Second-line treatments for dyslipidemia in patients at risk of cardiovascular disease.

Previous studies have shown that approximately 50% patients at risk of cardiovascular disease do not achieve lipid management goals. Thus, improvements dyslipidemia management are needed. We investigated the clinical choice and efficacy of second-line treatments for dyslipidemia in the Japanese clinical setting. Using a retrospective cohort design, we collected lipid profile data from patients who had been treated with hypolipidemic agents at a stable dosage for at least 12 weeks. These patients had then been administered a second-line treatment for dyslipidemia because they had not achieved the low-density lipoprotein cholesterol (LDL-C) management goals. We included data from 641 patients in our analysis. The top three choices for second-line treatment were adding ezetimibe, switching to strong statins (statin switching), and doubling the original statin dosage (statin doubling). Adding ezetimibe, statin switching, and statin doubling decreased LDL-C levels by 28.2 ± 14.5%, 23.2 ± 24.4%, and 23.5 ± 17.2%, respectively. Among these three strategies, adding ezetimibe decreased LDL-C levels to the maximum extent. In patients with dysglycemia, baseline-adjusted change in hemoglobin A1c (HbA1c) levels decreased slightly in the adding-ezetimibe, statin-switching, and statin-doubling groups, but the differences were not statistically significant among the groups (-0.10 ± 0.62%, -0.22 ± 0.54%, and -0.12 ± 0.52%, p = 0.19). In conclusion, the most common second-line treatment options for dyslipidemia were adding ezetimibe, statin switching, or statin doubling. Adding ezetimibe resulted in the highest reduction in LDL-C levels. These strategies did not increase HbA1c levels when administered with conventional diabetes treatment.

Prevalence and Risk Factors for Nocturia in an Outpatient Clinic.

OBJECTIVES: We evaluated the prevalence of and risk factors in patients with nocturia at a general medical clinic in Naha, Japan. METHODS: We enrolled patients who had been regularly followed-up at a general medical clinic in Naha. Patients were asked to complete a self-reported questionnaire regarding medical history and the frequency of nocturnal voids in the last month with anonymity. Univariate and multivariate logistic regression tests were used to evaluate the risk factors for clinically significant nocturia. RESULTS: In total, 357 patients (men, 192; women, 165; mean age, 60 years) were eligible for analysis. The prevalence rate of clinically significant nocturia in patients was 33.8%. Univariate, as well as multivariate, analysis revealed that age, gender, and hypertension were significant risk factors for nocturia. CONCLUSION: Clinically significant nocturia is common among patients seen at a general medical clinic. Age and gender are the most definitive risk factors for nocturia. Hypertension may also be related to nocturia. Thus, it is important to evaluate not only urological problems but other medical problems in patients with nocturia.

SNP (-617C>A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma in Japanese non-smoking women.

PURPOSE: The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer. EXPERIMENTAL DESIGN: We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients' overall survival. RESULTS: Patients harboring wild-type (WT) homozygous (c.-617C/C), SNP heterozygous (c.-617C/A), and SNP homozygous (c.-617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.-617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.-617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021). CONCLUSION: SNP homozygous (c.-617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

Effect of low-protein diet on kidney function in diabetic nephropathy: meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate the effect of low-protein diet on kidney function in patients with diabetic nephropathy. DESIGN: A systematic review and a meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number (ISRCTN) Register and University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) from inception to 10 December 2012. Internet searches were also carried out with general search engines (Google and Google Scholar). STUDY SELECTION: Randomised controlled trials that compared low-protein diet versus control diet and assessed the effects on kidney function, proteinuria, glycaemic control or nutritional status. PRIMARY AND SECONDARY OUTCOME MEASURES AND DATA SYNTHESIS: The primary outcome was a change in the glomerular filtration rate (GFR). The secondary outcomes were changes in proteinuria, post-treatment value of glycated haemoglobin A1C (HbA1c) and post-treatment value of serum albumin. The results were summarised as the mean difference for continuous outcomes and pooled by the random effects model. Subgroup analyses and sensitivity analyses were conducted regarding patient characteristics, intervention period, methodological quality and assessment of diet compliance. The assessment of diet compliance was performed based on the actual protein intake ratio (APIR) of the low-protein diet group to the control group. RESULTS: We identified 13 randomised controlled trials enrolling 779 patients. A low-protein diet was associated with a significant improvement in GFR (5.82 ml/min/1.73 m(2), 95% CI 2.30 to 9.33, I(2)=92%; n=624). This effect was consistent across the subgroups of type of diabetes, stages of nephropathy and intervention period. However, GFR was improved only when diet compliance was fair (8.92, 95% CI 2.75 to 15.09, I(2)=92% for APIR <0.9 and 0.03, 95% CI -1.49 to 1.56, I(2)=90% for APIR ≥0.9). Proteinuria and serum albumin were not differed between the groups. HbA1c was slightly but significantly decreased in the low-protein diet group (-0.26%, 95% CI -0.35 to -0.18, I(2)=0%; n=536). CONCLUSIONS: Low-protein diet was significantly associated with improvement of diabetic nephropathy. The adverse effects of low-protein diet were not apparent such as worsening of glycaemic control and malnutrition.

Defining criteria for the introduction of liraglutide using the glucagon stimulation test in patients with type 2 diabetes.

AIMS/INTRODUCTION: To define a set of criteria using indices of ß-cell function, including results from the glucagon stimulation test, for liraglutide introduction in patients with type 2 diabetes. MATERIALS AND METHODS: In the present retrospective cohort study, patients were included in our analysis if their ß-cell function had been evaluated with a glucagon stimulation test and a 24-h urinary C-peptide (U-CPR) excretion test before switching from insulin therapy to liraglutide monotherapy. The efficacy of liraglutide was determined by the extent to which glycemic control was achieved or if glycated hemoglobin levels were maintained at <7.0% after liraglutide monotherapy for 24 weeks. RESULTS: Liraglutide was effective in 36 of 77 patients. In the liraglutide-effective cases, the following parameters were higher: fasting C-peptide (CPR0) levels, C-peptide levels 6 min after glucagon stimulation (CPR6), the C-peptide index (CPI; CPR0 × 100/fasting plasma glucose) and stimulated C-peptide index (S-CPI; CPR6 × 100/plasma glucose 6 min after glucagon stimulation). U-CPR did not differ between liraglutide-effective and liraglutide-ineffective cases. Using receiver operating characteristic analysis adjusted for baseline characteristics, the independent cut-off value for effective liraglutide introduction was 0.72 for CPI and 1.92 for S-CPI. CONCLUSIONS: Evaluation of ß-cell function using the glucagon stimulation test is useful for determining the efficacy of liraglutide introduction in patients with type 2 diabetes.

Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia.

AIM: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed diet-induced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial. METHODS: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe- or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers. RESULTS: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p<0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment. CONCLUSION: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.

Pravastatin potentiates increases in serum adiponectin concentration in dyslipidemic patients receiving thiazolidinedione: the DOLPHIN study.

AIM: A reduced risk of type 2 diabetes has been reported following treatment with pravastatin. Adiponectin is an adipocyte-derived protein that has an antidiabetic property. The objective of this study was to evaluate the effect of pravastatin on serum adiponectin concentration and other influencing factors. METHODS: This study was a multicenter observational study: Dyslipidemia Open-labeled observational study by Lipid-lowering therapy with Pravastatin of the effect on High-molecular weight adiponectin in Nippon Yokohama (DOLPHIN). The protocol was registered in the UMIN Clinical Trial Registry as UMIN000000791. All patients received pravastatin 10 mg/day for 6 months and the change in concentration of total and high molecular weight adiponectin was assessed before and after follow-up. The difference in the change in total adiponectin concentration by patient characteristics was analyzed by an unpaired t-test. Influences of continuous variable factors on the change in total adiponectin concentration were estimated by simple linear regression analyses. Finally, in order to estimate the influences of factors that potentially affect the change in total adiponectin concentration induced by pravastatin, multiple linear regression analysis was conducted. RESULTS: After 6 months, total adiponectin concentration was increased significantly by 23.2% from 11.7±6.4 to 13.7±8.6 µg/mL (p=0.002). The use of thiazolidinedione as a concomitant medication was the only significant influencing factor (ß=0.580, p<0.001). CONCLUSION: Pravastatin increased the serum adiponectin concentration in Japanese dyslipidemic patients without previous coronary artery disease. Interestingly, this effect was seen synergistically in combination with thiazolidinedione.

Self-injection of insulin using appropriate supportive devices in handicapped subjects with diabetes.

BACKGROUND: To self-inject insulin, individuals with diabetes must be able to attach the needle to the injector, recognize the appropriate insulin dosage, detach the needle from the injector, and perform a series of operations necessary for the actual injection. These tasks require a grip strength that is strong enough to hold the necessary devices, eyesight, the use of both hands, and at least a minimum intellectual capacity. Subjects who are unable to grasp or handle the devices required for insulin injection often have difficulties with the self-injection of insulin. METHODS: We treated four diabetes patients who had trouble grasping objects and using both hands. One patient had lost five fingers in an accident, two patients had suffered from ischemic cerebral infarction resulting in complete one-sided hemiplegia with no movement in one arm, and one patient had limited muscular power in an arm as a result of spinal cord disease. The plasma glucose control was poor, and the initiation of insulin therapy was necessary in each of these patients. In three cases, we used a commercially available self-injection device (HumaHelper; Eli Lilly Japan K.K., Kobe, Japan) to enable self-injection; in the fourth case, we used a newly manufactured device similar to HumaHelper. RESULTS: All the patients were able to inject insulin by themselves using the appropriate supplementary devices. The blood glucose control of all the patients subsequently improved. CONCLUSION: Existing or newly manufactured supportive devices can enable handicapped subjects to self-inject insulin.

Correlations of fasting and postprandial blood glucose increments to the overall diurnal hyperglycemic status in type 2 diabetic patients: variations with levels of HbA1c.

Studies from overseas have indicated that postprandial glucose excursions are predominant in subjects with moderate hyperglycemia, while fasting hyperglycemia become the predominant abnormality with worsening of hyperglycemia; however, few studies have yet investigated the correlation between HbA1c and fasting and/or postprandial hyperglycemia in Japanese subjects. We investigated the correlation between fasting and postprandial hyperglycemia and the overall diabetic status, as assessed by measurement of HbA1c, in Japanese patients with type 2 diabetes. Blood glucose (BG) concentrations were determined in the fasting state (8:00 A.M.), during the postprandial phases (at 10:30 A.M., 2:30 P.M. and 8:30 P.M.) and during the postabsorptive periods (at 11:30 A.M. and 17:30 P.M.) in 66 patients with type 2 diabetes who were not being treated with prandial/premixed insulins or alpha-glucosidase inhibitors. The areas under the curve above the fasting BG concentrations (AUC1) and over 110 mg/dl (AUC2) were calculated for further evaluation of the correlations of the postprandial (AUC1) and fasting (AUC2 - AUC1) BG increments to the overall diurnal hyperglycemic status. Subjects were separated into two groups using the HbA1c cutoff value of 8%. The fasting BG was not correlated with the HbA1c in the group with a HbA1c values of less than 8% (r = 0.125, p = 0.473). On the other hand, fasting hyperglycemia was strongly correlated with the HbA1c level in the group with HbA1c values of over 8.0% (r = 0.406, p = 0.023). Furthermore, postprandial hyperglycemia was strongly correlated with the HbA1c in the group with HbA1c levels less than 8.0% (r = 0.524, p = 0.001). Thus, there existed a progressive shift in the contribution of fasting and postprandial hyperglycemia to the overall hyperglycemic status with progression from moderate to severe diabetes mellitus in Japanese type 2 diabetic patients.

Comparative study of effectiveness of multiple-daily injections of insulin versus twice-daily injections of biphasic insulin in patients with type 2 diabetes.

To evaluate the efficacy of a multiple-daily injection regimen and a twice-daily injection regimen using biphasic insulin, we performed an observational study of 56 insulin-naïve patients with type 2 diabetes mellitus who began receiving insulin therapy while they were hospitalized. The subjects were divided into two groups: a multiple-daily injection group (n = 33), and a twice-daily injection group (n = 23). At baseline, the demographic and clinical characteristics were comparable between the two groups. The HbA1c levels were 10.0 +/- 1.6% and 9.5 +/- 2.2% (p = 0.36), respectively. At 12 weeks, the HbA1c levels decreased equally in the two groups (7.2 +/- 1.8% in the multiple-daily injection group and 7.3 +/- 1.6%, p = 0.80 in the twice-daily injection group). The baseline HbA1c, the duration of diabetes, and the endogenous insulin secretory capacity did not affect the change in HbA1c in either group. These results suggest that twice-daily insulin regimen using biphasic insulin is as effective and beneficial as multiple-daily injection regimen for the treatment in type 2 diabetic patients with very poor glycemic control and that in order to achieve the targeted glycemic goal, insulin therapy should be initiated at an early stage.

A novel initial codon mutation of the thiazide-sensitive Na-Cl cotransporter gene in a Japanese patient with Gitelman's syndrome.

We here report a novel mutation of the thiazide-sensitive Na-Cl cotransporter (TSC) (SLC12A3) gene in a Japanese patient with Gitelman's syndrome (GS). GS is characterized by a renal disorder and is associated with hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria arising from the defective tubular reabsorption of magnesium and potassium. This disease is reportedly caused by mutations in the TSC gene. A 52-year-old man was referred to our hospital because of sleeplessness and tinnitus. He exhibited hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemic hyperaldosteronism. A renal clearance study revealed that the administration of furosemide decreased chloride reabsorption; however, the ingestion of thiazide failed to decrease chloride reabsorption. A diagnosis of GS was made based on the clinical features, laboratory data and renal function test results. Sequencing of the patient's genomic DNA revealed an A to T transition at the initial codon of exon 1 of the TSC gene (c1A>T). Knowledge of this novel mutation may be helpful for understanding the pathophysiology of GS and the function of TSC as well as for providing genetic counseling.

Administration of miglitol until 30 min after the start of a meal is effective in type 2 diabetic patients.

Miglitol, a pseudomonosaccharide alpha-glucosidase inhibitor (alphaGI), was more effective at reducing blood glucose levels at 30 and 60 min after a meal than voglibose. Speculating that miglitol administered even after the start of a meal may be effective, we evaluated the timing of administration of miglitol on the plasma glucose and serum insulin levels in 13 type 2 diabetic patients. Miglitol was administered in four different intake manners in each patient (control: no miglitol; intake 1: just before breakfast; intake 2: 15 min after the beginning of breakfast; intake 3: 30 min after the beginning of breakfast). The area under the curve (AUC) of plasma glucose was significantly decreased under all the intake conditions, as compared with the AUC in the control. The AUC of serum insulin tended to be lower in all the three groups than in the control, although the differences were not statistically significant. Thus, miglitol administered anytime within 30 min after the start of a meal is effective for glycemic control. These results suggest that if patients miss taking miglitol at the beginning of a meal, they can still take the drug until 30 min after starting their meal.