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An Alpha-Glucosidase Inhibitor Acarbose Reduces Body Weight Irrespective of Glycemic Control Status

Body weight (BW) control is often difficult in patients with type 2 diabetes mellitus (T2DM). Among several classes of oral anti-diabetic drugs alpha-glucosidase inhibitor (AGI) was shown as BW neutral with a tendency of reduction or BW beneficial in several meta-analyses of randomized control trials [1-3]. In order to examine the effect of AGI in real life setting we pooled 10 Post-Marketing Surveillances and Non-Interventional Studies (PMS/NIS). Ten PMS/NISs from all over the world from the launch of acarbose to date were pooled in one database and exploratory analyzed by baseline BW or glycemic parameters. In total 62 905 patients were pooled from 21 countries and regions. Mean follow up ( SD) was 12.2 4.8 weeks (Min:0.1 Max:108.9). Mean HbA1c decreased from 8.4% at baseline by 1.09 1.31% at the last visit in total population (p<0.0001). BW data both at baseline and at the last visit were available for 54 760 patients. Mean reduction ( SD) of BW in total population was 1.16 2.57 kg (p<0.0001) at 3 months ( 4 weeks) visit (n=43 510) and 1.12 2.58 kg (p<0.0001) at the last visit (n=54 760). BW reductions were baseline BW-dependent and in the highest BW category (100 kg) 3.12 5.02 kg reduction (p<0.0001 n=3 000) was observed at the last visit. The BW reduction was independent of baseline glycemic parameters (postprandial plasma glucose fasting plasma glucose and HbA1c by quartiles). Consistent with RCT meta-analyses post-hoc analysis of real life data showed acarbose treatment reduces BW. The effect was independent of the glycemic control status but dependent on baseline BW. 1. Phung OJ et al. JAMA. 2010;303:1410. 2. McIntosh B et al. Open Med. 2011;5:e35 3. Gross JL et al. Ann Intern Med. 2011;154:672

Effect of Metformin and Acarbose in Islet a Cell Function in Overweight and/or Obese Patients With Newly Diagnosed Type 2 Diabetes
Aims: To explore the effect of metformin and acarbose on islet cell function in overweight and/or obese patients with newly diagnosed type 2 diabetes. Materials and methods: Drug nave patients with newly diagnosed type 2 diabetes whose HbA1c between 6.3% and 9% BMI greater than 24Kg/m2 were enrolled. Patients were randomly assigned to metformin (1.5g/d) and acarbose (100mg tid) group for a predictive follow-up period of 24 weeks. Plasma glucose insulin and glucagons at 0 0.5h and 2 h after the meal and HbA1c were measured at baseline and 24 weeks. Results: 108 patients with the mean age of 51years HbA1c 7.7% BMI 26.8Kg/m2 were enrolled. 54 patients were assigned in metformin group the other in acarbose group. Baseline characteristics of both groups were even. After 24-week treatment glucose control improved significantly in both metformin group and acarbose group (HbA1c:-1.24% and -1.28%; fasting plasma glucose: 2.09 mmol/L and 1.53 mmol/L; 0.5h postprandial glucose: 2.27mmol/L and 2.87 mmol/L; 2h postprandial glucose: 3.19mmol/L and 3.25 mmol/L respectively); The early-phase insulin secretion index I30/G30 was improved only in acarbose group; Body weight decrease (metformin:-2.3Kg vs acarbose: -2.6Kg); Decrease of fasting and 0.5h postprandial glucagon in acarbose group was markedly greater than that in metformin group (fasting glucagon: 11.4pg/mL vs. -0.5pg/mL; 0.5h postprandial glucagon: 5.7 pg/mL vs. -10.7pg/mL respectively. P<0.05). Conclusion: In newly diagnosed type 2 diabetic patients. metformin and acarbose have similar effect on improving glucose control and decreasing body weight as monotherapy. It seemed that acarbose may improve islet cell function better than metformin representing by the greater decrease of fasting and 0.5h postprandial glucagon. Although the improvement of I30/G30 can decrease postprandial glucagon further studies are needed to explore the related pathophisiology mechanism.

Variants in AOX1 CYP11B1 GSTM5 SLCO1B1 SULT1E1 are Associated with Efficacy of Glibenclamide in Chinese Type 2 Diabetic Patients
Aim: The aim of this study was to investigate whether genetic variants can influence the efficacy of glibenclamide in type 2 diabetic patients. Methods: All of our 800 participants were enrolled from Xiaoke pills Clinical Trial. They were randomized into groups with glibenclamide or Xiaoke pills (Chinese traditional herb medicine plus glibenclamide) for 48 weeks. We tested 51 SNPs in 42 gene regions. Genotyping was performed for the selected SNPs on all the subjects by TimeOf-Flight Mass Spectrometry genotyping assays designed and manufactured by Sequenom (San Diego USA). Logistic regressions were used to evaluate the relationship between variants of genes and treatment failure or hypoglycemia during 48 weeks. Results: After following up for 48 weeks logistic regression showed significant association between variants of AOX1 (rs11684227 (OR=1.498 (95%CI 1.074-2.088) P=0.017) and rs3731722 (OR=0.306 (95%CI 0.121-0.774) P=0.012)) CYP11B1 (rs7003319 (OR=1.524 (95%CI 1.009-2.301) P=0.045)) GSTM5 (rs11807 (OR=1.751 (95%CI 1.127-2.721) P=0.013)) SLCO1B1(rs4149057(OR=0.698(95%CI 0.4910.993) P=0.046)) SULT1E1(rs4149528(OR=2.493(95%CI 1.178-5.277) P=0.017)) and treatment failure. And logistic regression also showed significant association between variants of ALDH2 (rs886205 (OR=2.020(95%CI 1.157-3.529) P=0.013)) CHST2(rs3755739 (OR=0.539 (95%CI 0.339-0.857) P=0.009) and rs4683739 (OR=0.604 (95%CI 0.373-0.977) P=0.040)) RGS4(rs7515900(OR=1.587(95%CI 1.026-2.454) P=0.036)) and hypoglycemia. Conclusion: Our study demonstrated that these genes can influence the efficacy of glibenclamide and hypoglycemia in Chinese.

Cost-Effectiveness of Statin Use for Preventing Cardiovascular Disease: Does the Increase in Diabetes Risk Matter?
Statin use reduces the risk of cardiovascular disease (CVD) but recent meta-analyses suggest that it increases diabetes (DM) risk. To assist clinical decisions we evaluated the costeffectiveness (CE) of using a statin for the primary prevention of CVD accounting for the elevated DM risk. We used a simulation model to assess the 30-year health outcomes and medical cost of a low-cost statin therapy (40mg daily) among persons at different levels of risk for CVD and DM. We categorized the risk of DM into 3 levels and the risk of CVD into 4 levels based on literature (Table). Statin effects were simulated based on data from published meta-analyses. Outcomes included the incidences of DM and CVD quality adjusted life years (QALY) and cost per QALY. Medical costs were assessed from a health-care system perspective. Statin use reduced CVD events but increased DM incidence over 30 years (Table). The CE of statin use largely depended on CVD risk but was also affected by DM risk. In persons with a 5year CVD risk >15% statin use was highly cost-effective regardless of DM risk. However statin use was not cost-effective if 5-year CVD risk was 2.5% particularly in persons with impaired glucose tolerance (IGT) plus impaired fasting glucose (IFG). In persons with a 5-year CVD risk of 7.5% statin use may not be cost-effective if they had IGT plus IFG. In conclusion DM risk reduces the CE of statin use and should be considered in recommending use of a statin for preventing CVD.

The Effect of High Versus Low Dose Atorvastatin on Central Arterial Stiffness in Male Patients with Type 2 Diabetes
Increased central arterial stiffness is associated with hypertrophy of the left ventricle and increased cardiovascular mortality. Patients with type 2 diabetes mellitus (T2DM) typically have increased arterial stiffness in comparison to age-matched controls. Statin therapy improves atherogenic lipid profiles and reduces inflammation within the vasculature but its effects on stiffness of the central arteries in T2DM are largely unknown. The primary aim of our study was to determine whether statin therapy reduces central arterial stiffness in a dose-dependent manner in male patients with T2DM. Central arterial stiffness was directly measured via carotid-femoral pulse wave velocity (PWV). The secondary aim was to determine the effects of statin intervention on circulating concentrations of osteoprotegerin (OPG) an indirect biomarker of atherosclerotic inflammation and arterial stiffness. Fifty-one male T2DM patients with microalbuminuria ceased statin therapy for 6 weeks followed by randomisation to either 10 or 80mg of atorvastatin. PWV and OPG were measured at randomisation 3 and 12 months. Groups were comparable at baseline. PWV decreased from 10.51.1 to 9.71.1m/sec (p<0.01 from baseline) at 3 months and 9.21m/sec (p<0.001 from baseline) at 12 month indicating a decrease in central arterial stiffness. OPG also decreased significantly at 3 and 12 months. The reductions in PWV and OPG did not differ between the groups. Baseline PWV and OPG values correlated strongly (r=0 48 p<0.01) as did their response to atorvastatin over 12 months (r=0.32 delta-OPG and delta-PWV p<0.05). Atorvastatin therapy reduced central arterial stiffness in this diabetes cohort with demonstrable effects at 3 months that persisted at 12 months with no dose-dependent effect observed. The correlation observed between reductions in PWV and reductions in concentrations of OPG suggests atorvastatin may reduce PWV via direct anti-inflammatory effects on the vasculature.

Effect of Pitavastatin on Glucose Metabolism in Patients with Type 2 Diabetes: Randomized Controlled Study of Pitavastatin versus Pravastatin
Several recent meta-analyses suggest that treatment with HMGCoA reductase inhibitors (statins) with the possible exception of pravastatin can not only increase the incidence of new-onset diabetes but also impair glucose metabolism. Pitavastatin is a new statin that has LDL-Clowering effects in the range of 35-45%; its effect on glucose metabolism remains unknown. In the present study we compared the effects of pitavastatin and pravastatin on glucose metabolism in Japanese patients with either IGT or mild type 2 diabetes mellitus (T2DM). The 38 patients (61.610.8 years HbA1c 6.40.5% LDL-C 149.330.4 mg/dL) were randomiozed to 10 mg pravastatin (M n = 12) 2 mg pitavastatin (LP n = 14) and 4 mg pitavastatin (HP n = 14). All patients were tested with a 75 g OGTT before as well as after 6 months of treatment. Six months after treatment LDL-C decreased by 21% in M 38% in LP and 45% in HP (P < 0.001). HbA1c increased by 0.090.21% in M 0.130.33% in LP and 0.060.26% in HP. However these changes in HbA1c from baseline were not significant in any of the groups. HOMA-IR increased by 0.521.28 in M but decreased by 0.301.72 in LP and increased by 0.051.51 in HP whereas HOMA- increased by 51.124.3 in M but decreased by 2.818.9 in LP and by 1.342.4 in HP with no significant inter-group differences. We next compared the change in incremental area under the OGTT curves (iAUC) for glucose from baseline to 6 months of treatment. iAUC was +31.663.7% for M +9.523.8% for LP and -5.932.3% for HP with no significant differences. In conclusion treatment of IGT or mild T2DM with 2 or 4 mg pitavastatin resulted in greater reductions in LDL-C levels than 10 mg pravastatin. Pitavastatin however had no significant effect on glucose tolerance insulin sensitivity or insulin secretion regardless of dose compared to pravastatin. The present study demonstrates that pitavastatin may be a useful and potent LDL-C lowering agent in patients with T2DM.

The Effects of Brain Insulin Action on Hepatic Glucose Metabolism Glucagon Secretion and Lipolysis in the Absence of Somatostatin Infusion
Previously we showed that physiologic increases in insulin secretion (portal vein delivery) did not inhibit hepatic glucose production. In those studies we used the pancreatic clamp technique which employs somatostatin (SRIF) infusion raising the possibility that SRIF impaired the impact of brain insulin action on the liver. To explore this question dogs underwent liver catheterization (femoral artery; portal and hepatic veins) and cannulation of the 3rd ventricle (ICV) two weeks prior to study. After a basal sampling period (-30 to 0 min) artificial cerebrospinal fluid (aCSF; n=5) or the PI3K inhibitor LY294004 (to block brain insulin action; LY; n=6) was infused ICV (0300 min) in conscious dogs. At 60 min insulin was infused intraportally (1.8 mU/kg/min) elevating peripheral and hepatic insulin levels 6-fold in both groups while euglycemia was maintained using glucose infusion. Hepatic sinusoidal plasma glucagon levels fell similarly in the presence and absence of brain insulin signaling ( -7918 vs -5811% p=0.32 aCSF vs LY respectively). The decreases in blood glycerol ( -509 vs -526%; p=0.90) and plasma NEFA ( -864 vs 883%; p=0.64) indicate that brain insulin action did not affect lipolysis or reesterification. Likewise brain insulin did not affect the time course or magnitude of insulins effects on glucose turnover or GIR. The suppression of endogenous glucose Ra ( -659 vs -574%; p=0.50) increase in whole body Rd ( 3.80.7 vs 4.70.5 fold; p=0.33) and net hepatic glucose uptake (0.360.23 vs 0.490.11 mg/kg/min; p=0.60) were similar in aCSF vs LY. Thus a 6-fold rise in brain insulin action had no impact on insulins effects on hepatic glucose metabolism glucagon secretion or lipolysis. Therefore the presence of SRIF did not explain our failure to detect an effect of brain insulin action on the liver in our earlier study.

Pitavastatin Improves the Estimated Glomerular Filtration Rate (eGFR) in Patients with Type 2 Diabetes and Hypercholesterolemia Treated with Sitagliptin
Previous studies have shown that statins improve renal function in patients with chronic kidney disease. In this study we examined the renal effect of pitavastatin in patients with type 2 diabetes and hypercholesterolemia who had already been treated with or without the DPP-4 inhibitor sitagliptin. The subjects in this study were 81 patients with type 2 diabetes and hypercholesterolemia. Twenty-nine patients were treated with sitagliptin (SITA) and 52 patients were not (no-SITA). The patients were treated with 2mg pitavastatin for 6 months and we evaluated the effects on eGFR lipid profile and glycemic control. Age (SITA 6212 vs. no-SITA 6310 years p=0.71) male gender (55 vs. 56 % p=0.96) body mass index (26.25.0 vs. 26.13.9 kg/m2 p=0.90) fasting plasma glucose (FPG; 17857 vs. 15157 mg/dl p=0.05) HbA1c (7.51.4 vs. 7.91.4% p=0.21) total cholesterol (TC; 25439 vs. 24334 mg/dl p=0.20) triglyceride (TG; 18993 vs. 178101 mg/dl p=0.62) HDL-C (5413 vs. 5616 mg/dl p=0.68) LDL-C (16436 vs. 15527 mg/dl p=0.22) apolipoprotein B-100 (ApoB; 13426 vs. 12620 mg/dl p=0.15) serum creatinine (Cr; 0.830.27 vs. 0.790.25 mg/dl p=0.57) and eGFR (71.323.2 vs. 73.320.1 ml/min/1.73m2 p=0.69) were not significantly different between the two groups. A significant increase of the eGFR was observed in the SITA group (p<0.001) but not in the no-SITA group (p=0.15) and the changes of Cr (-0.130.16 vs. -0.030.15 mg/dl p=0.0079) and eGFR (+12.916.3 vs. +2.814.2 mg/dl p=0.0049) were significantly different in the two groups after 6 months of pitavastatin treatment. Changes of lipid profile and glycemic control were not significantly different between the two groups. These findings suggest that combination therapy of pitavastatin and sitagliptin may exhibit a renal protective effect in patients with type 2 diabetes and hypercholesterolemia.

Statins Strongly Suppress Postprandial Increase of Serum Triglyceride Especially in Patients With Greater TG Increase_Possible Mechanism of Beneficial Effects of Statins
Statins decrease small dense low density lipoprotein (sdLDL) which production is stimulated in response to an increase of triglyceride (TG). We think that it is important to suppress dietary increase of TG (TG). We evaluated fasting and 3-hour postprandial lipid profiles in 86 patients with dyslipidemia (61 males 25 females) at baseline and 4 weeks after statin administration. Patients were randomly assigned to atorvastatin 10mg/day (n=25) rosuvastatin 5mg/day (n=35) or pisuvastatin 2mg/day (n=26). We evaluated dietary TG increase=postprandial TG - fasting TG at baseline (TGbase) and 4 weeks after statin administration (TGstatin) and TG ratio=(postprandial TG / fasting TG with statin) / (postprandial TG / fasting TG at base). Change of TG by statin administration (TGstatin - TGbase) was inversely correlated with TGbase (Figure) and was significantly smaller in patients group of TGbase 60mg/dl than in the group of TGbase < 60mg/dl (-87.584.7 vs. 20.358.1 p<0.0001). TG ratio was also smaller in the former group than the later (0.720.27 vs. 1.250.55 p<0.0001). Statins strongly suppressed postprandial TG increase especially in patients with greater postprandial TG increase. This suppressive effect of statins resulting in lowering sdLDL level all day long might be a possible mechanism of beneficial effects of statins.

Statin Efficacy in Type 1 and Type 2 Diabetes Mellitus


Statins lower total and LDL cholesterol (TC and LDLC) levels among patients with type 1 and 2 diabetes (T1DM and T2DM). Studies suggest patients with T1DM have high gut cholesterol absorption; hence cholesterol absorption inhibitors such as ezetimibe may be as effective. We compare the effects of statins and ezetimibe among T1DM and T2DM in this study. Subjects with T1DM and T2DM with hemoglobin A1C (HbA1C) 8.5% BMI 31 kg/m2 and no cardiovascular disease (CVD) were recruited. Subjects were assigned to alternating therapy with 40 mg of simvastatin (statin) or 10 mg of ezetimibe therapy for 6 weeks (with 4 week washout period between drugs). Lipids were obtained at baseline (after 4 weeks off anti-lipid drugs or 1st treatment drug) and after each drug. Twenty (55% male) T1DM and 27 (44% male) T2DM completed the study. T2DM were older (65 10 vs 49 13 years p < 0.01) had higher BMI (28 2 vs 26 3 kg/m2 p = 0.01) and lower HbA1C levels (6.4 0.8 vs 7.2 0.0 p < 0.01) than T1DM. There were no significant differences between mean lipids at 1st and 2nd baseline (after washout) within each group. The results (Table) remained significant after adjusting for age gender and baseline lipids. The study suggests that statins are not as effective in T1DM as in T2DM and ezetimibe should be considered for treatment of hyperlipidemia among patients with T1DM. Studies are needed to confirm these findings and assess CVD protection conferred by ezetimibe among subjects with T1DM.

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