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Aim: To examine the likelihood of mortality or rehospitalization following acute coronary syndrome with glyburide versus gliclazide use in adults with type 2 diabetes undergoing cardiac catheterization. Research Design and Methods: This retrospective cohort study used clinical data linked with administrative health data from Alberta, Canada between April 2008 and March 2021. Three methods were used to define exposure to glyburide and gliclazide in the year before catheterization. Multivariable logistic regression was used to compare the likelihood of a composite outcome of 1‐year mortality or rehospitalization with use of glyburide versus use of gliclazide. Results: A total of 11 140 individuals with type 2 diabetes had a cardiac catheterization for acute coronary syndrome. Their mean age was 66 years and 31% were female. In the year before catheterization, 5% used glyburide and 19% used gliclazide. Any glyburide or gliclazide exposure in the year before catheterization was associated with a similar likelihood of all‐cause mortality or rehospitalization (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 0.93–1.41; p = 0.20). However, current glyburide exposure (aOR 1.37, 95% CI 1.06–1.79; p = 0.018) and long exposure to glyburide (aOR 1.37, 95% CI 1.03–1.83; p = 0.030) were associated with a higher likelihood of the composite outcome compared to current and long exposure to gliclazide, respectively. Conclusions: Current and long exposure to glyburide was associated with a greater likelihood of mortality or rehospitalization following cardiac catheterization for acute coronary syndrome, when compared to similar gliclazide exposure definitions. This study adds further evidence of the need to avoid using glyburide if a sulphonylurea is required for type 2 diabetes management. [ABSTRACT FROM AUTHOR]

The sulfonylurea class of antidiabetic agents includes a range of closely related compounds, allowing for similar analytical approaches when combined with metformin. This article provides a comprehensive review of published methods for determining sulfonylureas and metformin combinations in bulk and pharmaceutical preparations. Various techniques such as highperformance liquid chromatography (HPLC), thin-layer chromatography (TLC), capillary zone electrophoresis (CZE), and spectrophotometric methods have been widely used for these compounds, yielding reliable results. Additionally, the article discusses the number of citations for each method and its specific purpose, offering critical commentary. [ABSTRACT FROM AUTHOR]

Aim: Fluoroquinolone‐related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population‐based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. Materials and Methods: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second‐generation sulphonylureas (1998‐2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent‐to‐treat exposure definition, we assessed the 30‐day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. Results: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91‐1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41‐5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79‐1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. Conclusions: In patients using second‐generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. Materials and Methods: This was a 52‐week, multicentre, randomized, parallel‐group, open‐label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1‐2 mg/day for 12 months as an add‐on to metformin. Baseline and end of study body composition evaluations included dual‐energy X‐ray absorptiometry and abdominal computed tomography scans. Results: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: −2.59 kg BF mass, −1.94% BF%, −17.55 cm2 VAT area, −18.39 cm2 SAT area, −0.46% glycated haemoglobin, −18.25 mg/dl fasting blood glucose, −3.7 kg weight, −2.21 cm waist circumference, −1.37 kg/m2 body mass index, −6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. Conclusion: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well‐tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add‐on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of gemigliptin on cardiac function and compare the effects of gemigliptin and glimepiride in patients with type 2 diabetes (T2D). Materials and Methods: Sixty T2D patients being treated with metformin were assigned to a gemigliptin group (50 mg daily) or a glimepiride group (2 mg daily) for 24 weeks. The preadjudicated extension period was up to 52 weeks. Glucose metabolism variables and cardiac biomarkers were measured. Echocardiography was used to evaluate cardiac functions. Results: The HbA1c levels decreased significantly from 8.1% ± 0.6% to 6.8% ± 0.6% in the gemigliptin group and from 8.1% ± 0.6% to 7.0% ± 0.7% in the glimepiride group, without a between‐group difference. Gemigliptin reduced insulin resistance, high sensitivity C‐reactive protein and low‐density lipoprotein cholesterol levels, and blood pressure, and increased adiponectin level compared with glimepiride therapy. Gemigliptin induced favourable changes in body composition. Left ventricular end‐diastolic volume decreased in the gemigliptin group but increased in the glimepiride group, with a borderline between‐group difference. Cardiac biomarkers did not change significantly in either group. At 52 weeks, the HbA1c levels in both groups increased slightly; 7.3% ± 0.8% in the gemigliptin group versus 7.7% ± 1.3% in the glimepiride group, without a between‐group difference. Conclusions: Gemigliptin had a comparable glucose‐lowering efficacy without deleterious effects on cardiac functions or on biomarkers reflective of myocardial injury or heart failure during the 24‐week observation period. However, larger, longer‐term studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

4 Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Before matching, patients in the SGLT2 inhibitor group were younger, more likely to be on metformin/glucagon-like peptide-1 receptor agonists/insulin, and had lower rates of comorbid heart failure, microvascular disease, stroke and chronic kidney disease (Table S2). Keywords: cardiovascular disease; real-world evidence; SGLT2 inhibitor; sulphonylureas; type 2 diabetes EN cardiovascular disease real-world evidence SGLT2 inhibitor sulphonylureas type 2 diabetes 2402 2409 8 07/04/23 20230801 NES 230801 INTRODUCTION Sulphonylureas (SUs) are widely used in type 2 diabetes (T2D), particularly in resource-constrained regions. Lower risk of cardiovascular events and death associated with initiation of sodium-glucose cotransporter-2 inhibitors versus sulphonylureas: Analysis from the CVD-REAL 2 study. [Extracted from the article]

Aims: The aim of our meta‐analyses was to compare the effects of glucose‐lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. Methods: Meta‐analyses comparing drugs within the classes of GLP‐1RAs and SGLT‐2 inhibitors were performed and compared to sulphonylureas and DPP‐4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose‐lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. Results: SGLT‐2 inhibitors and GLP‐1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP‐4 inhibitors and sulphonylureas. SGLT‐2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT‐2 inhibitors and GLP‐1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low‐risk subgroup. Conclusions: The findings from our analyses substantiate the relevance of treatment with SGLT‐2 inhibitors or GLP‐1RAs as an add‐on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT‐2 inhibitor treatment in patients with T2D and heart failure or established kidney disease. [ABSTRACT FROM AUTHOR]

Background and Objectives: Type 2 diabetes mellitus is a common metabolic disorder with immense social impact. Millions of patients are being treated with insulin either after primary failure or secondary failure with sulphonylurea therapy. Sulphonylureas have the potential to reduce the glucose levels by increasing the insulin secretion and insulin sensitivity. This study intends to know the effect on fasting and postprandial glucose levels on adding glibenclamide to daily insulin regimens and reduction of the dose of insulin requirement. Methods: The study conducted at Department of General Medicine, Siddartha Medical College, Vijaywada, Andhra Pradesh, India from July 2021 to June 2022. In 50 patients who met the inclusion criteria the fasting and postprandial glucose levels were recorded prior to the addition of glibenclamide and after addition of glibenclamide FBG and PPBG were recorded again and following statistical tests i.e., Fisher's F test and Student's 't' test and Gaussian tests were used to find significance. Results: At the end of study FBG decreased by 32.5%which was statistically significant (p<0.01) and the mean PPBG value decreased by 27.7% which was also statistically significant (p<0.05). Conclusion: Combination therapy with insulin and glibenclamide results in a significant improvement in glycemic control compared to insulin therapy alone. Combination therapy has no significant effect on insulin dosage. Risk of hypoglycemia can be lowered if the dose of glibenclamide is tailored to each patient's requirement. Compared to other insulin sensitizers' traditional drug like glibenclamide is the cheapest and most economical option available currently in the Indian market. [ABSTRACT FROM AUTHOR]

Introduction: Heterozygous activating mutations in KCNJ11 cause both permanent and transient neonatal diabetes. A minority of patients also have neurological features. Early genetic diagnosis has important therapeutic implications as treatment with sulfonylurea provides good metabolic control and exerts a protective effect on neuromuscular function. Case Presentation: A term female infant with normal birth weight (2.73 kg, z-score: −1.69) was admitted to the Neonatal Unit at Addenbrookes Hospital. She had been antenatally diagnosed with KCNJ11 mutation-R201C inherited from her glibenclamide-treated mother who continued sulfonylurea treatment throughout pregnancy. A continuous glucose-monitoring system inserted at 20 h of age showed progressive rise of blood glucose concentrations, prompting treatment with glibenclamide on day 2 of life. Initial attempts to treat with an extemporaneous solution of glibenclamide (starting dose 0.2 mg/kg/day) resulted in inconsistent response and significant hypoglycaemia and hyperglycaemia. A licenced liquid formulation of glibenclamide (AMGLIDIA) at a starting dose of 0.05 mg/kg/day was used with stabilization of blood glucose profile within 24 h. Other than a mild transient elevation in transaminase, treatment was well tolerated. At most recent review (age 12 months), the patient remains well with age-appropriate neurodevelopment. Overall glucose control is reasonable with estimated HbA1c of 7.6% (59.9 mmol/mol). Conclusion: Early postnatal glibenclamide treatment of insulin-naive patients with KATP-dependent neonatal diabetes is safe, provides good metabolic control, and has a potential protective effect on neurological function. The formulation of the medicine needs to be carefully considered in the context of the very small doses required in this age group. [ABSTRACT FROM AUTHOR]

Mexico has been under official epidemiological alert due to diabetes since 2016. This study presents new information on the frequency and variants of metformin transporters OCT1, OCT2, OCT3, ABCB1, and CYP2C9 variants as well. It also reports the association with HbA1c control on 103 DMT2 patients. They were genotyped through real-time PCR (TaqMan assays) and grouped according to treatment: metformin and metformin + glibenclamide. Metformin plasmatic levels were determined through mass spectrometry. The analysis of HbA1c showed statistical significance across genotypes in polymorphisms rs72552763 (p = 0.022), rs622342 (p = 0.009), rs1128503 (p = 0.021), and rs2032582 (p = 0.009) within the monotherapy group. Bivariate analysis found no association between any polymorphism and HbA1c control. Two logistic regression models accounted for two diplotypes in OCT1 and ABCB1, including statistically significant covariates. The first model yielded significance in age (p = 0.026), treatment period [p = 0.001], BMI ≥ 25 kg/m2 (p = 0.043), and combined therapy (p < 0.001). There was no association with GAT/GAT of rs72552763 or A/A rs622342 in OCT1. The second model yielded significance in age (p = 0.017), treatment period (p = 0.001), BMI ≥ 25 kg/m2 (p = 0.042), and combined therapy (p < 0.001), finding no association with C/C of rs1128503 or G/G of rs2032582 in ABCB1. Our multinomial logistic regression results may benefit future predictive analyses in diabetic populations. [ABSTRACT FROM AUTHOR]

Sulphonylureas (SU) form an important role in management of people with type 2 diabetes. This safety history of SU was tainted for various reasons, the predominant one being lack of demonstration of cardiovascular safety. Since its introduction, SU's have never been subjected to a formal study for its cardiovascular safety. The cardiovascular safety of SUs was derived from small, inadequately powered randomised controlled trials (RCT) and observational studies. CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) trial planned as a cardiovascular outcome trial randomised people with type 2 diabetes and high cardiovascular risk to Linagliptin and Glimepiride. This opinion paper outlines the salient features of this landmark trial and its implications in general cardiology practice.

Aim: To report the results of a 104‐week extension to a 52‐week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin. Materials and methods: This extension to a 52‐week global, multicentre, parallel‐group, active‐controlled, double‐blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1‐6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5‐91.3 mmol/mol [7.5%‐10.5%]), and a body mass index of 20.0 to 45.0 kg/m2, and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy. Results: Overall, 382 participants entered and 338 completed the 104‐week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156‐week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39‐0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23‐3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least‐squares mean difference from GLIM+MET −4.89%, −0.41 L and −0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents. Conclusions: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D. [ABSTRACT FROM AUTHOR]

Aims: To determine whether adiposity modified the effect on the cardiovascular safety of sulphonylureas as a first‐line therapy compared with metformin among patients with type 2 diabetes. Materials and Methods: Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulphonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction [MI], ischaemic stroke, cardiovascular mortality), and all‐cause mortality, comparing use of sulphonylureas with use of metformin, overall and within BMI categories (≤24.9 kg/m2, 25.0‐29.9 kg/m2, ≥30 kg/m2). Results: Compared with metformin, sulphonylureas were not associated with an increased risk of MACE either overall (HR 1.08, 95% CI 0.94‐1.23) or by BMI category. Similar findings were observed for MI and ischaemic stroke. By contrast, sulphonylureas were associated with an increased risk of cardiovascular mortality (HR 1.24, 95% CI 1.04‐1.48), primarily among obese patients (HR 1.52, 95% CI 1.08‐2.13), and not among normal‐weight patients (HR 1.00, 95% CI 0.72‐1.39; P‐interaction 0.21). Similar results were observed for all‐cause mortality (HR 1.47, 95% CI 1.32‐1.62), where an increased risk was observed among obese patients (HR 1.83, 95% CI 1.49‐2.25), but not normal‐weight patients (HR 1.18, 95% CI 0.99‐1.42; P‐interaction: 0.006). Conclusion: The findings of this study suggest that adiposity may have a modifying effect on the association between sulphonylureas and cardiovascular and all‐cause mortality compared with metformin. [ABSTRACT FROM AUTHOR]

Aims: Studies examining the prevalence of and factors associated with switching from sulphonylureas (SUs) to dipeptidyl peptidase 4 (DPP‐4) inhibitors in real‐world settings are lacking. We assessed the factors associated with switching from SUs to DPP‐4 inhibitors in the United States. Materials and Methods: This retrospective cohort study was conducted using the Optum Clinformatics® Data Mart (2009‐2018). Adults with type 2 diabetes and newly prescribed at least two SUs were included and were followed for 2 years after the initiation of SU (index date). We compared the characteristics of those who switched from SUs to DPP‐4 inhibitors (only; no additional antidiabetic drugs) with those who continued with SUs (without adding other antidiabetic drugs) using multivariate logistic regression. Multinomial regression analyses were also conducted to assess the factors associated with switching to different drug classes versus continuation with SUs. Results: In a sample of 119 107 new SU users, 2.2% (2633) switched to DPP‐4 inhibitors, 3.8% (4542) switched to antidiabetic drugs other than DPP‐4 inhibitors, 68.3% (81 394) discontinued SUs but did not switch to another antidiabetic drug, 12.9% (15 345) continued with SUs and added other antidiabetic drugs, and 12.8% (15 193) continued with SUs only. Multivariate logistic regression showed that those who had significantly higher likelihood of switching were younger, female [vs. males; adjusted odds ratio (AOR) = 0.70], and living in the south; had previous use of DPP‐4 inhibitors (AOR = 1.71); were not using antidiabetic drugs at baseline; had more baseline diabetes‐related emergency room visits (AOR = 1.13), depression (AOR = 1.34), post‐index hypoglycaemia (AOR = 2.20), and an earlier index year; and were glyburide users (vs. glimepiride users; AOR = 1.29). Conclusions: The discontinuation rate for SUs is high. Factors associated with switching from SUs to DPP‐4 inhibitors included age, sex, geographic region, baseline antidiabetic drug use, type of SU, baseline diabetes‐related emergency room visits, hypoglycaemia and depression. [ABSTRACT FROM AUTHOR]

Despite the importance of individualised strategies for patients with type 2 diabetes mellitus (T2DM) and the availability of alternative treatments, including glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), sulphonylureas are still widely used in practice. Clinical evidence shows that GLP‐1 RAs may provide better and more durable glycaemic control than sulphonylureas, with lower risk of hypoglycaemia. Other reported benefits of GLP‐1 RAs include weight loss rather than weight gain (as observed with sulphonylureas), blood pressure reduction and improvement in lipid profiles. In general, the main adverse events with GLP‐1 RAs are gastrointestinal in nature. The respective modes of action of GLP‐1 RAs and sulphonylureas contribute to differences in the durability of glycaemic control (related to effects on beta‐cells) and effects on body weight. Moreover, the glucose‐dependent mode of action of GLP‐1 RAs, which favours a low incidence of hypoglycaemia, contrasts with the glucose‐independent mode of action of sulphonylureas. Evidence from cardiovascular outcomes trials indicates a consistent finding of cardiovascular safety across the GLP‐1 RAs and suggests a class benefit for the long‐acting GLP‐1 RAs in reducing three‐point major adverse cardiovascular events, cardiovascular mortality and all‐cause mortality. In contrast, potential concerns relating to an increased incidence of adverse cardiovascular events with sulphonylureas have yet to be fully resolved. Recent updates to management guidelines recommend that treatment selection for patients with T2DM should consider clinical trial evidence of cardiovascular safety. Available evidence suggests that this selection should give preference to GLP‐1 RAs over sulphonylureas, especially for patients at high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background. Diabetic management during Ramadan fasting is a significant clinical challenge. Sodiumglucose co-transporter -2 inhibitors (SGLT2i) are a new class of antidiabetic medications known for the low frequency of associated hypoglycaemia. The present study aimed to evaluate the efficacy, safety and tolerability of SGLT2i in diabetic patients practising Ramadan fasting. Methods. The study included 94 patients. They comprised 51 patients who received metformin and sulfonylureas (SU): glimepiride (1-6 mg/d) or gliclazide MR (60-120 mg/d) and 43 patients who received metformin and SGLT-2 inhibitors: empagliflozin (25 mg), dapagliflozin (10 mg) or canagliflozin (300 mg). The study outcome parameters were frequency of hypoglycaemia episodes, volume depletion episodes, number of days with early fasting break and missed fasting days. Results. patients of SGLT-2i group experienced significantly fewer symptomatic (9.3% vs 35.3%, P = = 0.003) and documented (7.0% vs 25.5%, P = 0.017) hypoglycaemic episodes compared to those of SU group. However, there were no significant differences between the studied groups regarding the frequency of patients with volume depletion episodes (5.9% vs 16.3%, P = 0.1). Moreover, there were no significant differences between groups regarding the frequency of patients with early fasting break (11.8% vs 9.3%, P = 0.7) or missed fasting (3.9% vs 2.3%, P = 0.66). None of the studied patients discontinued the prescribed medications. Conclusions. The use of SGLT-2 inhibitors combined with metformin for diabetic patients during Ramadan fasting is effective, safe and well-tolerated with the advantage of reduced hypoglycaemic events. [ABSTRACT FROM AUTHOR]

Objective: To examine trends in the noninsulin drug treatment of type 2 diabetes, including first‐ and second‐line therapies on top of metformin, from 2015 to 2019. Participants and Methods: We conducted a descriptive analysis of cross‐sectional data using the IQVIA National Disease and Therapeutic Index, a nationally representative audit of ambulatory physician practices in the United States. We focused on the use of noninsulin pharmacological treatments for type 2 diabetes among individuals aged 35 years and older between January 1, 2015 and December 31, 2019. The main outcome was type 2 diabetes visits where a prescription drug was used ("treatment visit"). Results: Ambulatory diabetes visits decreased from 30.1 million treatment visits in 2015 to 29.5 million treatment visits in 2019. Among treatment visits where a single drug was prescribed, the use of metformin declined from 57.0% of monotherapy in 2015 to 46.0% of monotherapy in 2019, while during the same period the share of monotherapy accounted for by glucagon‐like peptide‐1 (GLP‐1) receptor agonists increased from 4.3% to 8.5% and the share accounted for by sodium‐glucose cotransporter‐2 (SGLT2) inhibitors increased from 7.3% to 19.5%. Among treatment visits where metformin plus another drug was prescribed, the share of second‐line therapy accounted for by dipeptidyl peptidase‐4 (DPP‐4) inhibitors decreased from 21.9% of treatment visits in 2015 to 20.8% of treatment visits in 2019; sulphonylurea use declined from 45.2% to 32.7%, use of SGLT2 inhibitors increased from 14.5% to 21.2% and use of GLP‐1 receptor agonists increased from 9.8% to 18.2%. Conclusions: Significant changes in the landscape of ambulatory care for diabetes have taken place during the past 6 years, including moderate declines in metformin monotherapy, moderate declines in second‐line sulphonylurea use, and large increases in SGLT2 use. These changes underscore the dynamic nature of drug utilization for diabetes in the United States, and reflect the effects of emerging evidence, evolving clinical guidelines and evolving regulatory and payment policies. [ABSTRACT FROM AUTHOR]

Sulphonylureas are widely used in the treatment of Diabetes mellitus, one of the main causes of death in human population. Their determination is essential in pharmacological research and in the development of new drugs. Generally, determination of sulphonylureas in biological matrices is performed using conventional sample preparation techniques, which frequently leads to an increase of analysis time and errors. In this context, a bioanalytical method for the simultaneous determination of sulphonylureas by direct injection of human plasma was developed and optimized. An automated column-switching high performance liquid chromatographic system with a restricted access media (RAM) column coupled to a fused-core column was employed. At the first dimension, a RAM column with mobile phase of ultrapure water pH 6.0 at a flow-rate of 1.0 mL min-1 was used. The valve switching time was 3 minutes. At the second dimension, a C18 guard-column coupled to a C18 fused core column with mobile phase of acetonitrile and 10 mM phosphate buffer pH 3.0 (54:46 v/v) at a flow-rate of 0.8 mL min-1 were employed. The column switching system was performed in backflush configuration with an analyte elution time of 1 minute. Flufenamic acid was used as the internal standard. The mean plasma protein exclusion percentage by the RAM-column was 104.5%. The developed and optimized method showed to be fast and simple, allowing the direct injection of biological sample into the chromatographic system and the simultaneous determination of three sulphonylureas in only 12 minutes, including the sample treatment, separation and detection.

Aims/hypothesis: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM.Methods: Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration.Results: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)].Conclusions/interpretation: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

Mexico has been under official epidemiological alert due to diabetes since 2016. This study presents new information on the frequency and variants of metformin transporters OCT1, OCT2, OCT3, ABCB1, and CYP2C9 variants as well. It also reports the association with HbA1c control on 103 DMT2 patients. They were genotyped through real-time PCR (TaqMan assays) and grouped according to treatment: metformin and metformin + glibenclamide. Metformin plasmatic levels were determined through mass spectrometry. The analysis of HbA1c showed statistical significance across genotypes in polymorphisms rs72552763 (p = 0.022), rs622342 (p = 0.009), rs1128503 (p = 0.021), and rs2032582 (p = 0.009) within the monotherapy group. Bivariate analysis found no association between any polymorphism and HbA1c control. Two logistic regression models accounted for two diplotypes in OCT1 and ABCB1, including statistically significant covariates. The first model yielded significance in age (p = 0.026), treatment period [p = 0.001], BMI ≥ 25 kg/m2 (p = 0.043), and combined therapy (p < 0.001). There was no association with GAT/GAT of rs72552763 or A/A rs622342 in OCT1. The second model yielded significance in age (p = 0.017), treatment period (p = 0.001), BMI ≥ 25 kg/m2 (p = 0.042), and combined therapy (p < 0.001), finding no association with C/C of rs1128503 or G/G of rs2032582 in ABCB1. Our multinomial logistic regression results may benefit future predictive analyses in diabetic populations.

Aim: To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses. Materials and Methods: People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1 to 4 mg. The primary endpoint was time to first occurrence of three‐point major adverse CV events (MACE: CV death, non‐fatal myocardial infarction, or non‐fatal stroke). We evaluated clinical and safety outcomes across age groups. Results: Of 6033 participants, 50.7% were aged <65 years, 35.3% were aged 65 to 74 years, and 14.0% were aged ≥75 years. During the 6.3‐year median follow‐up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for three‐point MACE 0.98, 95.47% confidence interval [CI] 0.84, 1.14) or across age groups (interaction P >0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate‐to‐severe hypoglycaemia was markedly reduced with linagliptin (HR 0.18, 95% CI 0.15, 0.21) with no differences among age groups (P = 0.23). Mean weight was −1.54 kg (95% CI –1.80, –1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin. Conclusions: Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk of hypoglycaemia and falls or fractures than glimepiride, including in "older‐old" individuals for whom these are particularly important treatment considerations. [ABSTRACT FROM AUTHOR]

Introduction: Recent guidelines for the treatment of type 2 diabetes mellitus (T2DM) provide evidence supporting limited use of sulphonylureas (SUs), especially in specific risk patient categories, yet data from national registries still suggest their widespread use. The aim of this study was to investigate characteristics of patients with diabetes treated with SUs and quantify the proportion of patients that met the recommendations for use of SUs by recent guidelines and of those presenting characteristics representing an inappropriate prescription risk (IPR). Methods: A multicenter, retrospective, cross-sectional, observational study in patients with T2DM receiving treatment with SUs (as monotherapy or in combination with another diabetes therapy) was conducted between 2017 and 2018 in 22 outpatient diabetes clinics across Italy. Exclusion criteria were type 1 diabetes, diabetes mellitus secondary to other conditions, and presence of severe/life-threatening diseases. Results: A total of 510 patients with T2DM (306 men, 204 women; mean age ± standard deviation 69.8 ± 9.3 years) who were receiving treatment with a SU (as monotherapy or in combination therapy) were assessed in the study. Overall, 70.6% [n = 360; 95% confidence interval (CI) 66.4%, 74.5%] were assessed to have an IPR. Of these, approximately half presented one factor for risk of inappropriate prescription, and 27 and 10.6% presented two and three factors, respectively. In terms of factors contributing to the total burden of risk of inappropriate treatment with SUs, 37.5% (95% CI 33.2%, 41.8%) of all patients were obese; 33.3% (95% CI 29.3%, 37.6%)] were aged ≥ 75 years; 18.6% (95% CI 15.3%, 22.3%) had a history of cardiovascular disease; 14.1% (95% CI 11.2%, 17.4%) had chronic renal insufficiency; 1.8% (95% CI 0.8%, 3.3%) had a history of severe hypoglycemia; 1.8% (95% CI 0.8%; 3.3%) had cognitive impairment; and 2.4% (95% CI 1.2%, 4.1%) had a risky occupation. Conclusions: The results of this study provide evidence of a high rate of inappropriate SU prescription risk among patients with T2DM, especially among those with overweight/obesity, older age, history of cardiovascular disease, and hypoglycemia. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is an unusual form of diabetes with specific features that distinguish it from type 1 and type 2 diabetes. There are 14 known subtypes of MODY, and mutations in three genes (HNF1A, HNF4A, GCK) account for about 95% of all MODY cases. Diagnosis usually occurs before the age of 25 years, although less frequent forms may occur more often—but not necessarily—later in life. The molecular diagnosis may tailor the choice of the most appropriate treatment, with the aim to optimize blood glucose control, reduce the risk of hypoglycemic events and long-term complications, and enable proper genetic counseling. Treatment is usually unnecessary for patients with mutations in the GCK gene, while oral hypoglycemic agents (generally sulphonylureas) are recommended for patients with mutations in the HNF4A and HNF1A genes. More recent data show that other glucose-lowering agents can be effective in the latter patients, and additional and alternative therapies have been proposed. Proper management guidelines during pregnancy have been developed for carriers of GCK gene mutations, but such guidelines are still a subject of debate in other cases, although some recommendations are available. The other subtypes of MODY are even more rare, and very little data are available in the literature. In this review we summarize the most pertinent findings and recommendations on the treatment of patients with the different subtypes of MODY. Our aim is to provide the reader with an easy-to-read update that can be used to drive the clinician's therapeutical approach to these patients after the molecular diagnosis. [ABSTRACT FROM AUTHOR]

In the last 3 decades, four large multicentre, randomized clinical trials of patients with type 2 diabetes (UKPDS, ADVANCE, ACCORD and VADT) have studied different approaches to achieving near normal glycaemic targets. Each was designed against a background of international and national guidelines recommending glycaemic targets of 6.5% or less to prevent diabetic complications. Collectively, these clinical trials provide the most robust evidence of the potential vascular benefits and risks of more versus less glucose control and provide critical insights into how therapies are used. In this review, the glucose‐lowering approach used by the ADVANCE trial is considered and compared with those used by the other trials. [ABSTRACT FROM AUTHOR]

Clonal insulin-secreting BRIN-BD11 cells were used to examine effects of chronic 72-144 h exposure to the sulphonylureas tolbutamide and glibenclamide on insulin release, cellular insulin content, and mRNA levels of the Kir6.2 and SUR1 subunits of the beta-cell KATP channel. Chronic exposure for 72-144 h to 5-100 µM tolbutamide and glibenclamide resulted in a time- and concentration-dependent irreversible decline in sulphonylurea-induced insulin secretion. In contrast, the decline in cellular insulin content induced by chronic exposure to high concentrations of sulphonylureas was readily reversible. Chronic exposure to tolbutamide or glibenclamide had no effect upon transcription of the Kir6.2 or SUR1 subunits of the pancreatic beta-cell KATP channel. Whilst further studies are required to understand the precise nature of the chronic interactions of sulphonylurea with the insulin exocytotic mechanism, these observations may partially explain the well-known progressive failure of sulphonylurea therapy in type 2 diabetes.

With the growing prevalence of type 2 diabetes, particularly in emerging countries, its management in the context of available resources should be considered. International guidelines, while comprehensive and scientifically valid, may not be appropriate for regions such as Asia, Latin America or Africa, where epidemiology, patient phenotypes, cultural conditions and socioeconomic status are different from America and Europe. Although glycaemic control and reduction of micro- and macrovascular outcomes remain essential aspects of treatment, access and cost are major limiting factors; therefore, a pragmatic approach is required in restricted-resource settings. Newer agents, such as sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in particular, are relatively expensive, with limited availability despite potentially being valuable for patients with insulin resistance and cardiovascular complications. This review makes a case for the role of more accessible second-line treatments with long-established efficacy and affordability, such as sulfonylureas, in the management of type 2 diabetes, particularly in developing or restricted-resource countries. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether weight change or hypoglycaemia mediates the association between insulin use and death. Materials and Methods: In a retrospective cohort of veterans who filled a new prescription for metformin and added insulin or sulphonylurea (2001‐2012), we assessed change in body mass index (BMI) and hypoglycaemia during the first 12 months of treatment intensification. Cox proportional hazards models compared the risk of death between treatment groups. Using the difference method, we estimated the indirect effect and proportion mediated through each mediator. A sensitivity analysis assessed mediators in the first 6 months of intensified therapy. Results: Among 28 892 patients surviving 12 months, deaths per 1000 person‐years were 15.4 for insulin users and 12.9 for sulphonylurea users (HR 1.20, 95% CI 0.87, 1.64). Change in BMI and hypoglycaemia mediated 13% (−98, 98) and −1% (−37, 71) of this association, respectively. Among 30 214 patients surviving 6 months, deaths per 1000 person‐years were 34.8 for insulin users and 21.3 for sulphonylurea users (HR 1.66, 95% CI 1.28, 2.15). Change in BMI and hypoglycaemia mediated 9% (1, 23) and 0% (−9, 4) of this association, respectively. Conclusions: We observed an increased risk of death among metformin users intensifying treatment with insulin versus sulphonylurea and surviving 6 months of intensified therapy, but not among those surviving 12 months. This association was mediated in part by weight change. [ABSTRACT FROM AUTHOR]

Summary: Certain glucose‐lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that thiazolidinedione use is associated with a higher risk of fracture, the effects of metformin, insulin, and sulphonylureas on the risk of fracture remain equivocal because these medications are not generally investigated in RCTs. A meta‐analysis of observational studies to provide further insights into the association between the use of metformin, insulin, sulphonylureas, or thiazolidinediones and the risk of fracture was performed. PubMed and Web of Science databases were searched to identify relevant observational studies. A random effects model was used to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). The use of insulin (RR 1.49, 95% CI 1.29, 1.73; n = 23 studies), sulphonylureas (RR 1.30, 95% CI 1.18, 1.43; n = 10), and thiazolidinediones (RR 1.24, 95% CI 1.13, 1.35; n = 14) was associated with an increased risk of fracture, whereas the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95% CI 0.75, 0.99; n = 12). Regarding types of thiazolidinediones, both pioglitazone (RR 1.38, 95% CI 1.23, 1.54; n = 5) and rosiglitazone (RR 1.34, 95% CI 1.14, 1.58; n = 5) were positively associated with the risk of fracture. In summary, there is compelling evidence to discourage the use of thiazolidinediones in individuals with an increased risk of fracture, whereas metformin appears to have a good safety profile for the risk of fracture. The reduced risk of fracture with metformin could possibly be due to the reduced overall risk of fracture among metformin users, as this medication is typically prescribed in the early stages of type 2 diabetes mellitus. The use of insulin or sulphonylureas may increase fracture risk; this risk is most likely attributed to an increased risk of hypoglycaemia‐induced falls. Further confirmation by additional RCTs is required to determine whether the observed association between the use of metformin, insulin, or sulphonylureas and the risk of fracture is due to treatment with these medications or confounding factors. [ABSTRACT FROM AUTHOR]

Aims: Two medication change protocols were tested, both based on haemoglobin A1c (HbA1c), with one protocol also accounting for hypoglycaemic events. The aim was to compare the two protocols during intermittent energy restriction (5:2 diet).Methods: Forty-two adults with type 2 diabetes (HbA1c ≥ 7% [53 mmol/mol], BMI of ≥27 kg/m2) treated with sulphonylureas and/or insulin were recruited and randomised 1:1 to fixed or adjusted medication protocols. Participants experiencing hypoglycaemia during a 2-week usual diet period then followed the 5:2 diet for 2 weeks (2 non-consecutive very-low-calorie days [500-600 kcal] and 5 habitual eating days/week), following the allocated medication protocol. The primary outcome was to determine if the adjusted protocol was superior to the fixed protocol at reducing hypoglycaemic events during the 5:2 diet. Flash glucose monitoring was used throughout to detect hypoglycaemia.Results: There was a significant difference in change in the number of hypoglycaemic events between fixed and adjusted protocols (-1.0 vs. -3.5; P = 0.04). Over 60% of participants on the adjusted protocol had no hypoglycaemic events.Conclusions: This pilot study demonstrates the importance of assessing the risk of hypoglycaemia before starting a 5:2 diet and that the adjusted medication protocol is likely the best option for patients at risk.Clinical Trial Registry: This study has been registered with the Australia New Zealand Clinical Trial Registry (ANZCTR) www.anzctr.org.au and given the registration number ACTRN12617000512325. [ABSTRACT FROM AUTHOR]

The role of sulphonylureas (SUs) in modern clinical practice poses ongoing clinical debate. With the advent of newer agents in diabetes management, there is an increasing shift away from the prescribing of SUs, but not necessarily to more effective agents. This review provides a different perspective on the debate, reflecting in depth upon the physiology of SUs, drawing on insights gained from monogenic diabetes to highlight the potential benefit of lower doses of SUs, and the probable benefit of gliclazide over most other, if not all SUs, in terms of sulphonylurea failure and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Introduction / Purpose: It is well known that diabetes mellitus (DM) is a chronic condition with increasing prevalence. In Greece, the percentage of diabetic patients is 8.7%, while the percentage of pre-diabetics is estimated at 6.4%. The present study aims to register the reasons why patients with DM visited the emergency department of General Hospital of Piraeus «Tzaneio» the years 2009-2017. Material and Method: The archives of the years 2009, 2011, 2013, 2015 and 2017 of the emergency department (ED) of the First Department of Internal Medicine were used for the register. Overall, data from 957 patients (452 males/505 females - mean age ± standard deviation: 70.1± 14.6 years) were recorded. The medication for diabetes, the reason for visiting (hypoglycemia or diabetic ketoacidosis) and the outcome (admission or not) were recorded as well. Results: The total number of diabetic patients that visited the ED was for the year 2009 302 patients, for 2011 221 patients, for 2013 140 patients, for 215 126 patients and for 2017 168 patients. The rate of diabetics that visited the ED because of hypoglycemia was for 2009 14.1%, for 2011 7.2%, for 2013 5%, for 2015 4.8% and for 2017 10.1%. The rate of sulpholynurea-induced hypoglycemic episodes was for 2009 24.1%, for 2011 25.3%, for 2013 16.9%, for 2015 29.2% and for 2017 20.8%. As for diabetic ketoacidosis, it accounts for 4.4% in 2009, 4.5% in 2011, 10% in 2013, 1.6% in 2015 and 1.2% in 2017 of the ED visits. Finally, the percentage of admissions in the First Department of Internal Medicine for patients with DM, independently of reason for visiting, was 3.61% in 2009, 4.49% in 2011, 6.9% in 2013, 3.5% in 2015 and 5.15% in 2017. Conclusions: The total number of diabetic patients that visited the ED was for the year 2009 302 patients, for 2011 221 patients, for 2013 140 patients, for 215 126 patients and for 2017 168 patients. The rate of diabetics that visited the ED because of hypoglycemia was for 2009 14.1%, for 2011 7.2%, for 2013 5%, for 2015 4.8% and for 2017 10.1%. The rate of sulpholynurea-induced hypoglycemic episodes was for 2009 24.1%, for 2011 25.3%, for 2013 16.9%, for 2015 29.2% and for 2017 20.8%. As for diabetic ketoacidosis, it accounts for 4.4% in 2009, 4.5% in 2011, 10% in 2013, 1.6% in 2015 and 1.2% in 2017 of the ED visits. Finally, the percentage of admissions in the First Department of Internal Medicine for patients with DM, independently of reason for visiting, was 3.61% in 2009, 4.49% in 2011, 6.9% in 2013, 3.5% in 2015 and 5.15% in 2017. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether tight glycaemic control achieved with metformin, insulin or sulphonylurea‐based pharmacotherapy increases all‐cause mortality in older people with type 2 diabetes. Materials and Methods: We conducted a prospective cohort study of individuals with known diabetes recruited between 2008 and 2011 and followed until 2016. The impact of baseline glycated haemoglobin (HbA1c) on mortality hazards was investigated in participants aged ≥75 years. Proportional hazards models for time to death were constructed from the baseline clinical assessment, then the variables of interest (HbA1c, treatment category and their interactions) were entered. Results: There were 367 participants (mean age 80.1 ± 3.9 years, median [interquartile range] HbA1c 50 [45‐56] mmol/mol or 6.7 [6.3‐7.3]%) who were followed for a median (interquartile range) 6.7 (4.5‐7.7) years, during which 40.9% of the participants died. At baseline, 60.4% were on metformin‐based treatment, 35.3% on sulphonylurea‐based treatment and 23.2% on treatment including insulin. Baseline HbA1c was significantly associated with mortality in a model that included interactions between HbA1c and the three treatment‐based groups compared with non‐pharmacological treatment. The metformin treatment group had higher mortality when HbA1c levels were <48 mmol/mol (<6.5%) and the sulphonylurea and insulin treatment groups had higher mortality when HbA1c levels were <52 mmol/mol (<7.0%), with hazard ratios of 2.63 (95% confidence interval [CI] 1.39‐4.97), 2.49 (95% CI 1.14‐5.44) and 2.22 (95% CI 1.12‐4.43), respectively. Conclusions: Tight glycaemic control may be hazardous in older people with type 2 diabetes when achieved with pharmacotherapy with metformin, and especially with insulin or sulphonylureas. These data confirm that overtreatment is likely to be an important clinical problem in this vulnerable population. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and safety of dapagliflozin and dapagliflozin plus saxagliptin vs glimepiride as add‐on to metformin in patients with type 2 diabetes. Research design and methods: This 52‐week, multicentre, double‐blind, active‐controlled study (NCT02471404) randomized (1:1:1) patients (n = 939; HbA1c 7.5%‐10.5%) on metformin monotherapy (≥1500 mg/day) to add‐on dapagliflozin 10 mg, dapagliflozin 10 mg plus saxagliptin 5 mg, or glimepiride 1 to 6 mg (titrated). The primary efficacy end point was change in HbA1c from baseline to Week 52. Results: Baseline mean age, diabetes duration and HbA1c were 58.4 years, 7.0 years and 8.3%, respectively. Adjusted mean HbA1c change from baseline was −1.20% with dapagliflozin plus saxagliptin and −0.82% with dapagliflozin, vs −0.99% with glimepiride (mean dose at Week 52, 4.6 mg). Changes in body weight (−3.2 kg and −3.5 kg vs +1.8 kg) and systolic blood pressure (SBP; −6.4 mm Hg and −5.6 mm Hg vs −1.6 mm Hg) were significantly greater with dapagliflozin plus saxagliptin and dapagliflozin than with glimepiride. FPG decreased significantly with dapagliflozin plus saxagliptin compared with glimepiride (−2.1 mmol/L vs −1.5 mmol/L) and was similar with dapagliflozin (−1.6 mmol/L) compared with glimepiride. Confirmed incidence of hypoglycaemia was lower with dapagliflozin regimens than with glimepiride (0 and 1 vs 13 patients) and fewer patients required rescue. Genital infections were more frequent with dapagliflozin; other AE profiles were similar. Conclusions: Dapagliflozin, saxagliptin and metformin improved glycaemic control compared with glimepiride plus metformin; add‐on of dapagliflozin alone showed efficacy similar to that of glimepiride. Both dapagliflozin regimens decreased body weight and SBP, with a lower incidence of hypoglycaemia compared with glimepiride. [ABSTRACT FROM AUTHOR]

Aim: To explore if clinical effects and hypoglycaemia risks associated with insulin glargine 300 U/mL (Gla‐300) and 100 U/mL (Gla‐100) differed by sulphonylurea and/or glinide (SU/G) treatment. Methods: A post hoc subgroup analysis of 12‐month treatment data from the EDITION Japan 2 trial, a randomized, open‐label, phase 3 study of Japanese people with type 2 diabetes receiving once‐daily Gla‐300/Gla‐100 + oral antihyperglycaemic drugs. Participants previously receiving SU/G (+SU/G) were compared with those not taking SU/G (‐SU/G). Endpoints included HbA1c, hypoglycaemia and body weight. Results: For +SU/G (n = 152, 63%), HbA1c was reduced from baseline to month 12 for Gla‐300 (8.1% to 7.6%) and Gla‐100 (8.2% to 7.8%). For ‐SU/G (n = 89, 37%), reductions were 7.8% to 7.4%, and 7.9% to 7.5% for Gla‐300 and Gla‐100, respectively. A lower annualized rate of hypoglycaemia with Gla‐300 versus Gla‐100 was observed at night (00:00–05:59 hours; p = 0.0001) and any time of day (24 hour; p = 0.0015). Irrespective of the insulin used, the incidence and rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia appeared higher in +SU/G versus ‐SU/G; overall, a reduced incidence of nocturnal hypoglycaemia, and rate of hypoglycaemia at any time, was observed in ‐SU/G versus +SU/G. In the ‐SU/G subgroup, body weight gain differences were observed between Gla‐300 and Gla‐100 (p < 0.0001). Conclusions: Participants with prior and continued SU/G use had similar therapeutic responses with basal insulin but greater risk of hypoglycaemia than those not using SU/G; hypoglycaemia risk was lower with Gla‐300 than Gla‐100 in both subgroups. [ABSTRACT FROM AUTHOR]

TOSCA.IT is an institutional, non-industry-supported, head-to-head study comparing long term cardiovascular effects, efficacy and safety of two antidiabetes drugs (pioglitazone vs sulphonylureas) used in combination with metformin in patients with type 2 diabetes mellitus. The study results show that in the absence of clinically evident cardiovascular disease both treatment strategies represent suitable alternatives; however, in consideration of the greater durability of the metabolic effects, the lower risk of hypoglycemia and the potential benefit on atherosclerotic cardiovascular disease, the combination of metformin and pioglitazone may be considered as the preferential therapeutic option. In this review the study is critically evaluated against the background of the evidence accumulated over the last decade on the impact of different glucose lowering drugs on cardiovascular events in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

We performed a meta‐analysis of randomized controlled trials (RCTs) to compare the long‐term glycaemic durability of dipeptidyl‐peptidase 4 (DPP‐4) inhibitors vs that of sulphonylureas (SUs) in patients with type 2 diabetes mellitus (T2DM), in terms of the changes in glycated haemoglobin (HbA1c) levels from an intermediate time point (26 or 52 weeks) to 104 weeks of treatment. The Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library) databases were searched for relevant RCTs. Eight RCTs were included. Compared with SUs, DPP‐4 inhibitors were associated with significantly smaller increases in the HbA1c level from 24 to 28 weeks to 104 weeks (mean difference [MD]: −0.16%, 95% confidence interval [CI]: −0.21 to −0.11; P < .001) and from 52 weeks to 104 weeks (MD −0.06%, 95% CI −0.10 to −0.02; P = .001). No significant heterogeneities were detected among the included comparisons (I2 = 0%). These results suggest that long‐term treatment with DPP‐4 inhibitors confers better durability of glycaemic response than treatment with SUs in patients with T2DM, which may indicate that DPP‐4 inhibitors better preserve islet β‐cell function compared with SUs. [ABSTRACT FROM AUTHOR]

We investigated the association between the current use of individual sulphonylureas and the risk of a first‐ever acute myocardial infarction (AMI) and all‐cause mortality, in a population‐based cohort study, using primary care data from the Clinical Practice Research Datalink database (2004‐2012). New users (N = 121 869), aged ≥18 years, with at least one prescription for a non‐insulin antidiabetic agent were included. The first prescription defined start of follow‐up. Time‐dependent Cox proportional hazard models were used to estimate the risk of a first‐ever AMI and all‐cause mortality associated with the use of individual sulphonylureas, and other non‐insulin glucose‐lowering drugs. No differences in risk of a first‐ever AMI (adjusted hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.70‐1.50) or all‐cause mortality (adjusted HR 0.97, 95% CI 0.80‐1.17) were observed when comparing gliclazide use with non‐gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated. [ABSTRACT FROM AUTHOR]

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea ( SU)-induced hypoglycaemia ( SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase ( POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty-nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three-fold higher odds of hypoglycaemia ( OR, 2.81; 95% CI, 1.30-6.09; P = .009) and better response to SU treatment (β, −0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment. [ABSTRACT FROM AUTHOR]

Aims To re-analyse data from a previous retrospective study on 127 555 patients, in which we showed that dipeptidyl peptidase-4 ( DPP-4) inhibitor therapy was associated with a lower risk of hospitalization for HF ( HHF) than sulphonylurea ( SU) therapy, in order to evaluate intraclass differences among DPP-4 inhibitors and SUs. Methods We included patients with type 2 diabetes ( T2D) initiating DPP-4 inhibitor or SU therapy, alone or in combination with metformin. Patients undergoing intraclass switch, those with a previous HHF, those receiving insulin treatment, and those with <6 months observation were excluded. We calculated the incidence of first and total HHF events/1000 person-years. Cox proportional hazard and Poisson multiple regression models, as well as propensity-score matching, were used to account for baseline confounders. Results The analysis included 17 615 DPP-4 inhibitor users (60.1% sitagliptin; 27.0% vildagliptin; 12.9% saxagliptin) and 86 734 SU users (37.5% glibenclamide; 34.6% glimepiride; 27.9% gliclazide). No intraclass difference in the incidence rate of first and total HHF events was noted among the 3 DPP-4 inhibitors or among the 3 SUs. Multivariable adjustments for baseline confounders or propensity-score matching did not change the results. In addition, no intraclass difference in HHF risk was observed in patients at high compared with low cardiovascular risk. Conclusions In a cohort of patients with T2D taken from approximately one-third of the Italian population, no intraclass difference was noted for DPP-4 inhibitor and SU therapy with regard to HHF risk. [ABSTRACT FROM AUTHOR]

Aims Certain treatments for type 2 diabetes mellitus cause hypoglycaemia and weight gain, and thus might counteract the benefits of intensive glucose control. We quantify the association of cardiovascular disease ( CVD) outcomes with hypoglycaemia and weight gain among patients with type 2 diabetes treated with sulfonylureas. Materials and Methods This cohort study included patients from January 2009 through December 2014 who were selected from within a deidentified nationwide electronic health records repository, including multiple provider networks and electronic medical records systems. Hypoglycaemia measures from structured data fields and free text clinical notes were categorized as serious or non-serious. Covariate adjusted Poisson regression analysis was used to assess the association between frequency of hypoglycaemia (by severity), or magnitude of weight change, and incidence of acute myocardial infarction ( AMI), congestive heart failure ( CHF) and stroke. Results Among 143 635 eligible patients, we observed 5669 cases of AMI, 14 109 incident cases of CHF and 7017 cases of stroke. Overall incidence rates were 1.53, 4.26 and 1.92 per 100 person-years for AMI, CHF and stroke, respectively. The associations between overall hypoglycaemia and each of the CVD outcomes were positive, with stronger associations observed for serious hypoglycaemia and attenuated or null associations observed for non-serious hypoglycaemia. Weight change exhibited a U-shaped association with increased risks associated with both weight loss and weight gain relative to stable weight. Conclusions This study provides evidence of increased CVD risk associated with hypoglycaemia, especially with serious hypoglycaemia events. While associations were attenuated with non-serious hypoglycaemia, the results were suggestive of a potential increased risk. [ABSTRACT FROM AUTHOR]

Aim To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas ( SUs) vs other glucose lowering drugs in patients with T2DM ( T2DM). Materials and methods A systematic review of Medline, Embase, Cochrane and was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios ( HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. Results The systematic review identified 82 randomized controlled trials ( RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined ( HR 1.26, 95% confidence interval [ CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 ( DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors ( HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. Conclusions The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs. [ABSTRACT FROM AUTHOR]

Background Diabetes mellitus is associated with an increased risk of hip fracture. The aim of this cohort study was to investigate whether glucose-lowering drugs influence the risk of hip fracture in patients with incident diabetes. Methods A study was performed on a cohort of patients with incident type 2 diabetes. Diabetes diagnosis was defined using information from the Danish National Patient Registry and reimbursement information of glucose-lowering drugs from the Register of Medicinal Product Statistics. The period of observation was from 01.01.1996 till 31.12.2011. The primary exposure was glucose-lowering drugs and the primary endpoint was hip fracture. Unadjusted, adjusted, and propensity score adjusted Cox regressions were performed. Results 5244 patients with type 2 diabetes with a mean follow up of 5.5 years were included in the study. Use of sulphonylureas within the last 90 days was associated with hip fracture in patients with type 2 diabetes, hazard ratio 1.64 (95% confidence interval: 1.54,1.75), whereas ever use of sulohonylyreas was not associated with an increased risk of fractures. Use of sulphonylureas within the last 90 days was also associated with an increased risk of fractures at other sites. Use of glitazones within the last 90 days was associated with an increased risk of hip fracture, hazard ratio 2.07 (95% confidence interval: 1.39,3.07), whereas ever use was not associated with an increased risk. Conclusions Current use of sulphonylureas was associated with hip fracture in patients with type 2 diabetes. Speculatively, this may be due to hypoglycemia resulting in falls. [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.