A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study.

AIM: To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS: In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. RESULTS: Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2 , 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C-peptide and high-density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). CONCLUSION: The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Risk factors for severe coronary artery disease - a case-control study of patients who have undergone coronary artery bypass grafting.

To investigate risk factors for coronary artery disease (CAD), we analyzed the clinical parameters of patients with a coronary artery bypass graft (CABG) in a case-control study. Eighty-eight patients (75 males and 13 females) who underwent CABG surgery between 2001 and 2002 were compared with age- and sex-matched healthy controls randomly chosen from the registry of Kobari Health Care Center. Wilcoxon's signed rank test and McNemar's test were used for pairwise comparisons. Multivariate logistic regression analysis was used to identify significant risk factors for CABG. Significant differences between the patients and controls were observed in HDL-C (p < 0.001), HbA(1c) (p < 0.001), Brinkman Index (BI; p < 0.001), body mass index (BMI; p = 0.002), and systolic blood pressure (SBP; p = 0.013). Subjects with an abnormal BMI, HbA(1c), or HDL-C or high BI value made up a significantly higher proportion of the patients who underwent CABG, compared to their age- and sex-matched controls. Multivariate logistic regression analysis identified high levels of HbA(1c), low levels of HDL-C, and high scores on the BI as significant risk factors for needing a CABG. These results demonstrate that, despite the modification of laboratory determinations by antecedent treatment, HDL-C, HbA(1c), BI, BMI, and SBP are significant indicators of risk for CAD.

Effect of the 2004 Mid Niigata Prefecture earthquake on glycemic control in type 1 diabetic patients.

At 5:56 p.m. on October 23, 2004, a major earthquake of magnitude 6.8 on the Richter scale struck the Chuetsu district of Niigata Prefecture, Japan, a rural area with mountain villages. Strong aftershocks of grade 5-6 on the Japanese Intensity Scale continued for 2 months. We investigated changes in the HbA1c levels of 65 type 1 diabetic patients with insulin therapy before and throughout the 12 months of aftershocks that followed the earthquake. All patients received insulin therapy via pens with replaceable cartridges or continuous subcutaneous insulin infusion (CSII). Most patients needed four daily insulin injections with rapid- and long-acting insulins. Nineteen percent of patients had the CSII therapy using rapid-acting insulin. The mean HbA1c level in all patients increased significantly (P<0.01) from 6.7+/-0.9% to 7.0+/-1.0% in the third month, peaked at the fifth month, and decreased at 12 months. Sixty percent of the patients stayed in their own houses after the initial shock, while 40% of patients moved into other houses. Seventeen percent of the patients had severely destroyed houses. The median PTSD score was low in all patients. Within 1 month after the earthquake, the pens with replaceable cartridges were discontinued and disposable pens with prefilled insulin cartridges were used. The incidence of nephropathy increased by 7% by the third month and returned to the pre-earthquake level by the sixth month. Over the 12-month observation period, no other micro- or macro-vascular diseases were newly diagnosed. One patient had transient severe acute hyperglycemia and one needed hemodialysis. However, none of the patients had ketoacidosis, and no other clinical manifestations of disease were noted. In conclusion, it is essential that neighboring organizations respond quickly with sufficient medical support for diabetic patients with insulin therapy following an earthquake. In particular, treatment with rapid- and long-acting insulin injections via disposable pens with prefilled insulin cartridges or CSII therapy is useful during a disaster. To take the medical support, patients should always have a note or copy of their medical records, including medical history and medications used.

Type 1 diabetes mellitus and isolated adrenocorticotropin deficiency manifested by parkinsonism: a case report and literature review.

A 67-year-old woman developed isolated adrenocorticotropin deficiency (IAD), which manifested as lethargy, a 20-kg body weight loss, hypoglycemia, and parkinsonism, and began corticosteroid replacement. Her symptoms resolved rapidly, and her weight returned to normal within six months. However, she then developed slowly progressive type 1 diabetes mellitus (T1D) with co-existing Hashimoto thyroiditis, and commenced insulin therapy. To our knowledge, this is the first reported case of parkinsonism associated with IAD. In addition, because diabetes mellitus, including T1D, could be latent in patients with untreated IAD, careful assessment of glucose metabolism is needed after commencing corticosteroid replacement until weight regain is achieved.

Lipoprotein lipase (LPL) mass in preheparin serum reflects insulin sensitivity.

Lipoprotein lipase (LPL) is one of the enzymes regulated by insulin and its plasma activity reflects insulin sensitivity. Although intravenous heparin injection is required to measure LPL activity, we can detect LPL mass in preheparin serum (Pr-LPL mass) by immunoassay. In this study, we examined whether Pr-LPL mass reflects insulin sensitivity. We measured Pr-LPL mass, insulin sensitivity (Si), and acute insulin release in response to a glucose bolus (AIRg) in subjects with normal glucose tolerance (NGT; n = 23), impaired glucose tolerance (IGT; n = 10), and Type II diabetes mellitus (DM; n = 48). Si and AIRg were determined by minimal model analysis. We also compared Pr-LPL mass with the homeostasis model assessment of insulin resistance (HOMA-R) and the urinary excretion of C-peptide (urine CPR). We found that Pr-LPL mass correlated significantly with Si ( r = 0.354, P < 0.01) in all the subjects. This correlation was still significant in the NGT group (P < 0.472, P < 0.05), DM group (r = 0.311, P < 0.01), and DM group with a fasting plasma glucose >150 mg/dl ( n = 20, r = 0.459. P < 0.05). Moreover, Pr-LPL mass correlated negatively with HOMA-R (r = -0.272. P < 0.05) and fasting IRI (r = -0.256, P < 0.05). By contrast, Pr-LPL mass was not correlated with either urine CPR or logAIRg that reflect the ability to secrete insulin. In conclusion, Pr-LPL mass reflects insulin sensitivity. We speculate that Pr-LPL mass might be used to assess insulin sensitivity not only in the general population but also in advanced diabetic patients.

Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy.

It is unknown whether the angiotensin receptor antagonist valsartan exerts a renoprotective effect on patients with type 2 diabetes and diabetic nephropathy independent of its hypotensive effects. Forty patients with type 2 diabetes participated in this study. All patients received valsartan 40 mg, a dose with no clinical effect on blood pressure levels. Blood pressure, urinary albumin excretion (UAE), and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted throughout the study. After 6 months of valsartan therapy, mean UAE decreased from 86.8 +/- 196 to 46.9 +/- 97 microg/min (n = 37). In addition, a significant decrease was observed in the UAE of the subgroup of patients displaying diabetic nephropathy (UAE > 20 microg/min, n = 14), from 219.4 +/- 275 to 102.7 +/- 141 microg/min, (P < 0.01). Changes in UAE for valsartan correlated significantly with UAE at baseline (r = -0.935, P < 0.0001). Serum creatinine levels and creatinine clearance remained stable before and after treatment with valsartan. No significant differences were observed between pre- and post-treatment body mass index, glycosylated hemoglobin, or systolic and diastolic blood pressure. In type 2 diabetic patients with diabetic nephropathy, 6 months of treatment with low dose valsartan, an angiotensin-II receptor antagonist, thus reduced UAE with no reduction in systemic blood pressure. The drug may be safely administered in this subset of type 2 diabetic patients. The long-term benefits in terms of risk reduction must still be evaluated in further trials.

Genotype Gly/Gly of the Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with elevated fasting serum insulin concentrations, but not with acute insulin response to glucose, in type 2 diabetic patients.

The beta(2)-adrenergic receptor (B2AR) is expressed in pancreatic beta-cells and modulates insulin secretion. The purpose of the present study was to evaluate the influence of the Arg16Gly variant allele of B2AR on insulin secretion in patients with type 2 diabetes. We used minimal model analysis of the frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) and polymerase chain reaction (PCR)-restriction fragment length polymorphism to examine differences of insulin secretion and insulin resistance among three genotypes. There were no significant differences in baseline clinical characteristics, HbA1c, uric acid, CRP or lipid profiles among the three groups. The Gly/Gly group had significantly higher levels of fasting insulin (38.2+/-4.7 pmol/l versus 23.6+/-3.5 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (1.90+/-0.19 versus 1.32+/-0.24), compared with the Arg/Arg group, but there were no significant differences in acute insulin response to glucose (AIRg) bolus, insulin sensitivity (Si), or glucose effectiveness (Sg) among the three genotypes. Several reports have speculated that the Gly16 allele of B2AR exhibits agonist-promoted downregulation, but our findings, elevated fasting insulin concentrations, and previous clinical studies of blood pressure and lypolysis are controversial. The direct mechanism by which the Gly16 allele of B2AR may influence insulin secretion of pancreatic beta-cells is unknown. Further studies of the expression of the allelic receptor in islet cells may help to resolve the role of B2AR in insulin secretion. However, increased sensitivity to catecholamine-induced lipolysis of the Gly allele promotes higher free fatty acids concentrations in the portal system, which could enhance the higher levels of fasting insulin.

Effect of the 2004 Mid-Niigata Prefecture earthquake on home blood pressure measurement in the morning in type 2 diabetic patients.

A major earthquake struck the Niigata Prefecture, Japan, on October 23, 2004. This study investigated the effect of the earthquake on morning home blood pressure (MHBP) measurements, as well as clinic blood pressure (CBP) and associated complications, in 222 type 2 diabetic patients who measured MHBP and CBP before the earthquake. Physical and laboratory examinations were assessed at every three months. Each patient completed a questionnaire on MHBP measurement, Japanese intensity grade (JIS), patient's lifestyle and psychological impact using posttraumatic stress disorder (PTSD) symptom score. Median JIS showed all patients lived in areas affected by strong aftershocks. Most patients stayed in their own houses, while one-third of patients sought refuge in other houses. No new clinical manifestations of disease were noted. Median PTSD score was low. Patients in public refuge houses had daytime blood pressure, but MHBP was not measured. In the first month, the number of patients who continued MHBP measurements decreased to 27% of pre-shock level. Many patients were unable to measure MHBP for several reasons, including losing MHBP equipment, having equipment destroyed, or suffering from anxiety due to the extensive devastation. Mean systolic MHBP and median urinary albumin excretion rate (UAER) increased significantly within three months and returned to pre-earthquake level at six months. On multiple regression analysis, increased systolic and diastolic MHBPs were significantly associated with UAER elevation. In type 2 diabetic patients following an earthquake, it is important to develop a device of MHBP measurement for maintaining control of MHBP to prevent vascular complications.

Effect of the 2004 mid niigata prefecture earthquake on patients with endocrine disorders.

A major earthquake (Richter scale magnitude 6.8) struck the Chuetsu district of Niigata Prefecture, Japan, a rural area with mountain villages, on October 23, 2004. Strong aftershocks (Grade 5-6 on the Japanese intensity scale, JIS) continued for 2 months. We analyzed the earthquake's impact on 229 patients with various endocrine disorders [6 central diabetes insipidus (CDI), 16 adrenal insufficiency (AI) including 5 panhypopituitarism, 10 ACTH isolated deficiency and 1 Addison's disease, 145 Graves' disease and 62 Hashimoto's disease]. The status of patients with CDI or AI was not adversely affected by the earthquake. Twenty-eight (19%) patients with Graves' disease developed more severe hyperthyroidism; the incidence of developing more severe hyperthyroidism increased with greater degrees of hyperthyroidism. Three (5%) patients with Hashimoto's disease developed increased TSH concentrations. Most patients stayed in their own houses following the first shock. The median PTSD total score for all patients was low. However, the PTSD total score in patients with CDI or Hashimoto's disease was significantly higher than in other patients, while the subscore of mental status in patients with AI was significantly much lower than in other patients. In patients with Hashimoto's disease, patients whose hypothyroidism worsened had higher total and environmental effects score than patients whose hypothyroidism remained stable. Comparing patients whose hyperthyroidism became more severe to those in whom it remained stable, as well as on multiple logistic regression analysis, serum TRAb was found to be a risk factor for developing more severe hyperthyroidism. In conclusion, our findings indicate that Graves' disease patients need to maintain their euthyroid state with a low serum TRAb titer to prevent the development of further thyroid dysfunction after an earthquake, and that all patients should continue to take their medication, since it is likely that their lives will be interrupted by environmental effects owing to earthquake-shock, especially patients with CDI or Hashimoto's disease. Due to the risk of medical facility closure during a disaster, all patients should always have a note or copy of their medical records, including medical history and medications used, to avoid relying on patients remembering their drug names and doses. Furthermore, appropriate information should be provided by all means possible, including the mass media, to affected individuals, particularly those with AI, to decrease the occurrence of adverse consequences.

A case of preclinical Cushing's syndrome associated with diurnal rhythms of ACTH and cortisol in blood: correlation with histological findings.

We describe a case of adrenocortical adenoma with preclinical Cushing's syndrome demonstrating diurnal rhythms of ACTH and cortisol in blood. A 50-year-old man was admitted to the hospital for the evaluation of incidental right adrenal mass with hyperglycemia and hypertension. On admission, there were no signs of clinical manifestation of hypercortisolism. The basal levels of cortisol (9.3 microg/dl) and ACTH (9.4 pg/ml) at 0800 h were not elevated and these diurnal rhythms were maintained. One or 8 mg of dexamethasone given orally overnight suppressed the plasma ACTH but not serum cortisol. Ultrasonogram, CT and scintiscan of (131)I adosterol all demonstrated an enlarged adrenal mass in the right adrenal gland. The right adrenal gland was subsequently resected by laparoscopic surgery. Histopathological findings of resected adrenal tumor were consistent with adrenocortical adenoma. Adjacent non-neoplastic adrenal tissue demonstrated adrenocortical atrophy but DHEA-sulfotransferase immunoreactivity in the zona reticularis was detected.

The bedtime administration of doxazosin controls morning hypertension and albuminuria in patients with type-2 diabetes: evaluation using home-based blood pressure measurements.

The control of high blood pressure (BP) after awakening in the morning (morning hypertension) as determined by home BP (HBP), as well as BP control throughout the day, may prevent diabetic vascular complications. We examined the effect of an alpha-adrenergic blocker (doxazosin) on BP measurements taken by HBP after awakening and during clinic visits (CBP) in 50 patients with type-2 diabetes and morning hypertension. We evaluated the urinary albumin excretion rate as an indicator of nephropathy. Doxazosin was taken orally once at bedtime for 1 to 3 months. The mean (+/- SD) dose was 2.9 +/- 2.1 mg/day (1 to 8 mg/day). The BP was measured monthly at the clinic during the day and at home after awakening in the morning. In this short-term trial (2.8 +/- 0.4 months), the systolic HBP decreased significantly from 164 +/- 17 mmHg before treatment to 146 +/- 19 mmHg after treatment, and the diastolic HBP decreased significantly from 85 +/- 14 mmHg before treatment to 80 +/- 9 mmHg after treatment. The systolic, but not the diastolic CBP, decreased significantly after treatment. There was no significant difference in the systolic or diastolic values between the HBP and the CBP after treatment. The percentage change in the systolic HBP after treatment was three times greater than for the systolic CBP. The median (interquartile) urinary albumin excretion rate decreased significantly (P < 0.001) from 62 (25-203) mg/g creatinine before treatment to 19 (9-76) mg/g creatinine after treatment. On multiple regression analysis, the decrease in the systolic HBP with treatment positively correlated with the reduction in urinary excretion of albumin. The control of morning hypertension reduced the albuminuria found in both untreated and treated hypertensive patients with type-2 diabetes. Bedtime administration of doxazosin appears to be safe and effective in reducing morning hypertension as measured by HBP. This finding also demonstrates that HBP taken in the morning has a stronger predictive power for the albuminuria level than does CBP.

A rare case of Graves' disease during regular hemodialysis.

We report a case of Graves' disease in a patient on regular hemodialysis. The patient also suffered from Wolff-Parkinson-White (WPW) syndrome and paroxysmal atrial fibrillation, which may both have been manifestations of the Graves' disease because of the increased oxygen demand. To our knowledge, this is the first case to illustrate the usefulness of the antithyroid agent propylthiouracil for Graves' disease complicated by endstage renal disease (ESRD) and WPW syndrome.