulin daily dose was significantly higher in the patient-led self-titration group, severe hypoglycemia did not occur in either group, and the frequency of hypoglycemia was similar in both groups. CONCLUSION: Self-measurement of blood glucose and self-titration of insulin enhanced the patients' self-efficacy without compromising their emotional distress or treatment satisfaction. Also, insulin self-titration was found to be safe and effective; it resulted in better glycemic control without severe hypoglycemia. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (registration number: UMIN000020316).

Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).

AIMS/INTRODUCTION: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear. MATERIALS AND METHODS: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated. RESULTS: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption. CONCLUSIONS: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.

Assessing Patient Satisfaction Following Sodium Glucose Co-Transporter 2 Inhibitor Treatment for Type 1 Diabetes Mellitus: A Prospective Study in Japan.

INTRODUCTION: In Japan, several sodium glucose co-transporter 2 (SGLT2) inhibitors have been used for type 1 diabetes mellitus as an adjuvant therapy to insulin therapy; however, there are no clinical reports regarding the satisfaction of its use. Therefore, we conducted a survey among patients with type 1 diabetes undergoing treatment using an SGLT2 inhibitor. METHODS: This is a single-arm open-label prospective study including 24 patients with type 1 diabetes who were to be initiated on ipragliflozin treatment between March and August 2019. All participants provided written informed consent. They completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for the survey and 3 months of observation after the administration of an SGLT2 inhibitor (50 mg of ipragliflozin), and changes from baseline diabetes treatment satisfaction were evaluated using modified DTSQ scores (five-step evaluation) and were analyzed. RESULTS: The average score for each question on DTSQ significantly increased [mean (standard deviation); 0.25 (0.25) vs 0.83 (0.77), P = 0.004]. Approximately 75% of the patients perceived an improvement in glycemic control over short periods of time. Finally, 54.2% of patients were highly satisfied and would recommend the SGLT2 inhibitor treatment [0.0 (0.0) vs. 0.92 (1.32), P < 0.001]. After the administration of ipragliflozin, reductions in body weight [24.0 (2.9) vs. 23.4 (2.9) kg/m2, P = 0.002], total insulin [39.1 (12.9) vs. 34.3 (12.5) units, P = 0.013], and glycated hemoglobin [7.77 (0.97) vs. 7.40 (0.86) %, P = 0.013] were observed, without any severe side effects. Improvements in glycemic variability indexes were observed through flash glucose monitoring. CONCLUSIONS: SGLT2 inhibitors may improve clinical treatment satisfaction by improving glycemic variability in patients with type 1 diabetes mellitus, while not inducing severe side effects with careful use. TRIAL REGISTRATION: This study is registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000040487).

Correction to: Study Protocol for the Effects of Formula Diet with Dapagliflozin on Metabolic Improvement and Body Composition in Type 2 Diabetes Mellitus.

In the original article, the 6th sentence of the section "FD and calorie intake" is incorrect. The correct sentence is "The protein component of FD consists of whey protein, casein, and soy protein".

Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m2 . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Study Protocol for the Effects of Formula Diet with Dapagliflozin on Metabolic Improvement and Body Composition in Type 2 Diabetes Mellitus.

INTRODUCTION: Sodium-dependent glucose transporter-2 (SGLT2) inhibitors such as dapagliflozin induce weight loss, but the mechanism is thought to involve loss of both body fat and skeletal muscle mass. The decrease in skeletal muscle mass may lead to worsening of insulin resistance in type 2 diabetes patients. On the other hand, formula diet (FD) is a low-calorie food containing low carbohydrates, low fat, and sufficient protein, vitamins, and minerals to support a healthy and balanced diet, and is used for the treatment of obesity or diabetes. Therefore, we examine whether the protein supplementation is superior to the fat supplementation in metabolic improvement of the poorly controlled type 2 diabetes patients treated with SGLT2 inhibitor. We compare the therapeutic effects using two types of FD; a high protein FD and a high fat FD. Patients are prescribed dapagliflozin and replacement of one of three meals with FD. We compare high protein FD and high fat FD with respect to improvement of glycemic control while maintaining skeletal muscle mass. METHODS: We conduct a prospective, multicenter, double-blinded, randomized, controlled, investigator-initiated clinical trial. Patients who satisfy the eligibility criteria will be randomized to two groups (1:1) and prescribed 5 mg of dapagliflozin once daily together with a high protein FD or high fat FD (same number of calories) to replace one of three meals a day (one meal with FD only and two normal meals). The observation period for both groups is 24 weeks. The primary endpoint is the change in HbA1c. PLANNED OUTCOMES: This study is ongoing and scheduled to complete in June 2019. The findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) 000024580. FUNDING: This study was carried out under contract with the specified nonprofit corporation Hokkaido Institute of Health Sciences, based on a grant from AstraZeneca Co., Ltd. and Ono Pharmaceutical Co., Ltd. for an investigator-initiated clinical trial. The authors funded the journals article processing charges.

Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study).

INTRODUCTION: In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. METHODS AND ANALYSIS: A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants. TRIAL REGISTRATION NUMBER: UMIN000015170, R000016861 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000016861); Pre-results.

Large-scale survey of rates of achieving targets for blood glucose, blood pressure, and lipids and prevalence of complications in type 2 diabetes (JDDM 40).

OBJECTIVE: The fact that population with type 2 diabetes mellitus and bodyweight of patients are increasing but diabetes care is improving makes it important to explore the up-to-date rates of achieving treatment targets and prevalence of complications. We investigated the prevalence of microvascular/macrovascular complications and rates of achieving treatment targets through a large-scale multicenter-based cohort. RESEARCH DESIGN AND METHODS: A cross-sectional nationwide survey was performed on 9956 subjects with type 2 diabetes mellitus who consecutively attended primary care clinics. The prevalence of nephropathy, retinopathy, neuropathy, and macrovascular complications and rates of achieving targets of glycated hemoglobin (HbA1c) <7.0%, blood pressure <130/80 mm Hg, and lipids of low-density/high-density lipoprotein cholesterol <3.1/≥1.0 mmol/L and non-high-density lipoprotein cholesterol <3.8 mmol/L were investigated. RESULTS: The rates of achieving targets for HbA1c, blood pressure, and lipids were 52.9%, 46.8% and 65.5%, respectively. The prevalence of microvascular complications was ∼28% each, 6.4% of which had all microvascular complications, while that of macrovascular complications was 12.6%. With an increasing duration of diabetes, the rate of achieving target HbA1c decreased and the prevalence of each complication increased despite increased use of diabetes medication. The prevalence of each complication decreased according to the number achieving the 3 treatment targets and was lower in subjects without macrovascular complications than those with. Adjustments for considerable covariates exhibited that each complication was closely inter-related, and the achievement of each target was significantly associated with being free of each complication. CONCLUSIONS: Almost half of the subjects examined did not meet the recommended targets. The risk of each complication was significantly affected by 1 on-target treatment (inversely) and the concomitance of another complication (directly). Total diabetes care including one-by-one management of modifiable risk factors and complications may be important for high-quality care. The future studies including more subjects and clinics with precise complication status are needed.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone (Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1): A multicenter, randomized, open-label, non-inferiority trial.

AIMS/INTRODUCTION: To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. MATERIALS AND METHODS: In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20-79 years with type 2 diabetes who had glycated hemoglobin 6.9-8.8% on stable metformin (500-1,500 mg/day) or pioglitazone (15-30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. RESULTS: After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were -0.70% in sitagliptin and -0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was -0.49% (95% confidence interval -0.66 to -0.32, P < 0.0001), meeting the predefined non-inferiority criterion (0.25%) and showing statistical significance. This statistical significance also continued after 24 weeks. Although sitagliptin did not affect bodyweight, α-glucosidase inhibitors decreased bodyweight significantly from baseline (-0.39 kg; P = 0.0079). Gastrointestinal disorders were significantly lower with sitagliptin than with an α-glucosidase inhibitor (6 [10.3%] patients vs 23 [39.7%]; P = 0.0003). Minor hypoglycemia occurred in two patients (3.5%) in each group. CONCLUSIONS: Sitagliptin showed greater efficacy and better tolerability than an α-glucosidase inhibitor when added to stable doses of metformin or pioglitazone. These findings support the use of sitagliptin in Japanese patients with type 2 diabetes inadequately controlled by insulin-sensitizing agents. This trial was registered with UMIN (no. 000004675).

Prognostic value of coronary flow reserve assessed by transthoracic Doppler echocardiography on long-term outcome in asymptomatic patients with type 2 diabetes without overt coronary artery disease.

BACKGROUND: Cardiovascular risk stratification of asymptomatic diabetic patients is important and remains a difficult clinical problem. Our aim was to test the hypothesis that coronary flow reserve (CFR) assessed by noninvasive transthoracic Doppler echocardiography predicts prognosis in those patients. METHODS: From February 2002 to January 2005, we evaluated 135 consecutive asymptomatic patients (74 male; mean age, 63 ± 9 years) with type 2 diabetes without a history of coronary artery disease. Adenosine triphosphate (0.14 mg/kg/min) stress Doppler echocardiography was performed to evaluate CFR of the left anterior descending artery. Patients with a CFR < 2.0 were also excluded based on the suspicion of significant coronary artery stenosis in the left anterior descending artery. RESULTS: There were 111 patients (60 male; mean age, 64 ± 9 years) enrolled. During a median follow-up of 79 months, 20 events (5 deaths, 7 acute coronary syndromes, 8 coronary revascularizations) occurred. The optimal cut-off value of CFR to predict events was 2.5 (area under the receiver-operating characteristic curve = 0.65). Multivariate analysis showed that the independent prognostic indicators were male gender (p < 0.05) and a CFR < 2.5 (p < 0.01). Kaplan-Mayer analysis revealed that the event rate was significantly higher (log-lank, p < 0.01) in patients with CFR < 2.5 than in those with CFR ≥ 2.5. CONCLUSIONS: CFR obtained by transthoracic Doppler echocardiography provides independent prognostic information in asymptomatic patients with type 2 diabetes without overt coronary artery disease. Patients with CFR < 2.5 had a worse long-term outcome.

[High expectation for combination tablets for diabetes treatment].

Recently, a combination therapy of several oral agents has been more common for antihyperglycemic therapy and four kinds of combination tablets are available in Japan. Any combination tablet is not allowed for the initial treatment but very useful for a numbers of patients who are already taking two-drug combinations and in stable condition to reduce the number of tablets. Additionally, a combination tablet is also beneficial for patients who are in inadequate glycemic control with a single agent to gain the better glucose lowing effectiveness with a single tablet of dual agents. For a favorable treatment outcome of chronic diseases, it is very important for physicians to enhance drug adherence rate of patients and utilize combination tablets more.

Effect of angiotensin-converting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus.

Measurements of serum asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy (2 mg/day) in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly (0.51+/-0.08 to 0.46+/-0.07 micromol/l, p<0.01) and CFVR increased significantly (2.78+/-0.36 to 3.35+/-0.46, p<0.001) after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR (r=-0.80, p<0.001). Temocapril reduced serum ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. Our results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes.

Vasopressin responders have a high prevalence of hypertension and insulin resistance in spite of a lower secretion of cortisol in subclinical Cushing's syndrome.

The hyper-responsiveness of plasma cortisol to vasopressin has been reported in patients with ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) and in certain cases of Cushing's adenomas with overexpression of V1a receptors in the adrenal gland. We previously reported a high prevalence of the adrenal hyper-responsiveness of plasma cortisol to vasopressin (vasopressin responders) in Japanese patients with Cushing's syndrome (CS), in which vasopressin responders had low autonomous cortisol secretion and were diagnosed as having subclinical CS. In the present study, we aimed to evaluate the pathophysiological significance of vasopressin responsiveness in patients with subclinical CS in terms of hormonal secretion and metabolic abnormalities. We compared 14 vasopressin responders and 13 non-responders with subclinical CS, admitted to Chiba University Hospital between 1999 and 2007. Among these patients, the vasopressin responders were found to have lower plasma cortisol levels than non-responders at midnight (P<0.05) and in the morning following overnight dexamethasone suppression at 1 mg (P<0.05). On the other hand, they showed a significantly higher frequency of hypertensive complications than non-responders. In addition, according to 75g-OGTT the vasopressin responders had significantly higher levels of plasma insulin at 60 min than the non-responders, and their cortisol response to vasopressin had a significantly positive association with HOMA-IR (r=0.671, P<0.05). A high expression level of V1a receptor mRNAs was observed in the resected adrenal glands of vasopressin responders with AIMAH and unilateral adenomas. Though vasopressin responders with subclinical CS had lower autonomous cortisol secretion, they had a high prevalence of hypertension, in which insulin resistance was closely correlated with cortisol response to vasopressin.

A possible association between aldosterone response to vasopressin and circadian change of aldosterone in the patients with aldosterone-producing adenoma.

Vasopressin was reported to stimulate secretion of both cortisol and aldosterone through eutopic V1a receptors in adrenal gland. Recently, adrenal hyper-responsiveness of plasma cortisol to vasopressin with eutopic overexpession of V1a receptors has been reported in Cushing's syndrome, such as a majority of cases of ACTH-independent macronodular adrenal hyperplasia and some cases of Cushing's adenomas. There were a few reports regarding the aldosterone response to vasopressin in aldosterone-producing adenoma. The aim of our study was to investigate the aldosterone response to vasopressin and its pathophysiological roles in the patients with aldosterone-producing adenoma. Vasopressin-loading test was performed in 10 patients with aldosterone-producing adenoma, and in 16 patients with non-functioning adrenal tumors. The roles of the aldosterone response to vasopressin were analyzed in terms of hormonal secretion and the expression of V1a receptor mRNA on the operated adrenal gland in aldosterone-producing adenoma. We found that (1) a varying aldosterone response to vasopressin was observed, (2) absolute response of plasma aldosterone in aldosterone-producing adenoma was significantly higher than that in non-functioning tumor, (3) aldosterone response rate to vasopressin was significantly and negatively correlated with the decline rate (%) in plasma aldosterone from morning to evening in aldosterone-producing adenoma, (4) V1a receptor mRNA was expressed at various values in aldosterone-producing adenoma, and (5) surgical removal of aldosterone-producing adenoma eliminated the aldosterone response to vasopressin observed in patients with aldosterone-producing adenoma. These findings indicated that vasopressin might be involved in the coordination of aldosterone secretion through eutopic expression of V1a receptor in aldosterone-producing adenoma.

Hyper-responsiveness of adrenal gland to vasopressin resulting in enhanced plasma cortisol in patients with adrenal nodule(s).

Hyper-responsiveness of plasma cortisol to vasopressin has been demonstrated in ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) and some adrenal adenomas with Cushing's syndrome (CS). However, the clinical significance of hyper-responsiveness of plasma cortisol to vasopressin has not been investigated systematically in adrenal nodule(s). The aim of this study was to clarify the prevalence of hyper-responsiveness of plasma cortisol to vasopressin (vasopressin responder) and their clinical characteristics in terms of hormonal secretion using vasopressin-loading test in the patients with adrenal nodule(s) except pheochromocytomas. A vasopressin-loading test was performed on 61 consecutive patients with adrenal nodules (CS: 33, aldosterone-producing adenoma: 10, non-functional tumor: 18). Vasopressin responders were observed in 36.1% of adrenal nodule(s), 42.4% of CS and 28.5% of non-CS. In responders with CS, eight patients had bilateral nodules that were diagnosed as AIMAH, and the remaining six patients had a unilateral nodule. These patients had lower plasma cortisol than non-responders at both morning (P<0.01) and midnight (P<0.05), as well as the morning following overnight dexamethasone suppression at 1mg (P<0.05) and 8mg (P<0.05). Hyper-responsiveness of the adrenal gland to vasopressin resulting in enhanced plasma cortisol was frequently observed among patients with adrenal nodule(s). The vasopressin responders among the patients with adrenal nodule(s) frequently had CS with low autonomous cortisol secretion.

Effect on coronary flow velocity reserve in patients with type 2 diabetes mellitus: comparison between angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist.

BACKGROUND: The effects of angiotensin antagonists on coronary circulation in type 2 diabetes are unclear. We aimed to assess whether 4 weeks of treatment with angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist improves coronary flow velocity reserve (CFVR) in patients with type 2 diabetes. METHODS: Twenty-four asymptomatic patients with type 2 diabetes were randomly assigned to temocapril (2 mg/d) or candesartan (8 mg/d). Coronary flow velocity reserve, calculated as the ratio of adenosine-induced hyperemic to basal coronary flow velocity, was measured with transthoracic Doppler echocardiography. Coronary flow velocity reserve measurement and venous blood sampling were performed before and after 4 weeks of treatment. We also obtained CFVR and venous blood data in the 8 healthy controls. RESULTS: Coronary flow velocity reserve was significantly lower in patients than controls (temocapril group 2.74 +/- 0.28, candesartan group 2.65 +/- 0.30, controls 3.53 +/- 0.23, P < .0001 for both, respectively). Blood pressure was reduced in both diabetic groups (n = 12 each) similarly 4 weeks after treatment. There were no significant differences between the 2 groups in venous blood data before or after treatment. However, CFVR increased significantly in the temocapril group (2.74 +/- 0.28 to 3.31 +/- 0.36, P < .0001), but not in the candesartan group (2.65 +/- 0.30 to 2.71 +/- 0.43, P = ns). CONCLUSIONS: Coronary flow velocity reserve in patients with type 2 diabetes improved after treatment with temocapril but not with candesartan, suggesting that angiotensin-converting enzyme inhibitor, but not angiotensin II type 1 receptor antagonist, might have beneficial effects on coronary microangiopathy associated with type 2 diabetes.

Acute pulmonary edema caused by hypoglycemia due to insulin overdose.

We report a very rare case of acute pulmonary edema caused by hypoglycemia from insulin overdose during an attempted suicide. A 16-year-old woman with type 1 diabetes was brought to our hospital because of hypoglycemic coma. She exhibited severe hypoxia; upon intubation, bloody froth poured out of the tube. Chest X-ray revealed bilateral infiltrates. Endocrinological data revealed high concentrations of catecholamines. This case indicates that pulmonary edema remains a potential complication of insulin overdose. The possible mechanisms of pulmonary edema associated with hypoglycemia are discussed.