Impact of glucagon like peptide-1 receptor agonist and sodium glucose cotransporter 2 inhibitors on type 2 diabetes patients with renal impairment.

INTRODUCTION: Diabetes mellitus is a progressive disease with cardiovascular complications. We evaluated the impact of a glucagon like peptide-1 (GLP-1) receptor agonist and sodium glucose cotransporter 2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on renal and cardiac function in type 2 diabetes patients with renal impairment. MATERIALS AND METHODS: A total of 156 patients referred with suboptimal glycemic control were assigned to Group G (GLP-1): n = 72 or Group S (SGLT-2 inhibitor)-dapagliflozin (n = 52) or empagliflozin (n = 32). Renal function was assessed every 3 months for 36 months. Cardiovascular parameters were evaluated every 12 months for 36 months. RESULTS: Compared with baseline, HbA1c and systolic blood pressure significantly decreased in both groups (p < 0.05). The estimated glomerular filtration rate decreased, but without significance. Albuminuria decreased significantly in both groups and then subsequently increased after 30 months in Group S. Diastolic cardiac function, assessed by E/e' or left atrial volume index, decreased only in Group G at 36 months. CONCLUSIONS: The GLP-1 receptor agonist and SGLT-2 inhibitors were effective for glycemic and blood pressure control and for maintaining renal function. The GLP-1 receptor agonist improved diastolic function at 36 months.

Quality of Life and Emotional Distress in Peritoneal Dialysis and Hemodialysis Patients.

Cardiovascular disease-associated morbidity and mortality are reportedly higher in hemodialysis (HD) patients compared with peritoneal dialysis (PD) patients. However, few studies have estimated changes in state of depression and cognitive impairment in patients undergoing HD and PD. The present study evaluated the impact of HD or PD on patients' quality of life (QoL), cognitive impairment, and depression status over 2 years. This 24-month observational, prospective study included 45 HD and 30 PD patients. Patients were assessed before and every 12 months after starting dialysis for 24 months. Measurements included QoL (36-Item Short-Form Health Survey [SF-36]), cognitive impairment (Mini-Mental State Examination [MMSE]), depressive state (Center for Epidemiologic Studies Depression Scale [CES-D]), grip strength, and 24-h urine volume (UV). Physical and social component scores of the SF-36 significantly improved in PD patients at 24 months compared with those observed at baseline (42.8 vs. 39.4; P < 0.05 and 46.4 vs. 37.3; P < 0.05, respectively); however, scores remained unchanged in HD patients. MMSE scores were significantly decreased at 12 and 24 months in HD patients (29.0 vs. 26.0, 25.0; P < 0.05), but remained unchanged in PD patients. Moreover, CES-D scores significantly worsened at 24 months in HD patients (12.8 vs. 16.5), but remained unchanged in PD. Preservation of UV and grip strength was associated with SF-36, CES-D, and MMSE scores. Our findings indicate that PD is associated with higher QoL and recovery from cognitive failure compared with HD.

Liraglutide relieves cardiac dilated function than DPP-4 inhibitors.

INTRODUCTION: Diabetes mellitus is a progressive disease with cardiovascular complications. This study evaluated the effects of liraglutide, a glucagon-like peptide-1 analogue and the dipeptidyl peptidase 4 inhibitors sitagliptin and linagliptin on cardiac function in type 2 diabetes patients with renal impairment. MATERIALS AND METHODS: A total of 139 patients who were referred because of suboptimal glycaemic control were randomly assigned to liraglutide 0.9 mg/d (n = 45), sitagliptin 50 mg/d, (n = 49) or linagliptin 5 mg/d (n = 45) at enrolment and were evaluated. Blood glucose, glycosylated haemoglobin and serum creatinine were assayed every 3 months for 48 months. Echocardiography was performed every 12 months for 48 months. RESULTS: Compared with baseline, fasting glucose, postprandial glucose, and systolic and diastolic pressure, but not estimated glomerular filtration rate, significantly decreased in all three groups. Albuminuria decreased from 24 to 48 months with liraglutide, but only from 24 to 30 months with sitagliptin and linagliptin. Diastolic function, assessed by E/e' or left atrial dimension improved only with liraglutide. CONCLUSIONS: Liraglutide was effective for glucose and blood pressure control, reduced albuminuria and improved diastolic function. Diastolic function was not improved by sitagliptin and linagliptin.

Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport.

AIMS/INTRODUCTION: Recent data showed that dipeptidyl peptidase 4 (DPP-4) inhibitors exert a lipid-lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action. MATERIALS AND METHODS: Male apolipoprotein E (ApoE)-deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14 C-labeled cholesterol (14 C-Chol). In additional experiments, effects of exendin-4 in mice and of anagliptin in DPP-4-deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice. RESULTS: The serum total and non-high-density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE-deficient mice. The cholesterol-lowering effect was predominantly observed in the chylomicron fraction. The plasma 14 C-Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14 C-Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP-4 activity, and exendin-4 had no effect on the 14 C-Chol transport in ApoE-deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport-related microsomal triglyceride transfer protein, acyl-coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin. CONCLUSIONS: These findings suggest that anagliptin might exert a cholesterol-lowering action through DPP-4-dependent and glucagon-like peptide 1-independent suppression of intestinal cholesterol transport.

Long Term Effects of Liraglutide in Japanese Patients with type 2 Diabetes Among the Subgroups with Different Renal Functions: Results of 2-Year Prospective Study.

Aims Very few studies have ever examined the effects of long-term (>1 year) administration of liraglutide in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Therefore, we conducted a 2-year study to prospectively examine the effects of liraglutide in those patients. Methods A total of 148 patients with T2DM were enrolled and treated with liraglutide (0.6 or 0.9 mg/day). 97 patients completed the 2-year study without protocol deviations. These patients were divided into 3 groups according to the baseline estimated glomerular filtration ratio (eGFR) (in mL/min/1.73 m2): group A, ≥60 (n=39); group B, ≥30 to <60 (n=38); and group C, <30 (n=20). The changes in blood and urine variables, and echocardiographic left ventricular mass index (LVMI) from baseline to 2 years were analyzed in each group. Primary outcomes were changes of the renal parameters of eGFR and albuminuria after the treatment of liraglutide. Results Blood glucose and systolic blood pressure decreased significantly after 24 months of liraglutide treatment in all groups compared with baseline (p<0.05). The eGFR increased significantly in group B (p<0.05), and remained unchanged in groups A and C. Albuminuria and LVMI decreased significantly in all 3 groups compared with baseline (p<0.05). Conclusions These findings suggest that 2 years of liraglutide treatment in Japanese patients with T2DM and impaired renal function was effective in terms of suppressing the deterioration of renal function, and reducing albuminuria. Long-term liraglutide treatment also improved glycemic control and blood pressure, and reduced left ventricular hypertrophy in this study.

The Vasopressin 2 Receptor Antagonist Tolvaptan Improves Nutrition and Inflammatory States in Peritoneal Dialysis Patients with Diabetes Mellitus.

Previously, we reported that, in peritoneal dialysis (PD) patients, tolvaptan preserves residual renal function and ameliorates left ventricular hypertrophy. Here, we evaluated the effect of tolvaptan in terms of nutrition and inflammatory states. Of 24 incident PD patients with diabetes, 12 were assigned to a control group that did not receive tolvaptan, and 12, to a group that, 2 weeks after initiation of PD, received tolvaptan 15 mg daily for 12 months. At baseline and at 6 and 12 months after initiation of PD, we evaluated serum C-reactive protein (CRP), albumin, urine volume, peritoneal ultrafiltration (UF), phosphate elimination, protein uptake, left ventricular mass index (LVMI), and the diameter of the inferior vena cava (IVC). Compared with the control group, the tolvaptan group experienced preserved urine volume and UF, lower LVMI and IVC diameter, and higher protein uptake. The average protein uptake was significantly correlated with urine volume, albumin, and CRP; and serum CRP was significantly correlated with albumin. Our study results suggest that tolvaptan improves not only fluid management, but also nutrition state in PD patients.

Liraglutide Improves Glycemic and Blood Pressure Control and Ameliorates Progression of Left Ventricular Hypertrophy in Patients with Type 2 Diabetes Mellitus on Peritoneal Dialysis.

Diabetes mellitus (DM) is a multifactorial disease associated with cardiovascular complications. Patients undergoing peritoneal dialysis also experience an increased incidence of cardiovascular disease. To prevent progression of cardiovascular complications in DM patients, glycemic control is important. In this study, we examined the efficacy and safety of the glucagon-like peptide analog liraglutide for treating type 2 diabetes patients undergoing peritoneal dialysis. Sixteen type 2 diabetes patients on peritoneal dialysis were enrolled. Before liraglutide initiation, 11 patients were on insulin therapy, three were on oral antidiabetic agents, and two were on diet therapy. Of the 16 patients, 12 had switched to liraglutide because of severe hypoglycemia and four because of hyperglycemia. Echocardiography was performed at baseline and 12 months after liraglutide initiation. Hemoglobin A1c, glycosylated albumin, and fasting/postprandial glucose levels gradually decreased after liraglutide initiation. After 6 and 12 months of treatment, postprandial glucose levels showed a significant difference from baseline. Moreover, the mean daily glucose level and glycemic fluctuations decreased. Systolic blood pressure upon waking also decreased. In addition, after 12 months, left ventricular mass index (LVMI) decreased and left ventricular ejection fraction increased. Changes in LVMI positively correlated with morning systolic blood pressure and fasting glucose levels. One patient restarted insulin because of anorexia but severe hypoglycemia was not observed. These findings suggest that liraglutide therapy in type 2 diabetes patients undergoing peritoneal dialysis is safe and effective for decreasing glucose levels, glycemic fluctuations, and blood pressure, apart from improving left ventricular function.

A Pilot Study Examining the Effects of Tolvaptan on Residual Renal Function in Peritoneal Dialysis for Diabetics.

BACKGROUND: For patients with end-stage renal disease (ESRD), peritoneal dialysis (PD) serves as a possible renal replacement therapy. However, most PD patients, particularly those with ESRD and diabetes mellitus, reportedly discontinue PD early, resulting in shorter survival periods and poorer prognosis because of overhydration. Recently, the vasopressin-2 receptor antagonist tolvaptan was approved for volume control in patients with heart failure. The present study aimed to identify the effects of tolvaptan in diabetic PD patients. METHODS: In this pilot study, the tolvaptan group (n = 12) were treated with 15 mg/day of tolvaptan 2 weeks after PD initiation and were prospectively analyzed for 1 year, and patients in the control group (n = 12) did not receive tolvaptan and were retrospectively analyzed for 1 year. In addition to the biochemical tests, echocardiograms, serum atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels, peritoneal Kt/V, and creatinine clearance (CCr) were examined at baseline and at 6 and 12 months after PD initiation. RESULTS: In the control group, the urine volume, renal Kt/V, and renal CCr levels consistently decreased; however, these parameters were stably maintained during the study period in the tolvaptan group. Atrial natriuretic peptide, CRP levels and the left ventricular mass index of the tolvaptan-treated group were significantly lower than those in the control group, whereas total protein and albumin levels were significantly higher at 6 and 12 months in the tolvaptan group. There were no obvious adverse effects. CONCLUSIONS: These data suggest that tolvaptan may preserve residual renal function and improve volume control in PD patients with diabetes mellitus.

When should icodextrin be started to improve atherosclerosis in peritoneal dialysis patients?

Icodextrin-based peritoneal dialysis (PD) has many advantages over glucose-based PD. The present study aimed to investigate when icodextrin should be started for better management of cardiovascular status (as defined by echocardiography findings) and residual renal function (RRF). We retrospectively analyzed 40 patients treated with continuous ambulatory PD or automated PD. The patients were divided into these groups: Group A: started icodextrin within 2 weeks after PD onset. Group B: started icodextrin 1 year after PD onset. Group C: started icodextrin 2 years after PD onset. Group D: never used icodextrin during the study period. At the start of PD, we observed no significant difference in left ventricular mass index (LVMI) or urine volume (UV) between the groups. At 4 years, LVMI and UV were both significantly improved in group A compared with group D. The amelioration in LVMI was negatively associated with phosphate elimination. Our study showed that icodextrin preserved RRF and ameliorated left ventricular hypertrophy. Moreover, the timing of icodextrin introduction in PD patients influenced the clinical effects, including progression of cardiac hypertrophy and RRF.

Icodextrin eliminates phosphate and ameliorates cardiac hypertrophy and valvular calcification in patients with end-stage renal disease and diabetes mellitus undergoing peritoneal dialysis.

Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico)-based peritoneal dialysis (PD) has many advantages over glucose (Glu)-based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Ico-based PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD andDM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination might potentially be a means of controlling cardiovascular disease in PD patients with DM.

Association between DNA methylation in the miR-328 5'-flanking region and inter-individual differences in miR-328 and BCRP expression in human placenta.

MicroRNA (miRNA) are non-coding small RNA that regulate gene expression. MiR-328 is reported to influence breast cancer resistance protein (BCRP) expression in cancer cells. As a large inter-individual difference in BCRP levels is observed in various human tissues, the contribution of miR-328 to these differences is of interest. We hypothesized that DNA methylation in the miR-328 promoter region is responsible for the difference in miR-328 levels, leading to inter-individual variability in BCRP levels in human placenta. The association between placental miR-328 and BCRP levels was analyzed, and then DNA methylation in the miR-328 5'-flanking region and regulatory mechanisms causing inter-individual differences in miR-328 and BCRP levels were examined. MiR-328 expression was significantly correlated with BCRP mRNA (Rs = -0.560, P < 0.01) and protein (Rs = -0.730, P < 0.01) levels. It was also up-regulated by the demethylating agent 5-aza-2'-deoxycytidine in BCRP-expressing cells. Luciferase assays with differentially methylated reporter constructs indicated that methylation in the miR-328 5'-flanking region including a predicted CpG island remarkably decreased transcriptional activity compared to that in unmethylated constructs. We selected CCAAT/enhancer binding protein α (C/EBPα), located within the predicted CpG island, by in silico analysis. To elucidate the role of C/EBPα in miR-328 expression, a chromatin immunoprecipitation assay, promoter deletion analysis, and electrophoretic mobility shift assay (EMSA) were performed. C/EBPα-binding site-truncated constructs showed significantly decreased promoter activity, and EMSA indicated that the C/EBPα-binding sites were located in the CpG island. Finally, the methylation patterns of several CpG dinucleotides proximal to two C/EBPα-binding sites in the miR-328 5'-flanking region were correlated negatively with miR-328 levels, and positively with BCRP levels in human placental samples. These results suggest that methylation patterns in the miR-328 5'-flanking region are involved in the inter-individual difference in BCRP levels in human placenta.

Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs.

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.

Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans.

1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [(14)C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces. 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was >73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively. 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for >1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.

The alpha-glucosidase inhibitor miglitol affects bile acid metabolism and ameliorates obesity and insulin resistance in diabetic mice.

OBJECTIVE: Alpha-glucosidase inhibitors (α-GIs) show various anti-diabetic or anti-obesity effects in addition to the suppression of postprandial hyperglycemia. Based on recent observations that bile acids (BAs) are involved in glucose and energy homeostasis, we examined the ability of miglitol, an α-GI, to influence BA metabolism and ameliorate insulin resistance and obesity. MATERIALS/METHODS: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet and treated with miglitol for 4 or 12 weeks. BAs were quantified in feces, blood from the portal vein or the vena cava and in the liver. The gene expression of type 2 iodothyronine deiodinase (D2) in brown adipose tissues, gluconeogenetic enzymes in the liver and adipokines in epididymal fat was measured, and portal blood glucagon-like peptide-1 (GLP-1) levels, body weight changes, glucose tolerance along with insulin sensitivity were evaluated. RESULTS: Miglitol significantly increased BAs in both feces and portal blood while the hepatic BA level was reduced. The drug clearly enhanced active GLP-1 secretion into the portal blood and there was a good positive correlation between the active GLP-1 levels and portal blood BA concentrations. D2 expression in brown adipose tended to increase in association with the elevated BA concentrations. Miglitol ameliorated body weight gain, glucose intolerance, insulin resistance and inflammatory adipokine upregulation that were induced by a high-fat diet. CONCLUSIONS: Collectively, miglitol substantially affects BA regulation in mice and this novel finding may explain in part the known favourable effects of the drug on diabetes and obesity.

Favorable changes in lipid metabolism and cardiovascular parameters after icodextrin use in peritoneal dialysis patients.

Better control of cardiovascular function in patients on peritoneal dialysis (PD) is critical because PD patients have a tendency to overhydration, which has been proved to be associated with cardiovascular and patient outcome. In the general population, lipid metabolism is also considered to be an important indicator of future cardiovascular events. Icodextrin has been used to improve ultrafiltration volume without increasing dextrose load. We therefore expected that parameters of lipid metabolism and cardiovascular function could both be improved, or at least maintained, after icodextrin use in PD patients. We therefore analyzed those parameters in 14 prevalent PD patients who required a switch from dextrose to icodextrin solution for the long dwell at 1 year before the switch, at the time of the switch, and at 1 and 2 years after the switch. In the study patients, cardiovascular remodeling evaluated by ultrasonographic left ventricular mass index was diminished, but the intima media area of the cervical artery was elevated after icodextrin use. Intima media thickness did not change over time. Biochemical indices such as brain natriuretic peptide, atrial natriuretic peptide, lipoprotein A, total cholesterol, and triglycerides were all lower after icodextrin use. These results indicate that icodextrin has the potential to improve lipid metabolism, volemic status, and cardiac hypertrophy in prevalent PD patients. However, atherosclerotic vascular change is refractory to improvement.

Longitudinal changes in parameters of cardiovascular function in patients treated for 8 years with hemodialysis or peritoneal dialysis.

Cardiovascular complications are obviously important in the management of dialysis patients, and ultrasonography can be used to evaluate cardiac indices that can predict these complications. However, long-term longitudinal changes in ultrasonographic cardiovascular indices in dialysis patients are not well known. Also, the implications of lipid metabolism for cardiovascular change in dialysis patients is controversial. We therefore analyzed ultrasonographic cardiac parameters and laboratory data for lipid metabolism in patients who had been on peritoneal dialysis (PD) or hemodialysis (HD) for 8 years and also in patients who had been on PD for 4 years followed by another 4 years on HD. We found that lipid metabolism was worse but that cardiovascular indices were more stable over time in PD patients than in HD patients. Mean blood pressure was also better maintained in PD patients. These results indicate that cardiovascular function can be maintained in PD patients over the long term, given that blood pressure is controlled even though dyslipidemia worsens.

Impact of dialysis modality on ultrasonographic cardiovascular parameters in elderly patients.

Cardiovascular complications are the major cause of mortality in end-stage renal disease (ESRD) patients. Some reports show that ultrasonographic parameters for cardiovascular remodeling predict mortality in ESRD patients as well as in the general population. In the present study, we compared long-term longitudinal changes in cardiac parameters between elderly patients on peritoneal dialysis (PD) and those on hemodialysis (HD). We analyzed 19 HD and 7 PD patients who were more than 75 years old at the start of dialysis and who had been treated with the same dialysis modality for more than 4 years. We compared ultrasonographic cardiovascular parameters such as left ventricular mass index (LVMI), left ventricular wall thickness (LVWT), intima media thickness and intima media area (IMA) over the 4 years of PD and HD treatment. As compared with values at the start of dialysis, values for LVMI, LVWT, and IMA were significantly elevated in HD patients after 4 years of treatment. In PD patients, we observed no changes in those parameters over time. Our findings indicate that cardiovascular remodeling is liable to deteriorate in elderly patients on HD, but that cardiac parameters in PD patients remain rather stable.