Reduced Fasting Plasma Glucose Research Articles

Effect of ursodeoxycholic acid on glycemic markers: A systematic review and meta-analysis of clinical trials.

Ursodeoxycholic acid (UDCA) is widely used to treat liver diseases; however, its potential effect on metabolic parameters has been poorly investigated. Additionally, owing to divergent data, the objective of this meta-analysis was to evaluate the effect of UDCA on glycemic parameters in clinical trials. Clinical trials investigating the impact of UDCA treatment on glycemic markers were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 16, 2018). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. Meta-analysis of seven studies comprising eight treatment arms revealed a significant reduction of fasting glucose levels following UDCA therapy (WMD: -3.30 mg/dL, 95% CI: -6.36, -0.24, p = 0.034; I2 = 28.95%). Also, meta-analysis of two treatment arms indicated a significant reduction of glycated hemoglobin (HbA1c) concentrations (WMD: -0.41% mg/dL, 95% CI: -0.81, -0.01, p = 0.042; I2 = 0%). Additionally, meta-analysis of four treatment arms also revealed a significant reduction in plasma insulin levels (WMD: -1.50 mg/dL, 95% CI: -2.81, -0.19, p = 0.025; I2 = 67.90%) but not significant effect HOMA-IR (WMD: -0.20 mg/dL, 95% CI: -0.42, 0.01, p = 0.057; I2 = 85.34%). Results of this meta-analysis showed that UDCA significantly reduces fasting plasma glucose, HbA1c, and insulin concentrations suggesting a positive impact on glucose homeostasis.

Effect of Telephone-Delivered Interventions on Glycemic Control in Type 2 Diabetes Treated with Glargine Insulin.

Background:Telephone-delivered intervention can provide support in diabetes self-management to improve glycemic control. "eStar® program" is a telephone support platform for type 2 diabetes on glargine insulin treatment. Its objective is to help patients to perform insulin titration to reach target fasting blood glucose levels. Patients are contacted by trained nurses on a regular basis to adjust the basal insulin dose and reinforce the diabetes education. This study aimed to evaluate if eStar program was effective in helping patients reach their optimal insulin glargine dose within 6 months.Materials and Methods:An observational prospective study was conducted with type 2 diabetes patients who were initiating insulin glargine or requiring dose titration and were eligible to be included in the eStar program. Those participants who followed the program comprised the intervention group, while those who discontinued, the control group. The primary outcome was to evaluate if this program was effective in helping patients reach their optimal insulin glargine dose within 6 months. Secondary outcomes included changes in glycosylated hemoglobin (HbA1C), fasting plasma glucose (FPG), insulin dose, and body mass index after 6 months.Results:A total of 228 subjects [intervention group, 143 (62.7%); control group, 85 (37.3%)] were included in the study. A significantly greater percentage of patients in the intervention group reached their optimal glargine dose than in the control group (83.8% vs. 31.5%; p < 0.001). After 6 months, significant reductions in mean HbA1C levels were observed in both groups: 1.49% (p < 0.001) for the intervention group and 1.08% (p < 0.001) for the control group. Furthermore, a mean reduction in FPG between group was achieved (34.96 mg/dL; p < 0.001).Conclusions:The eStar program is an effective way to help patients reach their optimal insulin glargine dose, besides improving their glycemic control.

Effectiveness of Second-Line Agents in the Treatment of Uncomplicated Type 2 Diabetes Mellitus: An Observational Tertiary-Care Based Study

Background: The rational prescribing of second-line drugs in type 2 diabetes mellitus (DM) require clear guidelines. There is no sufficient empirical evidence to support the use of one second-line agent over the other and when to initiate second-line drug is still under discrepancy. Objectives: To analyze the utilization pattern and effectiveness of second-line agents in uncomplicated type 2 DM. Methodology: 240 uncomplicated type 2 DM patients who were ≥ 18 years receiving either metformin/sulfonylurea or metformin+sulfonylurea was divided into four add-on treatment group 1, 2, 3, 4; that were added pioglitazone, dipeptidyl peptidase-4(DPP-4) inhibitor, voglibose, and insulin [pre-mixed insulin (30%regular/70%NPH)] respectively and received the second-line agents for a duration of 6 months or longer. Effectiveness was based on the reduction in glycosylated hemoglobin (HbA1C), fasting plasma glucose (FPG) and postprandial blood glucose (PPBG) values over 3 and 6 months was done using repeated measures analysis of variance (ANOVA). Results: The mean difference for reduction in HbA1C (%) values at 3rd and 6th month with respect to baseline values was 1.32±0.72 and 2.11±0.97; 1.19±0.27 and 1.81±0.53; 1.16±0.41 and 1.66±0.63; 0.97±0.16 and 1.46±0.47 for pioglitazone, DPP-4 inhibitor, voglibose, insulin respectively. The mean difference in FPG and PPBG levels at the 6th month from baseline was 75±31.06 and 115.3±40.32; 77.91±37.95 and 117±41.27; 85.87±21.75 and 118.75±55.86; 91.38±31.8 and 132.03±56.24 for pioglitazone, DPP-4 inhibitors, voglibose and insulin respectively. Reduction in HbA1C, FPG, and PPBG was statistically significant within each group at each time interval with p-value Key words: Anti-diabetic drugs, FPG, HbA1C, PPBG, Second-line agents.

Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders

BackgroundPrevious studies have shown that individuals with mood disorders have a higher prevalence of both hypercortisolemia and insulin resistance. Insulin resistance is posited to contribute to the cognitive deficits observed in individuals who have depression. However, the mechanistic relationship between cortisol and insulin within the central nervous system remains to be further elucidated. This study aimed to evaluate the effects of the antiglucocorticoid agent, mifepristone, on metabolic function and cognitive performance in individuals receiving treatment for depressive disorders who were euthymic at baseline. MethodsParticipants were administered a 600 mg/day dose of mifepristone for 28 days. Oral glucose tolerance tests (OGTTs) and cognitive assessments measuring verbal memory and executive functioning were administered at baseline and after 28 days of treatment. ResultsImprovements in attention and verbal learning were associated with reduction of fasting plasma glucose (FPG) in response to mifepristone treatment. LimitationsLimitations include the open-label design of this study and a small sample size. ConclusionsThe findings from this study suggest that improvement in fasting plasma glucose levels, upon administration of mifepristone, is associated with the improvement in early input of verbal information. Further studies are warranted in order to better evaluate the use of mifepristone or other antiglucocorticoid agents in treatment of mood disorders characterized by metabolic dysfunction.

HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study

The objective of this study was to evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were -0.37% and -0.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (-0.87 mmol/L; P = 0.008), weight (-2.92 kg; P < 0.001), and total daily insulin dose (-8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).

Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P&amp;lt;0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further. In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

The effects of probiotics and synbiotic supplementation on glucose and insulin metabolism in adults with prediabetes: a double-blind randomized clinical trial.

Probiotics and/or prebiotics could be a promising approach to improve metabolic disorders by favorably modifying the gut microbial composition. To assess the effects of probiotics and synbiotic on glycemic indices in prediabetic individuals who are at risk of type 2 diabetes and its complications. In a double-blind, randomized, placebo-controlled parallel-group clinical trial, 120 prediabetic adults participated and were randomly allocated to receive either probiotics or synbiotic or placebo supplements for 24weeks. Anthropometric measurements, food record, physical activity and glycemic biomarkers including glycated hemoglobin (HbA1C), fasting plasma glucose (FPG), fasting insulin levels (FIL), homoeostasis model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and β-cell function (HOMA-B) were assessed at baseline and repeated at 12 and 24weeks and compared within and between three groups using repeated measure ANOVA. Compared with the placebo, synbiotic supplementation resulted in a higher significant reduction in FPG (- 6.5 ± 1.6 vs. - 0.82 ± 1.7mg/dL, P = 0.01), FIL (- 2.6 ± 0.9 vs. - 0.8 ± 0.8 µIU/mL, P = 0.028), and HOMA-IR (- 0.86 ± 0.3 vs. - 0.16 ± 0.25, P = 0.007), and a significant elevation in the QUICKI (+ 0.01 ± 0.003 vs. + 0.003 ± 0.002, P = 0.006). In addition, significant decreases in HbA1C was seen following the supplementation of probiotics and synbiotic compared with the placebo (- 0.12 ± 0.06 and - 0.14 ± 0.05 vs. +0.07 ± 0.06%, P = 0.005 and 0.008, respectively). HOMA-B was not found to be different between or within the three groups. Glycemic improvement by probiotics and particularly synbiotic supplements in prediabetic individuals has been supported by current study. However, further studies are required for optimal recommendations in this important area of patient treatment. Iranian Registry of Clinical Trials: IRCT201511032321N2, Date registered February 27, 2016.

Fourteen-Day Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Background: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, has been shown to augment nitric oxide (NO) signaling and reduce fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In healthy adults, repeated oral doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a, double-blind, placebo (PBO)-controlled study assessed the effects of oral praliciguat in 26 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP-lowering therapy. Most (69%) were also on statins. Two praliciguat regimens were tested: (1) 40 mg QD for days 1-14 (N=10), and (2) 20 mg BID for days 1-7 then 40 mg QD for days 8-14 (N=10). Assessments included serum chemistry, fasting plasma glucose, BP and heart rate, platelet function, reactive hyperemia index (RHI), plasma biomarkers, and adverse events (AEs). Results: Results were similar for both praliciguat regimens and are here combined. After 14 days of treatment, praliciguat-treated patients had notable differences in least squares mean change from baseline (95% CI) relative to PBO in 24-hour mean arterial pressure [-4.7 mmHg (-10, 0.8)], heart rate [2.9 bpm (-0.7, 6.5)], fasting glucose [-13 mg/dL (-32, 7)], HOMA-IR [-26 (-58, 7)], total serum cholesterol [-26 mg/dL (-44, -7)], and LDL cholesterol [-20 mg/dL (-37, -3)]. Praliciguat had no effect on platelet function or RHI. Among the exploratory biomarkers tested, levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were lower in praliciguat vs. PBO recipients. Both praliciguat dose regimens were generally well tolerated. Except for one serious AE of upper gastrointestinal hemorrhage, AEs in praliciguat-treated patients were mild. Conclusion: In this initial trial, praliciguat had beneficial effects on BP and metabolic parameters in T2DM patients with hypertension on standard therapies. Further clinical investigation of praliciguat in T2DM patients is warranted. Disclosure J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. P. Miller: None. J. Chickering: None. L. Morrow: Stock/Shareholder; Self; ProSciento. Employee; Spouse/Partner; Eli Lilly and Company. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.

Rapid Dose Escalation Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Background: Impaired nitric oxide (NO) signaling through soluble guanylate cyclase (sGC) has been associated with microvascular complications of diabetes. Praliciguat (IW-1973), an sGC stimulator that enhances NO signaling, reduced fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In a Phase 1 clinical study in healthy adults, doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a open-label in-clinic study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of oral praliciguat in 11 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP therapy. Patients received sequential 3-day dosing cycles escalating through placebo (PBO), 10, 20, 30, 40 and 50 mg praliciguat QD. Assessments included adverse events (AEs), blood chemistry, ambulatory BP and heart rate, platelet function, and reactive hyperemia index (RHI). Results: The escalating dose regimen was generally well tolerated; there were no serious or severe AEs. Escalation in 2 patients was stopped due to asymptomatic BP lowering. Overall PK showed a median Tmax of 1-3 h, low to moderate variability, and ∼2-fold accumulation supporting QD dosing. Average 12-h daytime mean arterial BP decreased by 2 to 9 mmHg relative to time-matched PBO baseline across praliciguat dose levels, while heart rate increased 4 to 7 bpm. Notable changes from PBO baseline [mean (95% CI)] at the end of treatment were seen for fasting serum glucose [-26.5 mg/dL (-43.4, -9.5], HbA1c [-0.4% (-0.8, -0.04)], cholesterol [-43 mg/dL (-67, -20)], and body weight [-3.5 kg (-4.9, -2.0)]. Praliciguat had no effect on RHI or platelet function. Conclusion: T2DM patients with hypertension on standard therapy showed improvements in hemodynamics and metabolic parameters in this small in-clinic study. These results support further evaluation of praliciguat in T2DM patients including those with complications. Disclosure J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. D.P. Zimmer: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. M. Mihova: None. J. Chickering: None. D. Ruff: None. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.

Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) plus Basal Insulin vs. GLP-1RA in Type 2 Diabetes Mellitus—A Systematic Review and Meta-analysis

Combination therapy with Glucagon-like peptide-1 receptor agonist (GLP-1RA) and basal insulin represents a new therapeutic option for diabetes mellitus. We hypothesized that GLP-1RA plus basal insulin is more efficacious, safer and tolerable than GLP-1RA for patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials (RCTs) comparing GLP-1RA plus basal insulin vs. GLP-1RA were searched using PubMed, Cochrane library and www.ClinicalTrials.gov database. Inclusion criteria were: (1) RCTs; (2) comparison between GLP-1RA plus basal insulin vs. GLP-1RA; (3) duration of treatment between 24-30 weeks; and (4) T2DM. Four RCTs with 2,732 participants were included in this meta-analysis. Compared with GLP-1RA alone, GLP-1RA plus basal insulin was associated with a significant reduction in HbA1c (Mean difference [MD]: -0.79%; 95% CI [confidence interval]: -0.96,-0.61; P&amp;lt;0.001) and fasting plasma glucose (FPG) (MD: -2.03mmol/l; 95% CI: -2.28, -1.77; p&amp;lt;0.001). More participants achieved HbA1c ≤7% in the GLP-1RA plus basal insulin group (Odds ratio [OR]: 4.66; 95% CI: 3.00, 7.23; p&amp;lt;0.001). GLP-1RA plus basal insulin was associated with more symptomatic hypoglycaemia (OR: 7.04; 95% CI: 3.81, 13.00; p&amp;lt;0.001) and weight gain (MD: 2.46kg; 95% CI: 2.08, 2.84; P&amp;lt;0.001). There was no significant difference in treatment emergent adverse effects (OR: 0.80; 95% CI: 0.57, 1.11; p=0.18) and discontinuation due to adverse events (OR: 0.52; 95% CI: 0.26, 1.03; p=0.06) between both groups. GLP-1RA plus basal insulin is more efficacious for HbA1c and FPG reduction when compared with GLP-1RA in patients with T2DM. Symptomatic hypoglycaemia and weight gain were more common with GLP-1RA plus basal insulin, but discontinuation due to adverse events was similar between both groups. Disclosure M.M. Satti: None. T. O'Brien: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca. A. Liew: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S.

Disparity of the Efficacy of DPP-4 Inhibitors in Combination with Metformin vs. High Dose Metformin as Initial Treatment between Asian and Caucasian T2DM Patients

Background: To evaluate the efficacy and safety of DPP-4 inhibitors (DPP-4i) in combination with metformin as initial treatment vs. high or low dose of metformin in type 2 diabetes patients. Methods: Studies were identified by search of MEDLINE and EMBASE until Nov. 2017. Inclusion criteria were: T2DM; initial treatment; comparing metformin monotherapy vs.s DPP-4i in combination with metformin therapy; the primary endpoint was the change in HbA1c. Results: A total of 9 studies were included. In Asian drug-naïve T2DM patients, compared with high dose metformin monotherapy(2g/day), high dose metformin initial combine with DPP-4i therapy led to significant decrease in HbA1c (WMD -0.22%), while in Caucasian, combination therapy resulted in -0.53% change. The difference in the reduction of HbA1c between Asian and Caucasian of combination therapy vs. monotherapy was 0.31% with significance in favor of Caucasian population. In terms of fasting plasma glucose (FPG), in Asian patients, combination therapy vs. monotherapy led to -0.40mmol/L change, while in Caucasian, combination therapy vs. monotherapy led to -0.95mmol/L change. The difference in FPG reduction between Asian and Caucasian was 0.55mmol/L with significance in favor of Caucasian patients. The difference in postprandial glucose (PPG) reduction between Asian and Caucasian was 0.94mmol/L in favor of Caucasian. The difference in body weight changes between Asian and Caucasian was 0.50kg with significance body weight gain of Asian patients. Adverse effects were not increased when compared with combination therapy vs. monotherapy. Conclusion: DPP-4i with metformin as initial treatment was superior to metformin given alone in glycemic control of drug-naïve T2DM. The glucose-lowering efficacy of DPP-4i combination therapy was greater in Caucasian patients than in Asian. Disclosure X. Huang: None. X. Gao: None. X. Cai: None. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Eli Lilly and Company, Bristol-Myers Squibb Company, Novartis AG, Novo Nordisk A/S, Merck &amp; Co., Inc., Bayer AG, Merck Sharp &amp; Dohme Corp., Takeda Development Center Asia, Pte. Ltd., Sanofi, Roche Pharma, Boehringer Ingelheim GmbH. Research Support; Self; AstraZeneca, Roche Pharma, Sanofi, Merck Sharp &amp; Dohme Corp., Novartis AG, Eli Lilly and Company, Bristol-Myers Squibb Company.

Effect of a Controlled-Release Mitochondrial Protonophore (CRMP) on Healthspan and Lifespan in Mice

Caloric restriction without malnutrition (CR) is the most robust and reproducible way to extend lifespan and delay the onset of age-related diseases, such as hepatic steatosis, insulin resistance and type 2 diabetes (T2D). Unfortunately, the strict dietary regime necessary to achieve the beneficial effects of CR limits the use of this treatment to retard aging and disease in humans and new therapies are required. In this regard, our lab has recently developed a new class of therapeutic agents that are designed to safely promote liver-targeted mitochondrial uncoupling with a wide-therapeutic index. Our second-generation compound in this class is controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency. While we have previously demonstrated that this agent safely reverses hypertriglyceridemia, fatty liver, and hepatic inflammation/fibrosis in young-adult diet-induced rodent models of obesity, its effects on healthspan and lifespan remain to be determined. Here, we evaluated the impact of CRMP on hepatic steatosis and insulin action in aged 74-week-old male C57BL/6J mice fed a high-fat diet (HFD; 45% fat) for 12 weeks. Specifically, we demonstrate that CRMP treatment significantly reduced liver triglycerides, diacylglycerols, and transaminase levels independently of changes in body weight, whole-body energy expenditure or food intake. Additionally, long-term CRMP treatment reduced fasting plasma glucose concentrations (P &amp;lt;0.05) and improved whole-body insulin responsiveness, as reflected by a marked increase in the glucose infusion rate required to maintain euglycemia during a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide important proof-of-concept data to support the use of liver-targeted mitochondrial uncouplers to promote healthy aging. Disclosure L. Goedeke: None. J. Camporez: None. A. Nasiri: None. Y. Wang: None. X. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..

Effects of inositol on glucose homeostasis: Systematic review and meta-analysis of randomized controlled trials

The effect of inositol on glucose homeostasis is not well characterized. The aim of the present meta-analysis is to synthesize the effects of inositol on glucose homeostasis in different clinical conditions. We performed a systematic review (CRD42017057927) following PRISMA guidelines. Web of Science and Medline were searched for randomized controlled trials (RCTs) that addressed supplementation with compounds of the inositol family in humans and assessed their effects on glucose homeostasis. We screened 476 abstracts and included 20 RCTs with a total of 1239 subjects. Meta-analysis showed in the treatment arm a reduction in fasting plasma glucose (Mean difference (MD)-0.44mmol/l, 95% CI-0.65,-0.23), 2h PG after 75g OGTT (MD-0.69mmol/l, 95% CI-1.14,-0.23), abnormal glucose tolerance (Relative risk (RR) 0.28, 95% CI 0.12, 0.66), fasting insulin (MD-38.49pmol/l, 95% CI-52.63,-24.36), and HOMA-IR (MD-1.96mmol×mUI/l, 95% CI-2.62,-1.30). No differences were observed in BMI, HbA1c and % of patients requiring insulin treatment. Sensitivity analysis did not change treatment estimates. Mention to adverse events was only present in 13 articles with no sign of seriousness. Inositol supplementation decreases blood glucose through an improvement in insulin sensitivity that is independent of weight. Assessment of adverse effects is scarce among published trials and should be fully addressed before considering inositol as a therapeutic agent for glucose-related outcomes. The characterization of the subjects achieving benefit from the intervention and the formulations to be used should also be known.

PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner

The 8-globulin-rich mung bean protein (MPI) suppresses hepatic lipogenesis in rodent models and reduces fasting plasma glucose and insulin levels in obese adults. However, its effects on mitigating high fat diet (HFD)-induced obesity and the mechanism underlying these effects remain to be elucidated. Herein, we examined the metabolic phenotype, intestinal bile acid (BA) pool, and gut microbiota of conventionally raised (CONV-R) male C57BL/6 mice and germ-free (GF) mice that were randomized to receive either regular HFD or HFD containing mung bean protein isolate (MPI) instead of the dairy protein present in regular HFD. MPI intake significantly reduced HFD-induced weight gain and adipose tissue accumulation, and attenuated hepatic steatosis. Enhancement in the secretion of intestinal glucagon-like peptide-1 (GLP-1) and an enlarged cecal and fecal BA pool of dramatically elevated secondary/primary BA ratio were observed in mice that had consumed MPI. These effects were abolished in GF mice, indicating that the effects were dependent upon the presence of the microbiota. As revealed by 16S rRNA gene sequence analysis, MPI intake also elicited dramatic changes in the gut microbiome, such as an expansion of taxa belonging to the phylum Bacteroidetes along with a reduced abundance of the Firmicutes.

Influence of Time of Yoga Practice and Gender Differences on Blood Glucose Levels in Type 2 Diabetes Mellitus and Normal Healthy Adults

Prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Many studies have demonstrated the effectiveness of yoga in improving glycaemic control, whereas no studies are available showing the impact of time of practice on glucose levels. The current study explores the effect of time of yoga practice on glucose levels in community-dwelling adults with and without T2DM. A total of 189 subjects with T2DM and 121 subjects without T2DM underwent a 10-day yoga program which includes practical and theory lecture sessions for 60min every day, either in the morning or evening. Baseline and post-intervention assessments of fasting plasma glucose (FPG) were measured on day-1 and day-10, respectively. Data analysis were done using Statistical Package for the Social Sciences (SPSS), version 16. Results of the study showed that in individuals with T2DM, a significantly higher reduction in FPG was observed while practicing yoga in the evening sessions than in the morning sessions. Likewise, a significant reduction in FPG was observed only in women who practiced yoga in the evening than in the morning, in non-diabetic healthy individuals, while the reduction was not statistically significant in men. Results of this study suggest that reduction in FPG level was better while practicing yoga in evening than morning. Similarly, women had a better reduction in blood glucose level than men.

Comparison of effectiveness of premixed insulin with long-acting insulin in diabetes: evidence from real-world cohort studies—systematic review and meta-analyses

The purpose of this research is to perform a systematic review and meta-analysis to compare effectiveness of premixed insulin (PM) and long-acting insulin (LA) based on cohort studies. Embase, Pubmed, Web of Science, Clinical.gov , and Opengray were searched. We included all cohort studies comparing the effectiveness of PM with LA on intermediate- or long-term outcomes. The weighted mean difference (WMD) was recorded for intermediate outcomes, and the risk ratio (RR) estimates were combined and weighted to produce pooled RR for long-term outcomes. Subgroup analysis was conducted by different insulin type and population. Eight studies involving 95,415 patients were included, in which six studies were used for quantitative analysis. Follow-up duration ranged from 6 months to 5 years. The meta-analysis indicated a comparable effect of PM and LA on the mean reduction in hemoglobin A1c (HbA1c) (WMD = − 0.03% [95% CI − 0.12–0.07]). Less fasting plasma glucose (FPG) declines were noticed with PM than LA (0.11 mmol/L [95% CI 0.03–0.18]). There was not statistically significant difference for post-prandial glucose (WMD = − 0.61 mmol/L [95% CI [− 1.49–0.27]). PM was associated with further weight gain of 0.67 kg [95% CI 0.60–0.74] and more insulin consumption (WMD = 11.72 U/day [95% CI 8.02–15.43]. The rates of hypoglycemia events were low but varied considerably. There was no significant difference in the effectiveness of PM and LA in real-world setting on HbA1c reduction, although PM was related with less FPG reductions, slight weight gain, and more insulin consumptions. Future real-world studies should concern about balanced oral hypoglycemic agents regimens between insulin cohorts and other potential confounding factors and assess relevant complications and death rate.

Comparison of non-insulin antidiabetic agents as an add-on drug to insulin therapy in type 2 diabetes: a network meta-analysis

We aimed to evaluate the comparative efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), or thiazolidinedione (TZD) as an adjunctive treatment in patients with poorly controlled type 2 diabetes mellitus (T2DM) on insulin therapy. We searched Medline, Embase, the Cochrane Library, and ClinicalTrials.gov through April 2016. Bayesian network meta-analyses were performed with covariate adjustment. The primary outcome was the change in glycated hemoglobin A1c (HbA1c) from baseline. Fifty randomized controlled trials covering 15,494 patients were included. GLP-1RA showed the greatest HbA1c-lowering effect compared to the control (−0.84%; 95% credible interval, −1.00% to −0.69%), followed by TZD (−0.73%; −0.93 to −0.52%), SGLT2i (−0.66%; −0.84% to −0.48%), and DPP4i (−0.54%; −0.68% to −0.39%). SGLT2i showed the greatest fasting plasma glucose reduction. GLP-1RA and SGLT2i showed greater body weight reduction, whereas TZD increased body weight. TZD was ranked the highest in terms of insulin dose reduction. The risk of hypoglycemia was increased with TZD or GLP-1RA. The study provides the best available evidence on the comparative efficacy and safety of non-insulin anti-diabetic agents on top of pre-existing insulin therapy for inadequately controlled T2DM patients.

Clinical perspectives from the BEGIN and EDITION programmes: Trial-level meta-analyses outcomes with either degludec or glargine 300 U/mL vs glargine 100 U/mL in T2DM

AimsTo explore comparative glycaemic control and hypoglycaemia incidence with insulin degludec 100U/mL (IDeg) or insulin glargine 300U/mL (Gla-300) versus glargine 100U/mL (Gla-100) in trial-level meta-analyses of phase 3a clinical trials including people with type-2 diabetes. MethodsMeta-analyses of HbA1c, fasting plasma glucose (FPG), average 24h self-measured plasma glucose (SMPG), pre-breakfast SMPG and hypoglycaemia incidence and rate, using data from the BEGIN (IDeg) and EDITION (Gla-300) insulin development programmes, were performed. ResultsIn BEGIN, despite greater FPG reduction with IDeg than Gla-100, HbA1c reduction was greater with Gla-100 (mean difference [95% CI] in HbA1c change: 0.09 [0.01–0.18] %) whereas in EDITION, there was no difference in FPG and HbA1c reduction between Gla-300 and Gla-100. Risk of nocturnal confirmed (<3.1mmol/L [<56mg/dL]) or severe hypoglycaemia, but not anytime (24h) events, was lower with IDeg than Gla-100 (relative risk [RR] 0.79 [0.66–0.94]) whereas Gla-300 was associated with reduced risk of nocturnal (RR 0.75 [0.61–0.92]) and anytime (24h) (RR 0.81 [0.69–0.94]) confirmed (<3.0mmol/L [<54mg/dL]) or severe hypoglycaemia versus Gla-100. ConclusionsThese trial-level meta-analyses suggest that despite greater reductions in FPG, IDeg was associated with less improvement in HbA1c versus Gla-100, with a hypoglycaemia benefit only evident at night. In contrast, Gla-300 showed similar HbA1c reduction to Gla-100, accompanied by lower risk of hypoglycaemia both at night and at any time of day. Gla-300 and IDeg appear more similar than dissimilar, but head-to-head trials are required.

Low body mass index and old age are useful in predicting the hemoglobin A1c-lowering effect of switching from sitagliptin to dulaglutide in Japanese patients with type 2 diabetes mellitus: a single-center, open-label, single-arm, pilot study.

The purpose of this study was to clarify the predictive clinical characteristics of therapy switching from sitagliptin to dulaglutide in patients with type 2 diabetes mellitus. This single-center, open-label, investigator-initiated pilot study was conducted in 40 patients with type 2 diabetes mellitus. The patients, who had been treated with 50mg sitagliptin daily for at least 6months were switched to 0.75mg dulaglutide weekly. A total of 36 patients could be followed for 24weeks of treatment with dulaglutide. They were assessed for several clinical parameters before the start of and 24weeks after the study. Multiple linear regression analysis was used to search for independent predictors of reduction of hemoglobin A1c (HbA1c) levels after 24weeks of treatment switching from sitagliptin to dulaglutide. Dulaglutide administration for 24weeks resulted in significant reductions in fasting plasma glucose (FPG), HbA1c, and low-density lipoprotein cholesterol (LDL-C) levels. In addition, baseline HbA1c, FPG, body mass index (BMI), and age were significantly correlated with the change in HbA1c levels (ΔHbA1c). Furthermore, multiple linear regression analysis revealed that BMI and age significantly correlated with ΔHbA1c. In summary, our prospective 24-week study showed that baseline low BMI and old age are significantly useful in predicting the HbA1c-lowering effect of switching from sitagliptin to dulaglutide. UMIN Clinical Trials Registry (UMIN000023245).