Sulphonylurea Drugs Research Articles

The experience of blood glucose monitoring in people with type 2 diabetes mellitus (T2DM).

BackgroundFinger prick blood glucose (BG) monitoring remains a mainstay of management in people with type 2 diabetes (T2DM) who take sulphonylurea (SU) drugs or insulin.We recently examined patient experience of BG monitoring in people with type 1 diabetes (T1DM). There has not been any recent comprehensive assessment of the performance of BG monitoring strips or the patient experience of BG strips in people with T2DM in the UK.MethodsAn online self‐reported questionnaire containing 44 questions, prepared following consultation with clinicians and patients, was circulated to people with T2DM. 186 responders provided completed responses (25.5% return rate). Fixed responses were coded numerically (eg not confident = 0 fairly confident = 1).ResultsOf responders, 84% were treated with insulin in addition to other agents. 75% reported having had an HbA1c check in the previous 6 months.For those with reported HbA1c ≥ 65 mmol/mol, a majority of people (70%) were concerned or really concerned about the shorter term consequences of running a high HbA1c This contrasted with those who did not know their recent HbA1c, of whom only 33% were concerned/really concerned and those with HbA1c <65 mmol/mol of whom 35% were concerned.Regarding BG monitoring/insulin adjustment, only 25% of responders reported having sufficient information with 13% believing that the accuracy and precision of their BG metre was being independently checked. Only 9% recalled discussing BG metre accuracy when their latest metre was provided and only 7% were aware of the International Standardisation Organisation (ISO) standards for BG metres. 77% did not recall discussing BG metre performance with a healthcare professional.ConclusionThe group surveyed comprised engaged people with T2DM but even within this group there was significant variation in (a) awareness of shorter term risks, (b) confidence in their ability to implement appropriate insulin dosage (c) awareness of the limitations of BG monitoring technology. There is clearly an area where changes in education/support would benefit many.

Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitor drugs: Assessment of safety in Fasting Diabetics

Introduction: Ramadan is a holy month and the majority of Muslims fast in it, without considering background illnesses. SGLT-2 drugs were available for Pakistani patients recently, and this was the first year to fast in their presence.Objectives: To assess the risk of hypoglycemia in fasting diabetics using SGLT-2 drugs, comparing it with Sulphonylurea (SU) drugs. Also, a change in HbA1c and eGFR was checked. Hence, evidence was collected to recommend their use in fasting Diabetics with safety. Material and Methods: A total of 5500 patients from three different sites were included. Only 500 fulfilled the criteria of inclusion. Pregnant, lactating, advanced Chronic Kidney Disease (CKD), and those recording hypoglycemia frequently were not included. Ages between 20 to 70 years, HbA1c between 7 to 11, and patients taking SU or SGLT-2 were included. Conclusion: The eGFR was comparable in both groups post-Ramadan. HbA1c was significantly reduced in the SGLT-2 group. Bitter taste and thirst were common with the SU group. Hypoglycemia was comparable in both groups. We concluded that SGLT-2 drugs were safe during Ramadan, and caused more HbA1c reduction.

Hypoglycemia in Elderly Diabetic Patients with Good Glycemic Control attending Cardiology Out Patient Department of a Superspeciality Hospital

Objective-Clinical trials and observational studies have provided good evidence that early glycemic control leads to a reduction in complications and improved survival in diabetics. However, elevated risk of mortality has been reported at both the lower and upper ends of long-term glucose levels. Fear of hypoglycemia has been a significant factor in suboptimal glycemic control. In this retrospective analysis we aimed to identify the incidence of hypoglycemia and their precipitating factors in elderly diabetics on good glycemic control. Material and methods- Ninety seven elderly diabetic patients attending the cardiology Out-Patients Department of a super speciality private sector hospital from 1 December 2017 to 30 November 2018 were studied retrospectively. Their demographic profile, co-morbidities and pharmacological profile were recorded. Incidence of hypoglycemic episodes and their precipitating factor were then analyzed. Result-Mean age was 71.7± 6.3 years, and 64 (66%) were male. Mean duration of diabetes was 7.3± 1.3 years. All patients had type II diabetes mellitus. Mean fasting and random capillary blood glucose levels were 116.5 ±8.7 mg/dl and 169.5±13.5mg/dl, respectively. Mean HbA1c levels of the study population was 6.8±1.14. Over the study period, 23 (23.7%) patients experienced 39 episodes of any level of hypoglycemia. HbA1c Levels in the hypoglycemia group were not significantly different from those in no-hyperglycemia group (6.85±1.13 vs. 6.63±1.04). Mean random plasma glucose values were slightly higher in no-hypoglycemia group (170.9±14.5 vs 164.9±14.9), but the difference did not reach the statistical significance. There was a markedly significant difference in mean fasting plasma glucose values between hypoglycemia and no-hypoglycemia group (101.8±8.9 vs 116.5±12.7). Sulphonylurea and insulin use was more frequent in patients experiencing hypoglycemia (9.6% and 52.2% respectively) as compared with no-hypoglycemia group (33.8% and 39.1% respectively). The most common preceding event was either skipping a meal in 12(30.8%) patients or an unplanned change in diet in 23% patients. Conclusion- Patients with longstanding diabetes and loss of warning symptoms have increased risk of severe hypoglycaemic episodes. Risk of the hypoglycemic episode is better correlated with fasting plasma glucose levels and glycemic variability rather than with HbA1c Level. Sulphonylurea drug use was the only group associated with a statistically significant risk of hypoglycemia. Skipping of a meal or a sudden change in the diet and alteration in antidiabetic drug regimen are the most important precipitating factors for hypoglycemia.

Diethylnitrosamine and thioacetamide-induced hepatic damage and early carcinogenesis in rats: Role of Nrf2 activator dimethyl fumarate and NLRP3 inhibitor glibenclamide

Two-stage rat hepatocarcinogenesis model was used to induce early carcinogenesis in which thioacetamide (TAA) promotes diethylnitrosamine (DEN) initiated carcinogenesis. Dimethyl fumarate (DMF) used to treat multiple sclerosis, activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway during oxidative stress, and maintains antioxidant levels. Glibenclamide (GLB), a sulphonylurea drug used to treat type II diabetes, possesses anti-inflammatory properties and inhibits NLRP3 inflammasomes. The present study was designed to investigate the concurrent intervention of DMF and GLB on DEN + TAA-induced early hepatic carcinogenesis. DMF and GLB treatment improved DEN + TAA-induced decrease in body weight, increase in liver weight and plasma transaminases, histopathological alterations, DNA damage, and apoptosis. DMF and GLB intervention significantly ameliorated the DEN + TAA-induced alterations in the antioxidant (Nrf2, HO-1, SOD-1, catalase), inflammatory (NF-κB, NLRP3, ASC, caspase-1), fibrogenic (TGF-β1, collagen) and regenerative proliferative stress (GST-p, HGF, c-MET, TGFα, EGF, AFP) markers. The present results indicate that Nrf2/ARE activation and NLRP3 inhibition might be a rational approach to attenuate oxidative stress and chronic inflammation associated progression of hepatocarcinogenesis.

PPARγ Agonistic Activity of Sulphonylureas.

Sulphonylureas (SU) are known to cause weight gain. Some investigators have reported increased insulin sensitivity with some sulphonylurea agents. To review available evidence of SU agents having PPARγ agonist activity. We searched online databases of PubMed®, Embase®, Google Scholar® and Web of Science® as per current guidance, published in English, between 1st January 1970 and 31st December 2017. The search found 6 articles. None of the 1st generation SU drugs have any demonstrable PPARγ agonist activity. Most of the 2nd generation SU agents had a positive correlation between their concentration and PPARγ agonist activity except Gliclazide. The demonstrated PPARγ agonist activity was maximum in experiments with Glimepiride and Gliquidone and was seen in these in-vitro experiments at concentrations which were pharmacologically achievable in-vivo. The PPARγ agonist activity may be responsible for some sideeffect of the SU agents as weight gain. On the contrary, the clinical efficacy of the thiazolidinediones could theoretically be reduced when used in combination with the SUs with significant PPARγ agonist activity. The PPARγ agonist activity demonstrated in vitro experiments may have clinical connotations.

Design and Evaluation of Chitosan films for Transdermal delivery of Glimepiride

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. However, its oral therapy is encountered with bioavailability problems due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glimepiride. Chitosan polymer was utilized in developing transdermal films for glimepiride. Chitosan has film forming ability, bioadhesive and absorption enhancing properties. Aiming at optimizing the drug delivery and circumventing the skin barrier function, inclusion complexation of glimepiride with beta-cyclodextrin (β-CyD) as well as the use of several conventional penetration enhancers were monitored for augmenting the drug flux. The physical and mechanical properties of the prepared films were investigated using tensile testing, IR spectroscopy and X-ray diffractometry. Release studies revealed adequate release rates from chitosan films. Permeation studies through full thickness rat abdominal skin were conducted. High flux values were obtained from films comprising a combination of the drug with limonene and ethanol as well as from films containing glimepiride-β-CyD complex. In vivo studies on diabetic rats for selected formulae revealed a marked therapeutic efficacy sustained for about 48 hours. The above-mentioned results shed light on feasibility of utilizing chitosan as an effective, safe transdermal delivery system for glimepiride characterized by increased patient compliance and better control of the disease.

Interrogation of a longitudinal, national pharmacy claims dataset to explore factors that predict the need for add-on therapy in older and socioeconomically disadvantaged Australians with type 2 diabetes mellitus patients (T2DM).

The management of type 2 diabetes mellitus (T2DM) is complex. The aim of this work is to explore factors that predict the need for add-on therapy in patients with T2DM in the community. We accessed longitudinal, pharmacy payment claim records from the national Pharmaceutical Benefits Scheme (PBS) (Subsidises costs of medicines: government pays difference between patient co-payments, lower in concessional patients, and additional cost of drug.) for the period January 2006 to September 2014 (EREC/MI3127) from a 10% random sample of the Australian population validated to be representative of the population by the Australian Bureau of Statistics (ABS). Likely, T2DM patients were identified as those having been dispensed a single anti-hyperglycaemic drug (monotherapy). The time taken and possible factors that might lead to the addition of a second therapy were examined. An examination was made of trends in the co-prescription of either antihypertensive or anti-hyperlipidaemic agents in relation to the time (± 3years) of initiating an anti-hyperglycaemic agent. Most (83%) presumed T2DM patients were initiated with metformin. The average time until the second agent was added was 4.8years (95% CI 4.7-4.9). Satisfactory adherence, age, male gender, initiating therapy after 2012 and initiating with a sulphonylurea drug all were significant risks for add-on therapy. There was no overall trend in the initiation of antihypertensive and/or anti-hyperlipidaemic agents with respect to the time of anti-hyperglycaemic initiation. The usefulness of a longitudinal dataset of pharmacy-claim records is demonstrated. Over half of all older and socioeconmically disadvantaged T2DM patients captured in this longitudinal claims database will be prescribed a second anti-hyperglycaemic agent within 5years of their first drug therapy. Several factors can predict the risk of prescription of add-on therapy, and these should be considered when prescribing medications to treat T2DM.

Binding of sulphonylureas to plasma proteins - A KATP channel perspective.

Sulphonylurea drugs stimulate insulin secretion from pancreatic β-cells primarily by inhibiting ATP sensitive potassium (KATP) channels in the β-cell membrane. The effective sulphonylurea concentration at its site of action is significantly attenuated by binding to serum albumin, which makes it difficult to compare in vitro and in vivo data. We therefore measured the ability of gliclazide and glibenclamide to inhibit KATP channels and stimulate insulin secretion in the presence of serum albumin. We used this data, together with estimates of free drug concentrations from binding studies, to predict the extent of sulphonylurea inhibition of KATP channels at therapeutic concentrations in vivo. KATP currents from mouse pancreatic β-cells and Xenopus oocytes were measured using the patch-clamp technique. Gliclazide and glibenclamide binding to human plasma were determined in spiked plasma samples using an ultrafiltration-mass spectrometry approach. Bovine serum albumin (60g/l) produced a mild, non-significant reduction of gliclazide block of KATP currents in pancreatic β-cells and Xenopus oocytes. In contrast, glibenclamide inhibition of recombinant KATP channels was dramatically suppressed by albumin (predicted free drug concentration <0.1%). Insulin secretion was also reduced. Free concentrations of gliclazide and glibenclamide in the presence of human plasma measured in binding experiments were 15% and 0.05%, respectively. Our data suggest the free concentration of glibenclamide in plasma is too low to account for the drug’s therapeutic effect. In contrast, the free gliclazide concentration in plasma is high enough to close KATP channels and stimulate insulin secretion.

Population pharmacokinetics of gliclazide in normal and diabetic rabbits.

Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non-compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed-effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (ka ) were 5270ml/hr, 55700ml and 0.708hr-1 , respectively. The inter-individual variability in gliclazide CL, V and ka was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one-compartment model with first-order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.

No Impact of Pre-existing Cardiovascular Disease on Prescribing Patterns of Sulphonylureas in Denmark - A Registry-based Nationwide Study.

Uncertainty exists regarding cardiovascular (CV) safety of sulphonylureas (SUs) as reflected in package labels and treatment guidelines. This study evaluated clinical treatment practice for SUs by analysing prescription patterns for SUs relative to patient history of CV disease (CVD). Patients in Denmark initiating treatment with SU or other anti-hyperglycaemic drugs during 2006-12 were retrospectively identified using national health registries. Pre-existing (previous 12 years) overall CVD, coronary heart disease (CHD) and myocardial infarction (MI) were subsequently identified. Proportion of patients with pre-existing CVD was compared between new users of SU and new users of other anti-hyperglycaemic drugs. In total, 50,425 (42.2% females, mean ± SD age 63.3 ± 13.5 years) and 190,438 (46.5% females, age 60.3 ± 15.0 years) patients initiated treatment with SU or other anti-hyperglycaemic drugs, respectively, during 2006-12. The number of patients initiating SU treatment decreased by 63% during 2006-12. The proportion of patients with pre-existing CVD varied between 46.9% and 49.8% among new SU users versus 39.9% and 44.8% among new users of other anti-hyperglycaemic drugs. Corresponding proportions for CHD (17.9-19.9% versus 15.4-16.9%) and MI (6.3-7.5% versus 5.8-6.2%) showed the same pattern. Excluding new gliclazide users (9.6% of all new SU users) from the SU definition did not alter the results. Despite a potentially increased CV risk associated with use of SUs, pre-existing CVD did not decrease clinicians' relative prescriptions of SUs.

Potential Applications of Gliclazide in Treating Type 1 Diabetes Mellitus: Formulation with Bile Acids and Probiotics.

A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic β cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM.

Genetic Basis of Monogenic Diabetes

Advances in the understanding of monogenic causes of diabetes and the discovery of single-gene mutations responsible for different phenotypes have greatly increased our knowledge of β-cell physiology. Such advances have had implications for the individual patient diagnosed with the specific monogenic cause of diabetes, especially in maturity onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). Genetic diagnosis of MODY is also likely to have important prognostic and therapeutic implications in majority of the patients with confirmed HNF1A and HNF4A mutations. Genetic screening and analyses have helped several neonatal infants carrying mutations in the KCNJ11 and ABCC8 genes to shift from insulin treatment to oral sulphonylurea drugs. The progress in genomics of monogenic diabetic forms has helped in translating the discoveries from bench to bedside in clinical care. Therefore, there is an urgent need to incorporate genetic testing for the genes implicated in monogenic diabetes like MODY and NDM in the diabetes clinics. Discoveries in genetic research methodology and understanding of genetic etiology will have great translational implications for disease treatment and follow-up.

Pharmacological Principles Used in Patient Monitoring with Type 2 Diabetes

This study assessed the medication used in type 2 diabetes treatment, depending on the glycaemia level and set out the oral anti-diabetics which are recommended, in three study stages: admission, hospitalization and discharge. Eighty patients were selected and diagnosed with diabetes mellitus 2 type, who were registered in the diabetes and nutrition diseases department within Sf. Apostol Andrei Galati Hospital. They were subjected to a series of laboratory tests: blood count, glycosylated haemoglobin, glycaemia level. It were established main classes of anti-diabetic drugs outpatient used and the main types of anti-diabetic agents administrated to patients requiring hospitalization, compared to high glycaemia values. It was given also, the medication used to normalize blood glucose levels during hospitalization and also at discharge. The biguanides associated with sulphonylureas drugs did not provide an adequate glycaemia control, so insulin must be combined with Metformin to normalize blood glucose levels as soon as possible. Glycaemia control was improved and the hypoglycaemia risk was reduced regarding obese patient undergoing treatment with insulin, to whom biguanides were administered.

Primary care diabetes prescribing rates: latest analysis shows continued rise in volume and cost

Primary care diabetes prescribing rates: latest analysis shows continued rise in volume and cost

In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis

Recent epidemiological studies show conflicting data for the first-line anti-diabetic sulphonylureas drugs in treating cancer progression in type II diabetes patients. How sulphonylureas promote or diminish tumor growth is not fully understood. Here, we report that seven sulphonylureas exhibit different in vitro inhibition towards AKR1Cs (AKR1C1, AKR1C2, AKR1C3), which are critical steroid hormone metabolism enzymes that are related to prostate cancer, breast cancer and endometrial diseases. Interactions of the sulphonylureas and AKR1Cs were analyzed by X-ray crystallography.

Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.

Pharmacological antagonism and genetic depletion of pancreatic α2A-adrenoceptors increase insulin secretion in mice and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α2-adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α2-adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α2-adrenoceptor antagonist MK-467 alone and in combination with glibenclamide in non-diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose-dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK-467 and glibenclamide; the combinations were much more potent than glibenclamide or MK-467 alone. Furthermore, MK-467 had no effect on mean arterial pressure or heart rate in freely moving mice and did not prevent the centrally mediated hypotensive effect of the α2-adrenoceptor agonist medetomidine. Thus, peripheral blockade of α2-adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α2-adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α2-adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α2-adrenoceptor-mediated inhibition of insulin secretion.

QSAR study of some anti-hyperglycaemic sulphonylurea drugs

Sulphonylureas are widely used anti-hyperglycaemic drugs for the treatment of type 2 diabetes. The only published quantitative structure–activity relationship (QSAR) models for sulphonylurea drugs have been found to be questionable, for a number of reasons. We have re-analysed the human anti-hyperglycaemic potencies, acute mouse intraperitoneal toxicities (LD50) and plasma protein-binding abilities of the 15 drugs using multiple linear regression and obtained good QSAR models for each endpoint. The obtained QSARs all comply well with the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Validation of (Q)SARs. We could not carry out external validation of our models for acute toxicity and plasma protein-binding because of the very small datasets available.

Tetrabutylammonium methacrylate as a novel receptor for selective extraction of sulphonylurea drugs from biological fluids using molecular imprinting.

Glibenclamide (GLIB), an oral antidiabetic medication of the sulphonylurea drug family, was stoichiometrically imprinted using tetrabutylammonium methacrylate as the functional monomer, for the first time in molecular imprinting, and utilising the sulphonylurea affinity for carboxylate anions. Solution association between the drug and the novel functional monomer was studied by 1H-NMR titrations, whereby evidence of sulphonylurea deprotonation followed by the formation of "narcissistic" GLIB dimers was found when tested in CDCl3, while an affinity constant in excess of 105 L mol-1 was measured in DMSO-d6. Detailed analysis of GLIB binding on the subsequently prepared imprinted and non-imprinted polymers confirmed the deactivation of binding sites by exchange of a proton between GLIB and methacrylate, followed by extraction of the tetrabutylammonium counterion from the polymer matrix, resulting in overall reduced binding capacities and affinities by the imprinted material under equilibrium conditions. An optimised MI-SPE protocol, which included a binding site re-activation step, was developed for the extraction of GLIB from blood serum, whereby recoveries of up to 92.4% were obtained with an exceptional sample cleanup.

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review.

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups.

Molecular mechanism of sulphonylurea block of K(ATP) channels carrying mutations that impair ATP inhibition and cause neonatal diabetes.

Sulphonylurea drugs are the therapy of choice for treating neonatal diabetes (ND) caused by mutations in the ATP-sensitive K+ channel (KATP channel). We investigated the interactions between MgATP, MgADP, and the sulphonylurea gliclazide with KATP channels expressed in Xenopus oocytes. In the absence of MgATP, gliclazide block was similar for wild-type channels and those carrying the Kir6.2 ND mutations R210C, G334D, I296L, and V59M. Gliclazide abolished the stimulatory effect of MgATP on all channels. Conversely, high MgATP concentrations reduced the gliclazide concentration, producing a half-maximal block of G334D and R201C channels and suggesting a mutual antagonism between nucleotide and gliclazide binding. The maximal extent of high-affinity gliclazide block of wild-type channels was increased by MgATP, but this effect was smaller for ND channels; channels that were least sensitive to ATP inhibition showed the smallest increase in sulphonylurea block. Consequently, G334D and I296L channels were not fully blocked, even at physiological MgATP concentrations (1 mmol/L). Glibenclamide block was also reduced in β-cells expressing Kir6.2-V59M channels. These data help to explain why patients with some mutations (e.g., G334D, I296L) are insensitive to sulphonylurea therapy, why higher drug concentrations are needed to treat ND than type 2 diabetes, and why patients with severe ND mutations are less prone to drug-induced hypoglycemia.