All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.

Oral treatment for diabetes using α-glucosidase inhibitors was a risk factor for chronic obstructive pulmonary disease: a cohort study.

Objectives: Currently, diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) have proven to be risk factors for each other. This study aimed to determine the risk relationship between COPD and five common oral medications for DM among patients with DM. Methods: This population-based cohort study was conducted from 2008 to 2013. Patient data were retrieved from the Longitudinal Health Insurance Database (LHID) of the National Health Insurance Research Database (NHIRD). After pairing by gender, age, and index date, time-to-event analysis and multiple regression analysis were performed to determine the factors associated with COPD in patients taking oral medication for DM, including age, gender, income, and comorbidities. We identified 1,028 patients who took oral medication for DM and 1,028 controls who did not take oral medication for DM. Results: We observed that the use of α-glucosidase inhibitors was associated with a higher risk of COPD (hazard ratio [HR]: 1.964, 95% confidence interval [CI]: 1.207-2.380). Furthermore, compared with the control group, α-glucosidase inhibitor users had a higher risk of COPD (HR: 2.295, 95% CI: 1.304-4.038), and no significant difference was observed in other oral medications for DM. Conclusions: Based on present results, we could suggest that patients with DM who used α-glucosidase inhibitors are probably a higher risk of COPD. We recommend that in the future, treatment with α-glucosidase inhibitors upregulate the occurrence of COPD might through gastrointestinal side effects and malnutrition.

Bullous Pemphigoid and Diabetes medications: A disproportionality analysis based on the FDA Adverse Event Reporting System.

Background: The world's first Diabetes Medications (Insulin) was marketed in October 1923. Some studies suggested the association of diabetes medications with Bullous Pemphigoid (BP), especially the Dipeptidyl Peptidase 4 (DPP-4) inhibitors. The study aims to detect an association between diabetes medications (focusing on DPP-4 inhibitors) and bullous pemphigoid based on FDA Adverse Event Reporting System (FAERS). Methods: All spontaneous reports of diabetes medications inhibitors-related BP recorded in the FAERS between March 2004 and August 2020 were included in the present study. Disproportionality analysis was performed to find the signal between diabetes medications and BP. The Chi-Squared with Yates' correction (χ2 Yates), proportional reporting ratio (PRR) and the lower limit of the 95% confidence interval of the Reporting Odds Ratio (ROR025) were calculated as a measure. A signal was detected when ROR025 > 1, PRR > 2, χ2 Yates > 4 and at least 3 cases. Results: There were 3770 reports for BP in FAERS. The strongest signal for diabetes medications-BP association were DDP-4 inhibitors (ROR025: 13.700, PRR: 15.408), followed by Meglitinides (ROR025: 12.708, PRR: 16.777), Non-sulfonylureas (ROR025: 6.434, PRR: 7.016), Alpha-glucosidase inhibitors (ROR025: 6.105, PRR: 10.738), Sulfonylureas (ROR025:2.655, PRR: 3.200). Conclusions: This study detected a strong signal between BP and DDP-4 inhibitors, alpha-glucosidase inhibitors, meglitinides, non-sulfonylureas, and sulfonylureas in FAERS. The signal was significantly higher with alogliptin than with the other DPP-4 inhibitors. The study doesn't suggest the association between the incretin mimetics, insulin, SGLT-2 inhibitors, thiazolidinediones and BP in FAERS.

Association between α-glucosidase inhibitor use and psoriatic disease risk in patients with type 2 diabetes mellitus: A population-based cohort study.

AIMS: To investigate the association between the use of alpha-glucosidase inhibitors (AGIs) and the risk of psoriatic disease (ie, psoriasis and psoriatic arthritis) in patients with type 2 diabetes mellitus (T2DM) treated with metformin. METHODS: Using the 1999-2013 Taiwanese Longitudinal Cohort of Diabetes Patients Database, we identified patients with T2DM who initiated hypoglycaemic treatment between 2003 and 2012. After excluding patients with a history of psoriatic disease (International Classification of Disease, Ninth Revision, Clinical Modification codes 696.0-1) before T2DM diagnosis, patients who received antidiabetic treatment for <90 days, and patients aged <20 or >100 years, we identified 1390 patients who received metformin+AGIs (AGI exposure group) and 47 514 patients who received metformin only (comparison group). We matched the two groups at a 1:10 ratio by age, sex, and index date of T2DM drug use. The association between AGI use and psoriatic disease risk was analysed using a Cox proportional hazard mode; time-dependent covariates for factors were reported in terms of hazard ratios (HRs) with 95% confidence intervals (CIs) after age, sex, T2DM duration, and comorbidities were controlled for. RESULTS: After adjusting the AGI exposure and comparison groups for potential confounders, we found that psoriatic disease risk was associated with metformin+AGI use when AGI was discontinued for 30 days (HR, 8.77; 95% CI, 1.58-48.5) and when a high AGI dose was administered; furthermore, the risk declined during AGI discontinuation. CONCLUSIONS: This population-based study reports that AGI use and interruption of AGI use may be associated with increased psoriatic disease risk in treated patients with T2DM.

The effect of voglibose on metabolic profiles in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials.

OBJECTIVE: The effect of voglibose on metabolic homeostasis is not well characterized. Therefore, we conducted a systematic review and meta-analysis of clinical trials assessing the effect of voglibose on metabolic profile in patients with type 2 diabetes mellitus (T2DM). METHODS: Systematic searches were conducted in PubMed, Scopus, Embase, Google Scholar, Web of Science and Cochrane Library to identify clinical trials assessing the effects of voglibose supplementation on cardio-metabolic profile from incept up to 29 July 2019. Data was pooled using fixed- or random-effect models and weighted mean difference (WMD) as the effect size. RESULTS: Eight clinical trials from 1094 reports, were eligible for inclusion. Pooled findings identified significant reductions in hemoglobin A1c (HbA1c) (WMD= -0.27; 95 %CI -0.49 to -0.05; P = 0.01; I2 = 64.8 %) and an increase in LDL-cholesterol levels (WMD=5.97 mg/dl, 95 % CI 0.88, 11.06, P = 0.02; I2 = 0.0 %). However, no evidence of effect for voglibose intake on T2DM patients was observed for: fasting blood sugar (FBS) (WMD -7.43 mg/dl; 95 %CI -16.56 to 1.71; P = 0.110; I2 = 69.3 %), serum insulin (WMD= -0.15 µU/mL; 95 %CI -0.89 to 0.60; P = 0.70; I2 = 0.0 %), total-cholesterol (WMD=2.82 mg/dl, 95 %CI -2.36 to 8.01, P = 0.70; I2 = 49.7 %), triglycerides (WMD= -7.07 mg/dl, 95 %CI -21.76 to 7.62, P = 0.34; I2 = 0.0 %), HDL-cholesterol levels (WMD= -2.10 mg/dl, 95 %CI -4.48 to 0.27, P = 0.08; I2 = 0.0 %,), body mass index (BMI) (WMD=0.09 kg/m2, 95 %CI -0.70 to 0.87; P = 0.87; I2 = 0.0 %), body weight (WMD= -0.42 kg, 95 %CI -0.84 to 0.00; P = 0.05; I2 = 0.0 %), and adiponectin levels (WMD = 0.32 µg/mL, 95 %CI -0.74 to 1.38; P = 0.55; I2 = 0.0 %). CONCLUSIONS: The current meta-analysis identified a decrease in HbA1c and an increase in LDL-cholesterol with administration of voglibose. However, no significant effect was observed on FBS, insulin, bodyweight, BMI, adiponectin, triglycerides, total- and HDL-cholesterol levels.

Pneumatosis cystoides intestinalis induced by the alpha-glucosidase inhibitor complicated from sigmoid volvulus in a diabetic patient.

INTRODUCTION: We present the case of a diabetic patient on treatment with acarbose who had presented a sigmoid volvulus with localized cystic pneumatosis of the sigmoid colon. CASE REPORT: A 72-year-old patient with a medical history of atrial fibrillation, DNID in treatment since 10 years by acarbose. The patient was admitted to the emergency for abdominal pain and occlusive syndrome since 48 h without fever or nausea or vomiting. A CT scan was performed that showed a dolichocolon with a sigmoid volvulus. The colonic wall was thickening as well as submucosal and subserosal gas, without extra digestive air or collections. A rectosigmoidoscopy was achieving that showed a sigmoid volvulus with multiple small projections like a submucosa gas bubbles. A laparoscopic non-oncologic sigmoidectomy with primary termino terminal colorectal anastomosis was performed. During the surgical procedure, an aspect of PCI of the sigmoid colon was found. The sigmoid colon was long like a dolichocolon, dilated, and partially twisted. DISCUSSION: PCI is a rare condition characterized by the presence of multiple pneumokystes at different layers of the colonic wall. In emergency setting, the presence of colonic pneumatosis precludes the differential diagnosis between the PCI and mesenteric ischemia or ischemic colitis. It can be the cause of unnecessary explorative laparotomy. CONCLUSION: PCI is rare disease, in emergency setting, we had to consider in differential diagnosis with colonic vascular disorders.

Sulphonylureas monotherapy and risk of hospitalization for heart failure in patients with type 2 diabetes mellitus: A population-based cohort study in China.

PURPOSE: The risk of heart failure associated with sulphonylureas is unclear. We evaluated the association between sulphonylureas and hospitalization of heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) in China. METHODS: A retrospective cohort study was implemented using the Yinzhou Regional Health Care Database (YRHCD). We identified 15 752 adult patients with T2DM who were newly exposed to sulphonylurea monotherapy (N = 12 487) or acarbose monotherapy (N = 3265) from January 2010 to September 2016. Cox proportional hazards models weighted by inverse probability of treatment weights were used to compare the risk of HHF between initiators of sulphonylurea and acarbose. RESULTS: During a median follow-up of 0.55 (0.49, 1.11) and 0.49 (0.35, 0.70) years for sulphonylureas and acarbose initiators separately, 320 patients developed HHF, with 279 events in sulphonylureas group, and 41 events in acarbose group. The incidence rates of HHF among sulphonylureas initiators and acarbose initiators were 22.2 (95% CI 19.6-24.9) and 18.3 (95% CI 13.2-24.9) per 1000 person-years, respectively. The adjusted hazard ratio (aHR) of HHF for sulphonylureas vs acarbose was 1.61 (95% CI 1.14-2.27). When stratified by history of heart failure, aHR was 1.55 (95% CI 0.79-3.06) in patients with a history of heart failure, and 1.64 (95% CI 1.10-2.45) in patients with no history of heart failure. CONCLUSIONS: Our study suggested that use of sulphonylureas monotherapy compared with acarbose monotherapy for initial treatment of T2DM for approximately 0.5 years are significantly associated with a higher risk of HHF.

Effects of sitagliptin on exercise capacity and hemodynamics in patients with type 2 diabetes mellitus and coronary artery disease.

Sitagliptin attenuates left ventricular (LV) dysfunction and may improve oxygen uptake in animals. The effects of sitagliptin on oxygen uptake (VO2) and exercise hemodynamics have been unclear in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Thirty patients with T2DM and CAD were randomized into a sitagliptin (50 mg/day) or voglibose (0.6 mg/day) group. Patients underwent maximal cardiopulmonary exercise testing. VO2 and hemodynamics were evaluated at rest, anaerobic threshold and peak exercise. Resting LV diastolic function (E', peak early diastolic mitral annular velocity) and geometry were evaluated by echocardiography, and endothelial function by reactive hyperemia peripheral arterial tonometry. A total of 24 patients (69 ± 9 years) completed 6 months of intervention. Peak VO2 in the sitagliptin and voglibose groups (25.3 ± 7.3 vs. 24.0 ± 7.4, 22.7 ± 4.8 vs. 22.1 ± 5.2 ml/kg/min) was slightly decreased after 6 months (time effect p = 0.051; group × time effect p = 0.49). No effects were observed on LV ejection fraction, E', or reactive hyperemia index in either group. Heart rate during exercise was unaffected in both groups. Systolic blood pressure was unchanged by sitagliptin at rest and during exercise, but slightly lowered by voglibose at anaerobic threshold and peak exercise. In patients with T2DM and CAD, sitagliptin had little effect on resting LV and arterial function, exercise capacity, or exercise hemodynamics. Further studies need to be conducted with more patients as the number of the patients in this study was limited.

Meta-analysis of the impact of alpha-glucosidase inhibitors on incident diabetes and cardiovascular outcomes.

BACKGROUND: Alpha-glucosidase inhibitors (AGIs) have been shown to reduce incident type 2 diabetes but their impact on cardiovascular (CV) disease remains controversial. We sought to identify the overall impact of AGIs with respect to incident type 2 diabetes in individuals with impaired glucose tolerance (IGT), and CV outcomes in those with IGT or type 2 diabetes. METHODS: We used PubMed and SCOPUS to identify randomized controlled trials reporting the incidence of type 2 diabetes and/or CV outcomes that had compared AGIs with placebo in populations with IGT or type 2 diabetes, with or without established CV disease. Eligible studies were required to have ≥ 500 participants and/or ≥ 100 endpoints of interest. Meta-analyses of available trial data were performed using random effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and CV outcomes. RESULTS: Of ten trials identified, three met our inclusion criteria for incident type 2 diabetes and four were eligible for CV outcomes. The overall HR (95% CI) comparing AGI with placebo for incident type 2 diabetes was 0.77 (0.67-0.88), p < 0.0001, and for CV outcomes was 0.98 (0.89-1.10), p = 0.85. There was little to no heterogeneity between studies, with I2 values of 0.03% (p = 0.43) and 0% (p = 0.79) for the two outcomes respectively. CONCLUSIONS: Allocation of people with IGT to an AGI significantly reduced their risk of incident type 2 diabetes by 23%, whereas in those with IGT or type 2 diabetes the impact on CV outcomes was neutral.

Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors.

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.

Cardiovascular risks associated with dipeptidyl peptidase-4 inhibitors monotherapy compared with other antidiabetes drugs in the Japanese population: A nationwide cohort study.

PURPOSE: We evaluated the cardiovascular risk associated with dipeptidyl peptidase-4 inhibitors (DPP-4Is) as monotherapy compared with other antidiabetic drugs in Japan. METHODS: We conducted a nationwide cohort study involving 2 716 000 diabetes patients in Japan. New users of any antidiabetic drug as monotherapy between 1 April 2010 and 31 October 2014 were identified. Occurrences of myocardial infarction (MI), heart failure (HF), and stroke requiring hospitalization associated with DPP-4Is were compared with those associated with biguanides (BGs), sulfonylureas (SUs), or α-glucosidase inhibitors (α-GIs). Adjusted hazard ratios (aHRs) for these outcomes were estimated by Cox proportional hazards model. Propensity score standardization was used to control for confounding. RESULTS: We identified 1 105 103 patients using DPP-4Is, 278 280 patients using BGs, 273 449 patients using SUs, and 217 026 patients using α-GIs. The risks of MI and HF for DPP-4I users were significantly higher than those for BG users (MI: aHR, 1.48 [95%CI, 1.20-1.82], HF: aHR, 1.46 [95%CI, 1.31-1.62]), while significantly lower than those for SU users (MI: aHR, 0.84 [95%CI, 0.72-0.98], HF: aHR, 0.86 [95%CI, 0.81-0.92]). The risk of MI for DPP-4I users was similar to that for α-GI users, while the risk of HF for DPP-4I users was slightly higher than for α-GI users (MI: aHR, 0.98 [95%CI, 0.82-1.17], HF: aHR, 1.12[95%CI, 1.04-1.21]). CONCLUSIONS: Risk of MI and HF requiring hospitalization associated with DPP-4Is as monotherapy was significantly higher than BGs, significantly lower than SUs, and similar to α-GIs.

Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

Glitazones and alpha-glucosidase inhibitors as the second-line oral anti-diabetic agents added to metformin reduce cardiovascular risk in Type 2 diabetes patients: a nationwide cohort observational study.

OBJECTIVE: Metformin is the standard first-line drug for patients with Type 2 diabetes (T2DM). However, the optimal second-line oral anti-diabetic agent (ADA) remains unclear. We investigated the cardiovascular risk of various ADAs used as add-on medication to metformin in T2DM patients from a nationwide cohort. METHODS: T2DM patients using different add-on oral ADAs after an initial metformin therapy of > 90 days were identified from the Taiwan National Health Insurance Database. Five classes of ADAs, including sulphonylureas (SU), glinides, thiazolidinediones (TZD), alpha-glucosidase inhibitors (AGI), and dipeptidyl peptidase-4 inhibitors (DPP-4I) were selected for analysis. The reference group was the SU added to metformin. Patients were excluded if aged < 20 years, had a history of stroke or acute coronary syndrome (ACS), or were receiving insulin treatment. The primary outcomes included any major adverse cardiovascular event (MACE) including ACS, ischemic/hemorrhagic stroke, and death. A Cox regression model was used to estimate the hazard ratio (HR) for MACE. RESULTS: A total of 26,742 patients receiving their add-on drug to metformin of either SU (n = 24,277), glinides (n = 962), TZD (n = 581), AGI (n = 808), or DPP-4I (n = 114) were analyzed. After a mean follow-up duration of 6.6 ± 3.4 years, a total of 4775 MACEs occurred. Compared with the SU+metformin group (reference), the TZD+metformin (adjusted HR: 0.66; 95% CI 0.50-0.88, p = 0.004) and AGI+metformin (adjusted HR: 0.74; 95% CI 0.59-0.94, p = 0.01) groups showed a significantly lower risk of MACE. CONCLUSION: Both TZD and AGI, when used as an add-on drug to metformin were associated with lower MACE risk when compared with SU added to metformin in this retrospective cohort study. Trial registration CE13152B-3. Registered 7 Mar, 2013, retrospectively registered.

Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

BACKGROUND: Alpha-glucosidase inhibitors (AGI) reduce blood glucose levels and may thus prevent or delay type 2 diabetes mellitus (T2DM) and its associated complications in people at risk of developing of T2DM. OBJECTIVES: To assess the effects of AGI in people with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was December 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs), with a duration of one year or more, comparing AGI with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with IFG, IGT, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles or records, assessed quality and extracted outcome data independently. One review author extracted data, which were checked by a second review author. We resolved discrepancies by consensus or involvement of a third review author. For meta-analyses we used a random-effects model with assessment of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence by using the GRADE instrument. MAIN RESULTS: For this update of the Cochrane Review (first published 2006, Issue 4) we included 10 RCTs (11,814 participants), eight investigating acarbose and two investigating voglibose, that included people with IGT or people "at increased risk for diabetes". The trial duration ranged from one to six years. Most trials compared AGI with placebo (N = 4) or no intervention (N = 4).Acarbose reduced the incidence of T2DM compared to placebo: 670 out of 4014 people (16.7%) in the acarbose groups developed T2DM, compared to 812 out of 3994 people (20.3%) in the placebo groups (RR 0.82, 95% CI 0.75 to 0.89; P < 0.0001; 3 trials; 8008 participants; moderate-certainty evidence). One trial including participants with coronary heart disease and IGT contributed 64% of cases for this outcome. Acarbose reduced the risk of T2DM compared to no intervention: 7 out 75 people (9.3%) in the acarbose groups developed T2DM, compared to 18 out of 65 people (27.7%) in the no-intervention groups (RR 0.31, 95% CI 0.14 to 0.69; P = 0.004; 2 trials; 140 participants; very low-certainty evidence).Acarbose compared to placebo did not reduce or increase the risk of all-cause mortality (RR 0.98, 95% CI 0.82 to 1.18; P = 0.86; 3 trials; 8069 participants; very low-certainty evidence), cardiovascular mortality (RR 0.88; 95% CI 0.71 to 1.10; P = 0.26; 3 trials; 8069 participants; very low-certainty evidence), serious adverse events (RR 1.12, 95% CI 0.97 to 1.29; P = 0.13; 2 trials; 6625 participants; low-certainty evidence), non-fatal stroke (RR 0.50, 95% CI 0.09 to 2.74; P = 0.43; 1 trial; 1368 participants; very low-certainty evidence) or congestive heart failure (RR of 0.87; 95% CI 0.63 to 1.12; P = 0.40; 2 trials; 7890 participants; low-certainty evidence). Acarbose compared to placebo reduced non-fatal myocardial infarction: one out of 742 participants (0.1%) in the acarbose groups had a non-fatal myocardial infarction compared to 15 out of 744 participants (2%) in the placebo groups (RR 0.10, 95% CI 0.02 to 0.53; P = 0.007; 2 trials; 1486 participants; very low-certainty evidence). Acarbose treatment showed an increased risk of non-serious adverse events (mainly gastro-intestinal events), compared to placebo: 751 of 775 people (96.9%) in the acarbose groups experienced an event, compared to 723 of 775 people (93.3%) in the placebo groups (RR 1.04; 95% CI 1.01 to 1.06; P = 0.0008; 2 trials; 1550 participants). Acarbose compared to no intervention showed no advantage or disadvantage for any of these outcome measures (very low-certainty evidence).One trial each compared voglibose with placebo (1780 participants) or diet and exercise (870 participants). Voglibose compared to placebo reduced the incidence of T2DM: 50 out of 897 participants (5.6%) developed T2DM, compared to 106 out of 881 participants (12%) in the placebo group (RR 0.46, 95% CI 0.34 to 0.64; P < 0.0001; 1 trial; 1778 participants; low-certainty evidence). For all other reported outcome measures there were no clear differences between voglibose and comparator groups. One trial with 90 participants compared acarbose with diet and exercise and another trial with 98 participants reported data on acarbose versus metformin. There were no clear differences for any outcome measure between these two acarbose interventions and the associated comparator groups.None of the trials reported amputation of lower extremity, blindness or severe vision loss, end-stage renal disease, health-related quality of life, time to progression to T2DM, or socioeconomic effects. AUTHORS' CONCLUSIONS: AGI may prevent or delay the development of T2DM in people with IGT. There is no firm evidence that AGI have a beneficial effect on cardiovascular mortality or cardiovascular events.

Infantile gangliosidoses: Mapping a timeline of clinical changes.

BACKGROUND: Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases. OBJECTIVES: This study aimed to establish a timeline of clinical changes occurring in infantile gangliosidoses, prospectively, to: 1) characterize the natural history of these diseases; 2) improve planning of clinical care; and 3) identify meaningful future treatment outcome measures. METHODS: Patients were evaluated prospectively through ongoing clinical care. RESULTS: Twenty-three patients were evaluated: 8 infantile GM1, 9 infantile Tay-Sachs disease, 6 infantile Sandhoff disease. Common patterns of clinical change included: hypotonia before 6months of age; severe motor skill impairment within first year of life; seizures; dysphagia and feeding-tube placement before 18months of age. Neurodevelopmental testing scores reached the floor of the testing scale by 20 to 28months of age. Vertebral beaking, kyphosis, and scoliosis were unique to patients with infantile GM1. Chest physiotherapy was associated with increased survival in iGM1 (p=0.0056). Miglustat combined with a low-carbohydrate ketogenic diet (the Syner-G regimen) in patients who received a feeding-tube was associated with increased survival in infantile GM1 (p=0.025). CONCLUSIONS: This is the first prospective study of the natural history of infantile gangliosidoses and the very first natural history of infantile GM1. The homogeneity of the infantile gangliosidoses phenotype as demonstrated by the clinical events timeline in this study provides promising secondary outcome measure candidates. This study indicates that overall survival is a meaningful primary outcome measure for future clinical trials due to reliable timing and early occurrence of this event. Combination therapy approaches, instead of monotherapy approaches, will likely be the best way to optimize clinical outcomes. Combination therapy approaches include palliative therapies (e.g., chest physiotherapy) along with treatments that address the underlying disease pathology (e.g. miglustat or future gene therapies).

Synthesis, pharmacological screening and computational analysis of some 2-(1H-Indol-3-yl)-N'-[(un)substituted phenylmethylidene] acetohydrazides and 2-(1H-Indol-3-yl)-N'-[(un)substituted benzoyl/2-thienylcarbonyl]acetohydrazides.

The undertaken research was initiated by transforming 2-(1H-Indol-3-yl)acetic acid (1) in catalytic amount of sulfuric acid and ethanol to ethyl 2-(1H-Indol-3-yl)acetate (2), which was then reacted with hydrazine monohydrate in methanol to form 2-(1H-Indol-3-yl)acetohydrazide (3). Further, The reaction scheme was designed into two pathways where, first pathway involved The reaction of 3 with substituted aromatic aldehydes (4a-o) in methanol with few drops of glacial acetic acid to generate 2-(1H-Indol-3-yl)-N'-[(un)substitutedphenylmethylidene]acetohydrazides (5a-o) and in second pathway 3 was reacted with acyl halides (6a-e) in basic aqueous medium (pH 9-10) to afford 2-(1H-Indol-3-yl)-N'-[(un)substitutedbenzoyl/2-thienylcarbonyl]acetohydrazides (7a-e). All The synthesized derivatives were characterized by IR, EI-MS and 1H-NMR spectral techniques and evaluated for their anti-bacterial potentials against Gram positive and Gram negative bacterial strains and it was found that compounds 7a-d exhibited antibacterial activities very close to standard Ciprofloxacin. The synthesized derivatives demonstrated moderate to weak anti-enzymatic potential against α-Glucosidase and Butyrylcholinesterase (BChE) where, compounds 7c and 5c exhibited comparatively better inhibition against these enzymes respectively. Compounds 7a, 7d and 7e showed excellent anti-enzymatic potentials against Lipoxygenase (LOX) and their IC50 values were much lower than the reference standard Baicalein. Enzyme inhibitory activities were also supported by computational docking results. Compounds 5c, 7a, 7b and 7c also showed low values of % hemolytic activity as well, showing that these molecules were not toxic, indicating that these molecules can be utilized as potential therapeutic agents against inflammatory ailments.

Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy.

Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, ß blockers and mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic drugs that are used at present.

Efficacy of acarbose in different geographical regions of the world: analysis of a real-life database.

BACKGROUND: Alpha-glucosidase inhibitors are recommended in some international guidelines as first-line, second-line and third-line treatment options but are not used worldwide due to perceived greater effectiveness in Asians than Caucasians. METHODS: Data from ten post-marketing non-interventional studies using acarbose, the most widely used alpha-glucosidase inhibitor, from 21 countries, provinces and country groups were pooled. Effects on glycated hemoglobin (HbA1c ) were analysed for four major ethnicity/region groups (European Caucasians and Asians from East, Southeast and South Asia) to identify differences in the response to acarbose. RESULTS: The safety and efficacy populations included 67 682 and 62 905 patients, respectively. Mean HbA1c in the total population decreased by 1.12 ± 1.31% at the 3-month visit from 8.4% at baseline (p < 0.0001). Reductions in HbA1c , fasting plasma glucose and post-prandial plasma glucose were greater in patients with higher baseline values. Acarbose was well tolerated, with few episodes of hypoglycemia (0.03%) and gastrointestinal adverse events (2.76%). Data from 30 730 Caucasians from Europe and Asians from three major regions of Asia with non-missing gender/age information and baseline/3-month HbA1c data were analysed by multivariable analyses of covariance. After adjustment for relevant baseline confounding factors, Southeast and East Asians had slightly better responses to acarbose than South Asians and European Caucasians; however, the differences were small. CONCLUSIONS: Acarbose was effective in both European Caucasians and Asians; however, after adjustment for baseline confounding factors, significant small differences in response favoured Southeast and East Asians.

Glucose-lowering treatment of type 2 diabetes. Part II--Glucose-lowering drugs after metformin: a choice based largely on adverse effects.

Metformin alone is the glucose-lowering drug of first choice for patients with type 2 diabetes. None of the other glucose-lowering drugs available in 2014 have any proven efficacy in preventing diabetes complications. How important are adverse effects in the choice of glucose-lowering alternatives to metformin for patients with type 2 diabetes? What about their effects on HbA1c levels? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. Sulphonylureas have been in use for many years. These drugs lower HbA1c levels by an average of 1.5% when used alone, and by 0.8% to 1% when added to metformin. All sulphonylureas can cause dose-related hypoglycaemia. Available data do not rule out a tangible increase or decrease in cardiovascular mortality among patients treated with sulphonylureas. Comparative data suggest that the combination of metformin + sulphonylurea increases overall mortality. Human insulins have also been in use for many years. A daily injection of long-acting insulin, added to on-going oral glucose-lowering therapy, lowers HbA1c by 0.7% to 2.5% on average but causes weight gain and increases the risk of hypoglycaemia. It cannot be ruled out that insulin may increase the risk of certain cancers. Alpha-glucosidase inhibitors have a weak glucose-lowering effect. The average decline in HbA1c is about 0.7%, which is not sufficient to offset the gastrointestinal disorders caused by these drugs. The glucose-lowering effect of repaglinide is similar to that of sulphonylureas. Repaglinide can cause hypoglycaemia, particularly when co-administered with inhibitors of some cytochrome P450 isoenzymes. Glitazones have a clearly unfavourable harm-benefit balance, potentially causing fractures, heart failure, other cardiovascular events, bladder cancer. Gliptins lower HbA1c by 0.7% on average but can provoke anaphylactic reactions, Stevens-Johnson syndrome, and infections. Saxagliptin may increase the risk of fractures and heart failure. The long-term adverse effects of gliptins are poorly documented and may include an increased risk of pancreatic cancer. These risks are not offset by any proven clinical efficacy; patients should therefore not be exposed to these drugs. When they are combined with metformin, two injectable GLP-1 analogues, exenatide and liraglutide, have a glucose-lowering potency similar to one or two daily insulin injections. They have the advantage of inducing weight loss, without increasing the risk of hypoglycaemia. Gastrointestinal adverse effects such as nausea are frequent at the beginning of treatment. A possible increase in the risk of pancreatitis, pancreatic cancer and thyroid cancer has not been ruled out. Gliflozins reduce HbA1c by 0.6-0.7% on average. These drugs are already known to have a burdensome adverse effect profile despite their relatively recent market introduction. There are also safety signals concerning serious long-term adverse effects. Patients should not be exposed to these risks.