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Background. The safety and efficacy of combination tablets of metformin plus sulfonylurea or plus dipeptidyl peptidase-4 inhibitors have not been studied previously. This study aimed to compare the efficacy and safety of Gliconorm versus Sitavia plus among patients with type 2 diabetes mellitus who fast Ramadan. Methods. This was an open-label study conducted from 1 May 2018 till 1 July 2018. People with type 2 diabetes mellitus who were drug-naive or on metformin only, with HbA1c < 10 % were included. The participants were divided into two groups. The first group was given Gliconorm (glibenclamide 5 mg + metformin 1000 mg), while the second group was given Sitavia plus (sitagliptin 50 mg + metformin 1000 mg) imme-diately after Iftar. Glycated hemoglobin (HbA1c) was measured before and after Ramadan. Several home recordings of blood glucose were collected. In addition, patients were asked to report any hypoglycemic or severe hyperglycemic episodes. Results. A total of 34 participants (18 women) (19 in the first group and 15 in the second group) were involved the study. The mean age was 49.6 ± 9.3 years. HbA1c reduced from 8.7 % (72 mmol/mol) to 7.6 % (60 mmol/mol) and from 8.7% (72 mmol/mol) to 7.7 % (61 mmol/mol) in the first and second group, respectively (p < 0.0001). Only one patient in the first group experienced one episode of hypoglycemia and hyperglycemia. Conclusion. Both medications seem to be safe and effective during Ramadan fasting.

OBJECTIVE Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. RESEARCH DESIGN AND METHODS As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10−8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10−8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10−58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10−8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10−7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Background: Hypoglycemia occurs when the blood sugar level is

У лекції розглянуті фармакологічні й клінічні аспекти використання глімепіриду, препарату сульфонілсечовини ІІІ покоління, у сучасній терапії цукрового діабету 2-го типу. Препарат має доведену ефективність і безпеку, є економічно доступним, характеризується низкою сприятливих позапанкреатичних ефектів, у тому числі кардіопротективними властивостями, що дозволяє з упевненістю рекомендувати його для лікування цукрового діабету 2-го типу.

Background Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to have kidney-protective benefits. To elucidate how antidiabetic agents prevent diabetic kidney disease progression, it is important to investigate their effect on the kidney environment in type 2 diabetes mellitus (DM) patients. Herein, we investigated the expression pattern of urinary exosome-derived microRNA (miRNA) in patients taking a combination of DPP-4 inhibitor and metformin (DPP-4 inhibitor group) and compared them with patients taking a combination of sulfonylurea and metformin (sulfonylurea group). Methods This was a prospective study involving 57 patients with type 2 DM (DPP-4 inhibitor group, n = 34; sulfonylurea group, n = 23) and healthy volunteers (n = 7). We measured urinary exosomal miRNA using the NanoString nCounter miRNA array (NanoString Technologies) across the three groups (n = 4 per each group) and validated findings using real-time polymerase chain reaction. Results Twenty-one differentially expressed candidate miRNAs were identified, and six (let-7c-5p, miR-23a-3p, miR-26a-3p, miR-30d, miR-205, and miR-200a) were selected for validation. Validation showed no significant difference in miRNA expression between the DPP-4 inhibitor and sulfonylurea groups. Only miR-23a-3p was significantly overexpressed in the diabetes group compared with the control group (DPP-4 inhibitor vs. control, p = 0.01; sulfonylurea vs. control, p = 0.007). This trend was consistent even after adjusting for age, sex, and body mass index. Conclusion There was no significant difference in urine exosome miRNA expression between diabetic participants taking DPP-4 inhibitor and those taking sulfonylurea. The miR-23a levels were higher in diabetic participants than in nondiabetic controls.

Objective The study aimed to assess the long-term persistent symptoms of patients with diabetes mellitus (DM) and COVID-19 infection at 9 months after acute infection. Methods This single-center cross-sectional study was conducted from May 20 to June 1, 2021. Results A total of 112 patients were included in the present study. The most frequently reported persistent symptoms among DM group were fatigue (p = 0.01), shortness of breath (p = 0.01), and chest pain (p = 0.02) compared to non-DM group. Sulfonylurea use was associated with persistent cough (p = 0.04). Conclusion Long-term persistent symptoms of COVID-19 infection are common among patients with DM.

Introduction In the randomized, open-label, parallel-arm, active-controlled phase III AWARD-CHN2 trial, once-weekly dulaglutide plus concomitant oral antihyperglycemic medications (OAMs) improved HbA1c over 26 weeks compared with once-daily insulin glargine in patients with type 2 diabetes mellitus (T2DM). This post-hoc subgroup analysis of AWARD-CHN2 investigated the pancreatic safety of dulaglutide in Chinese patients with T2DM, stratified by potential influencing factors. Methods Changes in pancreatic enzyme (pancreatic amylase, total amylase, and lipase) levels over 26 weeks were assessed and stratified by patient age ( 0.05) or clinically significant between-group differences for age (

Medications used to treat diabetes mellitus are heterogeneous, with widely differing safety profiles in therapeutic use and in overdose. Insulin overdose may produce severe and prolonged hypoglycemia. Sulfonylurea poisoning should be treated with octreotide, sparing intravenous dextrose where possible. Acute metformin overdose may lead to life-threatening acidosis with elevated lactate concentrations, which may require hemodialysis. Glucagon-like peptide 1 agonists and dipeptidyl peptidase 4 inhibitors are benign in overdose in diabetic patients but may produce profound hypoglycemia in nondiabetic patients. Euglycemic diabetic ketoacidosis may develop in critically ill patients taking sodium-glucose co-transporter 2 inhibitors.

Increased drug related problems in diabetic patients treated with combinations of high doses of sulfonylureas and metformin was recently reported. This review article is aimed towards the assessment of drug related problems in patients treated with low-doses of sulfonylureas and biguanides. Sulphonylureas the second most commonly used antidiabetic drugs after metformin; there have been concerns regarding the cardiovascular safety of sulfonylureas. These safety concerns initiated with the University Group Diabetes Program conducted in the 1960s, found a sulfonylurea, tolbutamide, where tolbutamide is a first-generation sulfonylurea and was associated with an increased risk of all-cause and cardiovascular problems compared with placebo. Indeed, sulfonylureas have been associated with known cardiovascular risk factors like weight gain, fluid retention, and hypoglycemia. Phenformin, a biguanide, was related to lactic acidosis and withdrawn from use after causing increased risk factors within the University Group Diabetes Program since then, a more modern biguanide, metformin, has risen to its current place because the leading oral therapy for diabetes supported its relative lack of hazard from lactic acidosis and evidence especially from a subgroup of participants in the UK Prospective Diabetes Study, that it can reduce cardiovascular risk and other drug related problems. But there are certain studies showing that combination treatment with metformin and sulfonylurea is more effective, than drugs alone in enabling glycemic control in type 2 diabetes. However, safety of such combinations deserves further investigation. Keywords: Type2 diabetes mellitus, T2DM, drug related problems, sulfonylureas, biguanides.

Osteoporosis and diabetes mellitus (DM) are widespread diseases and have a significant health burden. Type-1 diabetes mellitus (T1DM) and Type-2 diabetes mellitus (T2DM) are associated with an increased bone fracture. In T1DM, the increased risk of bone fracture is associated with low bone mass. In patients with T2DM, the risk of fracture of the bone is increased due to low quality of bone, despite increased bone mineral density (BMD). In type 2 diabetic patients, bone fragility depends on the quality of bone instead of a reduction in bone mass. Thiazolidinediones (TZD) cause differentiation of adipocytes and inhibit differentiation of osteoblast and bone marrow stromal stem cells (BMSC). In this review, we have described the effect of anti-diabetic drugs and diabetes mellitus on bone health and our finding shows that sulfonylureas and metformin have no negative effect on bone health and protect bones against fractures.

Since their inception in the commercial market in the mid-twentieth century, sulfonylureas (SUs) have remained a therapeutic option in the management of type 2 diabetes (T2D). Despite their established glucose-lowering effects, there is no consensus among global experts and modern guidelines regarding the priority of SUs in relation to other therapeutic options, given the lack of evidence that SUs are associated with a low risk of macrovascular events and excess mortality. However, findings from recent trials and real-time observations have resolved this contentious issue somewhat, albeit to varying degrees. The present consensus discusses the role of SUs in contemporary diabetes management in the Gulf Cooperation Council (GCC) countries. Regional experts from these countries gathered virtually to formulate a consensus following presentations of topics relevant to SU therapy with an emphasis on gliclazide, including long-term efficacy, cost, end-organ benefits, and side effects, based on up-to-date evidence. The present narrative review reflects the conclusions of this assembly and provides a platform upon which future guidelines for the use of SUs in the GCC can be tailored.

Hypoglycemia and acute metabolic complications (AMCs; ketoacidosis, hyperosmolarity, and coma) are glycemic outcomes that have high cost and high morbidity; these outcomes must be taken into consideration when choosing initial second-line therapy after metformin. We conducted a retrospective cohort study analyzing national administrative data from adults with type 2 diabetes mellitus who started a second-line diabetes medication (sulfonylureas [SFUs], thiazolidinediones [TZDs], glucagon-like peptide 1 [GLP-1] agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, basal insulin, or sodium-glucose contransporter 2 [SGLT-2] inhibitors) between April 1, 2011 and September 30, 2015 (N=43,288) and compared rates of hypoglycemia and AMCs. Most patients (24,506 [56.6%]) were prescribed sulfonylurea as second-line treatment, followed by DPP-4 inhibitors (7953 [18.4%]), GLP-1 agonists (3854 [8.9%]), basal insulin (2542 [5.9%]), SGLT-2 inhibitors (2537 [5.9%), and TZDs (1896 [4.4%]). Baseline rates of hypoglycemia varied more than 5-fold across initial second-line antidiabetic medication classes, and rates of AMCs varied 7-fold. Compared with patients taking an SFU, lower adjusted rates of hypoglycemia were associated with taking a DPP-4 inhibitor (63% lower rate; incidence rate ratio [IRR], 0.37; 95% CI, 0.25 to 0.57), SGLT-2 inhibitor (54% lower; IRR, 0.46; 95% CI, 0.22 to 0.94), or TZD (79% lower; IRR, 0.21; 95% CI, 0.08 to 0.56) but not a glucagon-like peptide 1 agonist or basal insulin. For AMCs, only initiation of a DPP-4 inhibitor (43% lower rate; IRR, 0.57; 95% CI, 0.41 to 0.81) was associated with a lower adjusted rate compared with SFU. Use of SGLT-2 inhibitors was not associated with a substantially increased rate of acute metabolic complications compared with SFU. Special attention still needs to be paid to glycemic outcomes when choosing a second-line diabetes therapy following metformin.

Introduction VERTIS CV is the cardiovascular outcome trial for the sodium–glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU). Methods Patients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0–10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c

Introduction Neonatal diabetes mellitus (NDM) may be transient or permanent, and the majority is caused by genetic mutations. Early diagnosis is essential to select the patients who will respond to oral treatment. In this investigation, we aimed to present the phenotype and genotype of our patients with NDM and share our experience in a single tertiary center. Methods A total of 16 NDM patients from 12 unrelated families are included in the study. The clinical presentation, age at the diagnosis, perinatal and family history, consanguinity, gender, Hemoglobin A1c (HbA1c), C-peptide, insulin, insulin autoantibodies, genetic mutations, and response to treatment are retrospectively evaluated. Results The median age at diagnosis of diabetes was five months (4 days-18 months), 6 patients with a confirmed genetic diagnosis were diagnosed after 6 months. Three patients had KCNJ11 mutations, six had ABCC8 mutations, three had EIF2AK3 mutations, and one had a de novo INS mutation. All the permanent NDM patients with KCNJ11 and ABCC8 mutations were started on SU treatment resulting in a significant increase in C-peptide level, better glycemic control, and discontinuation of insulin. Conclusions Although NDM is defined as diabetes diagnosed during the first six months of life, and a diagnosis of type 1 diabetes is known much more common between the ages of 6 and 24 months, in rare cases it may present as late as 12 or even 24 months of age. Molecular diagnosis in NDM is important for planning treatment and predicting prognosis. Therefore, genetic testing is essential in these patients.

Background Results regarding the cardiovascular (CV) effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconsistent. This study aimed to assess the effects of teneligliptin, a DPP-4 inhibitor, on the risk of major CV outcomes in type 2 diabetes mellitus (T2DM) patients compared to sulfonylurea. Methods From January 1, 2015 to December 31, 2017, we conducted a retrospective cohort study using the Korean National Health Insurance Service database. A total of 6,682 T2DM patients who were newly prescribed DPP-4 inhibitors or sulfonylurea were selected and matched in a 1:1 ratio by propensity score. The hazard ratios (HRs) for all-cause mortality, hospitalization for heart failure (HHF), all-cause mortality or HHF, myocardial infarction (MI), stroke, and hypoglycemia were assessed. Results During 641 days of follow-up, the use of teneligliptin was not associated with an increased risk of all-cause mortality (HR, 1.00; 95% confidence interval [CI], 0.85 to 1.19), HHF (HR, 0.99; 95% CI, 0.86 to 1.14), all-cause mortality or HHF (HR, 1.02; 95% CI, 0.90 to 1.14), MI (HR, 0.90; 95% CI, 0.68 to 1.20), and stroke (HR, 1.00; 95% CI, 0.86 to 1.17) compared to the use of sulfonylurea. However, it was associated with a significantly lower risk of hypoglycemia (HR, 0.68; 95% CI, 0.49 to 0.94) compared to sulfonylurea therapy. Conclusion Among T2DM patients, teneligliptin therapy was not associated with an increased risk of CV events including HHF, but was associated with a lower risk of hypoglycemia compared to sulfonylurea therapy.

AIM: This research aims to compare the effectiveness of three medicines groups in controlling glycemic and glycated hemoglobin (HbA1c) levels in the newly diagnosed diabetes mellitus type 2. METHODS: One hundred fifty newly diagnosed patients with type 2 diabetes were treated by mono therapy and divided into three groups. Each group of 50 patients was treated by one medicine: Group 1 using Diamicron MR 30 mg (Sulfonylurea) – three capsules per day, Group 2 using metformin 500 mg – 1–3 capsules per day, and Group 3 using Januvia (sitagliptin, dipeptidyl peptidase-4 inhibitor) 100 mg – 1 capsule per day. The evaluation of glucose control was based on fasting plasma glucose and HbA1c concentration and divided into three levels: Excellent, good, and poor. The assessment was carried out after every 3 months of treatment, at 3rd month, 6th month, and 12th month (WHO, 2002). RESULTS: After treatment 3, 6, and 12 months, glucose level was decreased when compared to before treatment in all three groups (pall < 0.001). At the month 6th, the groups treated by sulfonylurea and sitagliptin had lower glucose level than metformin (with p values were 0.04 and 0.01, respectively), and maintained the low glucose level from the month 6th to month 12th (with p values were 0.71 and 0.77, respectively) while glucose level of the metformin group increased (p = 0.005). HbA1c has decreased dramatically in all three groups after treatment (p values of sulfonylurea group at the month 3rd, 6th, and 12th vs. before treatment were 0.006, 0.021, and 0.001, respectively; all p values of metformin group at the month 3rd, 6th, and 12th vs. before treatment were below 0.001; all p values of sitagliptin group at the month 3rd, 6th, and 12th vs. before treatment were below 0.001). The group treated by sitagliptin got the highest ratio of excellent HbA1c control (82% after 12 months of treatment). CONCLUSION: Significant improvement of glucose and HbA1c levels was observed in all three groups. Glucose control level of group treated with sulfonylurea was markedly improved and the group treated with sitagliptin achieved optimal control of HbA1c.

Despite the extensive efforts of physicians to achieve better control and management for blood glucose level in type 2 diabetics, maintaining near normal blood glucose level in these patients remain unsatisfactory. The objective of the study was to compare the effectiveness of sulfonylureas, metformin and combination of metformin plus sulfonylureas in controlling blood glucose in type 2 diabetics. Retrospective cohort research design conducted during the period of two months from 1st November 2019 to 1st March 2020 at Northern Area Armed Forces Hospital in Hafr Al Batin- Saudi Arabia on sample of 217 diabetic patients’ files, all data coded with serial number and analyzed by SPSS program through and inferential and descriptive statistics. Mean decrease in HbA1c for metformin therapy was 1.5(%), for sulfonylurea was 1.4(%), for combination therapy was 1.9(%). Mean decrease in HbA1c fasting blood glucose for metformin therapy was 1.8(mmol/l), for sulfonylurea was 1.6(mmol/l), for combination therapy was 3(mmol/l). Mean decrease in postprandial blood glucose for metformin therapy was 3.2(mmol/l), for sulfonylurea therapy was 3(mmol/l), for combination therapy was 3.7(mmol/l). There was a significant difference between levels of HbA1c between metformin group and combination group (metformin and sulfonylurea) (p = 0.002) and also there was a significant difference between sulfonylurea group and combination group (metformin and sulfonylurea) in relation to HbA1c levels (p = 0.001). However, there was no significant difference between metformin and sulfonylurea in decreasing HbA1c (p = 0.09). In conclusion, metformin or sulfonylurea as a single therapy is similar in efficacy in reducing glycosylated hemoglobin level, fasting and post-prandial plasma glucose levels to equal degree. However, combination of both therapies resulted in significant greater control of blood glucose level.

Background Clinical guidelines recommend a stepped-escalation treatment strategy for type 2 diabetes (T2DM). Across multiple treatment strategies varying in efficacy and costs, no clinical or economic studies directly compared them. This study aims to estimate and compare the cost-effectiveness of 10 commonly used pharmacologic combination strategies for T2DM. Methods Based on Chinese guideline and practice, 10 three-stepwise add-on strategies were identified, which start with metformin, then switch to metformin plus one oral drug (i.e., sulfonylurea, thiazolidinedione, α-glucosidase inhibitor, glinide, or DPP-4 inhibitor) as second line, and finally switch to metformin plus one injection (i.e., insulin or GLP-1 receptor agonist) as third line. A cohort of 10,000 Chinese patients with newly diagnosed T2DM was established. From a healthcare system perspective, the Cardiff model was used to estimate the cost-effectiveness of the strategies, with clinical data sourced from a systematic review and indirect treatment comparison of 324 trials, costs from claims data of 1164 T2DM patients, and utilities from an EQ-5D study. Outcome measures include costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). Results Over 40-year simulation, the costs accumulated for a patient ranged from $7661 with strategy 1 to $14,273 with strategy 10, while the QALY gains ranged from 13.965 with strategy 1 to 14.117 with strategy 8. Strategy 7 was dominant over seven strategies (strategies 2~6, 9~10) with higher QALYs but lower costs. Additionally, at a willingness-to-pay threshold of $30,787/QALY (i.e., 3 times GDP/capita for China), strategy 7 was cost-effective compared with strategy 1 (ICER of strategy 7 vs. 1, $3371/QALY) and strategy 8 (ICER of strategy 8 vs. 7, $132,790/QALY). Ranking the strategies by ICERs and NMBs, strategy 7 provided the best value for money when compared to all other strategies, followed by strategies 5, 9, 8, 1, 3, 6, 10, 2, and 4. Scenario analyses showed that patients insist on pharmacologic treatments increased their QALYs (0.456~0.653) at an acceptable range of cost increase (ICERs, $1450/QALY~$12,360/QALY) or even at cost saving compared with those not receive treatments. Conclusions This study provides evidence-based references for diabetes management. Our findings can be used to design the essential drug formulary, infer clinical practice, and help the decision-maker design reimbursement policy.

OBJECTIVE ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM. RESEARCH DESIGN AND METHODS We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods. RESULTS Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1–13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%). CONCLUSIONS Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.

Sulfonylureas are widely used in patients with type 2 diabetes; meanwhile, the increasing fractures risks especially in the old are gradually taken into consideration. This meta-analysis aimed at investigating whether sulfonylureas could influence the risk of fractures in type 2 diabetes (T2DM) in the elder patients (≥ 65 years old). We searched the PubMed and other databases to screen eligible studies. Two authors independently extracted data according to the selection criteria for each study. The Newcastle–Ottawa scale was used to evaluate the quality. Subgroups and sensitivity analyses were performed and publication bias was assessed. A total of 7 studies involving 464,121 individuals were included in our meta-analysis. The pooled risk ratio for developing fracture in sulfonylurea users with type 2 diabetes (≥ 65 years old) was 1.26 (95% CI 1.15–1.39). Sensitivity analyses confirmed the stability of the results and there was no publication bias. Sulfonylureas could add the risk of fractures among the old with type 2 diabetes. Initial sulfonylureas therapy in both men and women should be done prudently.

Objectives Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that is usually diagnosed in the first six months of life. Case presentation We report on a male infant with neonatal diabetes who presented with diabetic ketoacidosis at two months and 16 days. A novel homozygous missense mutation (c.259T>G) was identified in the ABCC8 gene. In this case, insulin was replaced with glimepiride at a dosage of 0.49 mg/kg/day at five months, and this achieved metabolic control and satisfactory growth as observed at follow-up. Conclusions This report improves our understanding of the mutational spectrum of ABCC8, which is normally associated with NDM, and shows that the treatment regimen for this condition can be successfully switched from insulin therapy to the use of sulfonylurea.

Hypoglycemia related to treatment of type 2 diabetes mellitus patients constantly represents a substantial problem. It is connected with higher mortality and lower quality of life, mostly displayed with elder patients. Therefore it is vital to revise the antidiabetic therapy regularly and to inquire for the associated risks. Nevertheless, elder patiens are often following the inadvisable treatment by sulphonylureas derivates, which represent the second most risky medication causing hypoglycemia after insulin. In our retrospective study we analysed the occurence of serious hypoglycemia, caused by any factor, with severe diabetics urgently hospitalised at The Department of Internal Medicine of Masaryk Hospital in Usti nad Labem, in relation to the applied antidiabetic therapy. We suspected a negative influence of hypoglycemizing therapy (above all sulphonylureas) with the elderly patiens. In sum, we hospitalised 32 patients with type 2 diabetes mellitus (average age 76,5 ± 8,2 years), 18 of these using sulphonylureas (average age 77,4, with a relatively wide range from 65 to alarming 93 years). The average figure of estimated glomerular filtration rate (eGFR) was 0,745 (±0,293) ml/s/1,73m2. Moreover, the patients manifested polmorbidity - the average of comorbidities was 3,125, and even 3,5 with patiens on sulphonylureas. Following the arguments summarised above, we believe that hypoglycemic episodes are extremely dangerous especially for elder patients with T2DM, and from this point of view, the medication using sulphonylureas derivates seems to be inappropriate.

Background. Endothelin (ET) is one of the most significant regulators of the functional state of vascular endothelium. ET‑1 is the principal cardiovascular isoform of the endothelin system. ET‑1 has both inflammatory and proliferative affects and contributes to pathogenic processes in the cardiovascular system. In diabetes, the rise of glucose concentration effects the formation of ET‑1. The aim of the work was to study the content of ET‑1 in the blood of patients with diabetes treated with various hypoglycemic agents. Material and methods. The amount of ET‑1 was evaluated via ELISA in 103 individuals: 17 healthy volunteers and 86 patients with diabetes. To determine the concentration of ET‑1 the endothelin (1-21) EIA kit (Biomedica) was used. Glycated hemoglobin wasdetermined using one HbA1c FS kit — DiaSys Diagnostic Systems. Results. The average level of endothelin in the blood of patients with diabetes was 0.536±0.047 fmol/ml vs. control — 0.118±0.017 fmol/ml. We did not observed changes of ET‑1 levels during monotherapy with metformin or insulin. At metformin + insulin + dapagliflosin, insulin + metformin and sulfonylurea + metformin but not DPP‑4 inhibitor + metformin combinations (T2D) there was decrease of ET‑1 level in the blood. It is of interest that DPP‑4 inhibitor + metformin caused significant increase (0.767±0.043 fmol/ml) of ET‑1 concentration. Conclusion. Thus, with combination therapy, except pair DPP‑4 inhibitor + metformin, the level of ET‑1 in the blood of patients with diabetes decreased significantly more than with monotherapy.

Despite the long-term renoprotective effects of Metformin, a recent study on data from the U.S. Food and Drug Administration reported a possible nephrotoxic effect, contributing to the development of acute kidney injury (AKI). We investigated the association between metformin and AKI in patients admitted with the AKI-prone condition of acute infection and compared results with corresponding results of other antidiabetics. In a nationwide register-based case–control study, we identified Danish patients with type 2 diabetes hospitalized with acute infection between 2008 and 2018. Cases of AKI had an increase in plasma creatinine ≥ × 1.5 during admission, controls did not. Antidiabetics were identified up to 6 months before admission. Odds ratio (OR) of each antidiabetic was computed in separate multiple logistic regression models adjusted for relevant medication and comorbidities and results compared. We included 46,811 patients, hereof 9454 AKIs (20%) and 2186 (4.7%) severe AKIs. Overall, 56% were males, median age (IQR) was 73 (65–81). Sixty percent received metformin, 13% sulfonylurea, 31% insulin and 8% dipeptidyl peptidase-4 inhibitors (DPP-4i), with equal distribution between cases and controls. Metformin was associated with increased OR (CI) for AKI, 1.07 (1.02–1.12), equally to sulfonylurea, 1.10 (1.03–1.18) and DPP-4i, 1.11 (1.02–1.20), but not insulin, 0.99 (0.93–1.05). In severe AKI, results for metformin were 1.27 (1.25–1.40) but increased equivalently to other antidiabetics. In patients with type 2 diabetes hospitalized with acute infection, metformin was not independently associated with AKI, since other antidiabetics were also significantly associated, indicating confounding by indication.

Objective. Mutations of the KCNJ11 gene are the most common cause of the permanent neonatal diabetes mellitus (PNDM). Majority of people with KNCJ11-PNDM have a de-novo mutation. We aimed to compare diabetes phenotype in two children and their mothers with PNDM carrying the same sulfonylurea-sensitive KCNJ11 variants. Methods. We have compared glibenclamide (sulfonylurea) dose, C-peptide, and HbA1c serum levels in two children and their mothers with PNDM up to 5.5-year follow-up. All of them were carrying a heterozygous activating KCNJ11 pathogenic variant (p.R201H in Family 1 or p.H46Y in Family 2). The mothers were initially treated with insulin and successfully switched to sulfonylurea at the age of 24 and 11 years, respectively. Both children were treated with sulfonylurea since the diagnosis of PNDM. Results. Glibenclamide dose was similar in both children (0.02–0.03 mg/kg/day), but lower compared to their mothers (0.1–0.4 mg/kg/day) (p Conclusions. Evaluation of the treatment in people with sulfonylurea-sensitive KNCJ11-PNDM should respect the age of patients together with the type of mutation and duration of diabetes at therapy start and may differ within one family.

OBJECTIVE To examine the comparative effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes. RESEARCH DESIGN AND METHODS U.S. veterans initiated on SGLT2i (n = 18,544), GLP-1 (n = 23,711), DPP-4 (n = 39,399), or sulfonylureas (n = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores. RESULTS Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR CONCLUSIONS In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.

Background: The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. Objective: We conducted a narrative review of low-cost OHMs. Results: We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. Results: We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500–2,000/1,500–2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5–5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12–20 (sulfonylureas), 25–39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p Conclusion: Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

Introduction Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. Methods Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised–Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed‐effects models with inverse probability treatment weights. Results In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase‐4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. Discussion Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

A precision medicine approach is used to improve treatment of patients with monogenic diabetes. Herein, we searched SU efficiency according to the genotype-phenotype correlation, dosage used, and side effects.Systematic review conducted according the PRISMA control criteria identifying relevant studies evaluating the in vivo and in vitro sensitivity of ATP-dependent potassium channels according to the characteristics of genetic mutation.Hundred and three selected articles with complete data in 502 cases in whom 413 (82.3%) had mutations in KCNJ11 (#64) and 89 in ABCC8 (# 56). Successful transfer from insulin to SU was achieved in 91% and 86.5% patients, respectively, at a mean age of 36.5 months (0-63 years). Among patients with KCNJ11 and ABCC8 mutations 64 and 46 were associated with constant success, 5 and 5 to constant failure, and 10 and 4 to variable degrees of reported success rate, respectively. The glibenclamide dosage required for each genotype ranged from 0.017 to 2.8 mg/kg/day. Comparing both the in vivo and in vitro susceptibility results, some mutations appear more sensitive than others to sulfonylurea treatment. Side effects were reported in 17/103 of the included articles: mild gastrointestinal symptoms and hypoglycaemia were the most common. One premature patient had an ulcerative necrotizing enterocolitis which association with SU is difficult to ascertain.Sulfonylureas are an effective treatment for monogenic diabetes due to KCNJ11 and ABCC8 genes mutations. The success of the treatment is conditioned by differences in pharmacogenetics, younger age, pharmacokinetics, compliance, and maximal dose used.

Background Recent randomized control trials have described a protective cardiovascular effect of novel glucose lowering drugs in patients at high cardiovascular risk. Whether these second-line agents have similar effects in the general population is unknown. We aimed to compare the risk of major cardiovascular and adverse events in new users of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitor (DPP-4i), glucagon-like peptide 1 agonist (GLP-1a), and sulfonylurea in T2DM patients not controlled on metformin therapy. Methods Retrospective cohort study using the MarketScan database (2011–2015). We selected T2DM individuals who were newly dispensed sulfonylureas, SGLT-2i, DPP-4i, or GLP-1a, as second-line therapy, added to metformin. Cohort entry was defined by date of first prescription of the second-line agent. Time to first non-fatal cardiovascular or adverse event was compared using Cox regression models adjusted for confounders. Results Among 118,341 T2DM patients using metformin (mean age: 56), most were at low cardiovascular risk (4% with previous cardiovascular or cerebrovascular event). During a median follow-up of 10 months compared with sulfonylureas users, cardiovascular risk was lower in users of SGLT-2i (aHR = 0.61; 95% CI: 0.40–0.97), DPP-4i (aHR = 0.79; 95% CI: 0.69–0.90) and GLP-1a (aHR = 0.65; 95% CI: 0.48–0.89). Serious adverse events were rare but compared with sulfonylurea, the risk was lower in new users of novel glucose lowering agents. Conclusion In our analyses, which included patients with and without prior cardiovascular disease, initiating novel glucose lowering drugs as second-line therapy for T2DM was associated with a lower risk of cardiovascular and adverse events than sulfonylurea initiation.

In France, the implementation of mutant herbicide-tolerant crops and the use of the related herbicides - sulfonylureas and imidazolinones - have triggered a strong societal reaction illustrated by the intervening actions of environmentalist groups illegally mowing such crops. Trials are in progress, and therefore should be addressed the questions of the environmental risks and the toxicity of these herbicides for the animals and humans consuming the products derived from these plants. Regulatory authorities have allowed these mutant and herbicide-tolerant plants arguing that the herbicides against which they resist only target an enzyme found in 'weeds' (the acetolactate synthase, ALS), and that therefore all organisms lacking this enzyme would be endowed with immunity to these herbicides. The toxicological literature does not match with this argument: 1) Even in organisms displaying the enzyme ALS, these herbicides impact other molecular targets than ALS; 2) These herbicides are toxic for animals, organisms that do not possess the enzyme ALS, and especially invertebrates, amphibians and fish. In humans, epidemiological studies have shown that the use and handling of these toxins are associated with a significantly increased risk of colon and bladder cancers, and miscarriages. In agricultural soils, these herbicides have a persistence of up to several months, and water samples have concentrations of some of these herbicides above the limit value in drinking water.

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1α (HNF1A) diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) is characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A diabetes is currently unknown. To investigate this, 10 HNF1A mutation carriers and 10 control subjects without diabetes were recruited for a double-blinded, placebo-controlled, crossover study including 6 experimental days in a randomized order involving 2-h euglycemic-hyperglycemic clamps with coadministration of: 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min), or saline (NaCl). In HNF1A mutation carriers, we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP-1, respectively, and 4) increased fasting and arginine-induced glucagon levels compared with control subjects without diabetes. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A diabetes via potentiation of glucose-stimulated insulin secretion.

PURPOSE To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. METHODS We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). RESULTS We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). CONCLUSIONS Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

Neonatal diabetes mellitus is a monogenic disease that can present with hyperglycemia, dehydration, failure to thrive, and ketoacidosis within the first six months of life. Neonatal diabetes mellitus can be transient or permanent. Here, we describe a 10-week-old infant with transient neonatal diabetes mellitus who presented with diabetic ketoacidosis and was found to have heterozygous a de novo mutation, p.Thr1381Asn in the ABCC8 gene, which encodes the SUR1 protein. There was no family history of diabetes mellitus and the parents were negative for the mutation at ABCC8. The patient started on insulin therapy and remission of diabetes occurred at 4 months of age. The patient remained euglycemic over a 2-year follow-up period without necessitating any medicine.

Meisam Saberi,1 Zahra Ramazani,1 Homeira Rashidi,2 Alihossein Saberi3 1Department of Medical Chemistry, School of Pharmacy, Ahvaz Jundishpur University of Medical Sciences, Ahvaz, Iran; 2Diabetic Research Center, Ahvaz Jundishpur University of Medical Sciences, Ahvaz, Iran; 3Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranCorrespondence: Alihossein SaberiDepartment of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranTel +98-9161133488Fax +98-6133332036Email saberi-a@ajums.ac.irAim: Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered.Patients and Methods: The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography.Results: The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05).Conclusion: The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.Keywords: CYP2C9, glibenclamide, gliclazide, retinopathy, nephropathy

Background: Due to several limitations in the study designs of sulfonylurea pharmacogenomics studies, we investigated the clinical and genetic predictors of secondary sulfonylurea failure in Type 2 diabetes patients. Materials & methods: Patients receiving the maximum sulfonylurea and metformin doses for >1 year were enrolled. Secondary sulfonylurea failure was defined as HbA1c >7.0% (>53 mmol/mol) after a 12-month follow-up. Results: By multivariate analysis, increased insulin resistance (HOMA2-IR), baseline HbA1c >7.0%, residing in eastern Peninsular Malaysia, and the CC genotype of rs757110 ABCC8 gene polymorphism were independent predictors of secondary sulfonylurea failure (p

The main goal of treating patients with type 2 diabetes mellitus at the present stage is to influence the cardiovascular risks taking into account the assessment of heart and kidney function. The 2020 American Diabetes Association Recommendations emphasize that lifestyle modification and metformin use are still considered the cornerstones of treatment for type 2 diabetes. The leading role is given to metformin as the first line of pharmacological treatment of such patients. In a DPP study, it was shown that when combining lifestyle changes and prescribing metformin, the likelihood of transition of pre-diabetes to diabetes decreased by 89 %.With high hyperglycemia, the Recommendations of the American Diabetes Association in 2020 suggest starting treatment of type 2 diabetes mellitus with the so-called dual therapy. The combination of metformin and sulfonylurea (glimepiride) preparations is effective for the prevention of both macrovascular and microvascular complications; therefore, it is the most frequent combination in the world that is recommended for use as the first or second stage of treatment for patients with type 2 diabetes.Patients with diabetes have a very high risk of death with COVID-19 – the second place after cardiovascular complications, which are also characteristic of such patients. Management tactics for patients with diabetes mellitus and COVID-19 include increasing the amount of fluid consumed and discontinuing all drugs, including sugar-lowering drugs, which can negatively affect the cardiovascular system and kidneys due to dehydration and potentiation of acidosis. In viral infections, patients with diabetes can safely use sulfonylureas and insulin preparations, as well as metformin (with mild to moderate severity of COVID-19).

In patients with type 2 diabetes mellitus (T2DM) who require additional glucose-lowering on top of first-line metformin monotherapy, sulfonylureas are the most common choice for second-line therapy followed by dipeptidyl peptidase inhibitors (DPP-4i). This article summarises presentations at a symposium entitled "Real-World Evidence and New Perspectives with Gliclazide MR" held at the International Diabetes Federation Congress in Busan, South Korea on 4 December 2019. Although guideline recommendations vary between countries, the guidelines with the highest quality ratings include sulfonylureas as one of the preferred choices as second-line therapy for T2DM. Data from randomised controlled trials (RCTs) have consistently demonstrated that sulfonylureas are effective glucose-lowering agents and that the risk of severe hypoglycaemia with these agents is low. In addition, both RCTs and real-world observational studies have shown no increased risk of mortality or cardiovascular disease with the use of newer-generation sulfonylureas compared with other classes of glucose-lowering treatments. However, differences between sulfonylureas do exist, with gliclazide being associated with a significantly lower risk of mortality or cardiovascular mortality compared with glibenclamide, as well as the lowest incidence of severe hypoglycaemia compared with other agents in this class. Recent real-world studies into the effectiveness and safety of gliclazide appear to confirm these findings, and publication of new data from these studies in patients with T2DM in the UK, and in Muslim patients who are fasting during Ramadan, are awaited with interest. Another study being undertaken with gliclazide is a pan-India study in patients with maturity-onset diabetes of the young (MODY) subtypes 1, 3 and 12. Patients with these MODY subtypes respond particularly well to sulfonylurea treatment, and sulfonylureas are the first-line agents of choice in these patients. These new and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes.

Background: The specific treatment recommendations for type 2 diabetes mellitus (T2DM) differ based on a particular guideline. The goal of pharmacotherapy is to achieve the target HbA1c and fasting and postprandial blood glucose levels to avoid disease complications. Objective: To evaluate the profile of T2DM patients on different antidiabetic treatment regimens and the factors leading to dose escalation in these patients. Methods: A prospective descriptive study was conducted at Kasturba Medical College Hospital, Mangalore, a tertiary care teaching hospital, over a period of one year. The study population comprised of patients with T2DM for ≥5 years. The demographic and clinical data were collected during the baseline and follow-up visits. Results: Of the 119 patients studied, 59.7% were males; 32.8% were ≥65 years of age. A significant decrease in the fasting blood glucose (FBG) on follow-up was seen (p = 0.028) in patients on sulfonylurea and metformin combination. A significant decrease in the glycated haemoglobin (HbA1c) was seen in patients on sulfonylurea with metformin and pioglitazone (p = 0.011); sulfonylurea with metformin, pioglitazone, and sitagliptin (p = 0.026); and metformin with insulin (p = 0.001). Patients who received dose escalation had a longer duration of the disease (p = 0.042), higher FBG (p = 0.039) and HbA1c (p = 0.05). Conclusion: A combination of metformin with sulfonylurea was the preferred first-line treatment; insulin was added when HbA1c was >9. Patients who received dose escalation had a longer duration of the disease and higher FBG and HbA1c.

Verification of the type of diabetes mellitus in young people is of high clinical significance in the clinical practice since the purpose of treatment depends on this: from the correction of carbohydrate metabolism by a rational diet to the administration of oral hypoglycemic drugs and insulin therapy. The chosen therapy has a significant impact on the quality of life of the patient. With the most common types of diabetes in young people the appointment of therapy is not in doubt, since with type 1 diabetes mellitus there is an absolute need for the maintenance of exogenous insulin, and with type 2 the administration of metformin is pathogenetically substantiated. In more rare forms of diabetes which MODY belongs to sulfonylurea preparations are recommended in most cases and there are few conflicting data on the effects of newer classes (DPP4, SGLT2 inhibitors, GLP1 agonists) with monogenic forms. Using the method of continuous monitoring of glucose (CGMS) and glycemic variability indicators it is possible to determine the effectiveness of various classes of sugar-lowering drugs for rare types of diabetes mellitus which will help practitioners in choosing therapy. In the literature single studies using CGMS have been described in this group of patients. In Turkey CGMS was performed for 8 patients with GCK-MODY; it was shown that in 50% of patients the glucose values during the day exceeded the normal ranges. Italian scientists conducted a study in which they diagnosed glycemic variability, in particular episodes of hypoglycemia, in patients with HNF4AMODY diabetes (MODY1) using CGMS. The clinical consequence of episodes of asymptomatic hypoglycemia in the MODY cohort remains unknown. Diagnosing the predominance of fasting or postprandial hyperglycemia, the determination of hypoglycemia can help in the appointment of pathogenetic therapy and improve the quality of life of people diagnosed with MODY-diabetes.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects., SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.

In 70 % of cases, diabetes is detected and treated on an outpatient basis at the primary level of medical care by general practitioners and general practitioners. Type 2 diabetes mellitus, which accounts for 90–95 % of all cases of diabetes in the structure of morbidity, is a disease of malnutrition and an unhealthy lifestyle. The 2020 American Diabetes Association Recommendations noted that type 2 diabetes is always preceded by prediabetes, which should be considered as a factor in the increased risk of developing both diabetes itself and cardiovascular diseases. Therefore, preventive treatment should begin already at the stage of prediabetes, when cardiovascular complications of the future disease are formed. Lifestyle modification (diet, increased physical activity) in combination with taking metformin reduces the likelihood of transition of diabetes to diabetes by almost 90 %.The global goal of treating patients with type 2 diabetes is to address cardiovascular risks, taking into account the assessment of heart failure and renal function. The combination of metformin and sulfonylurea preparations shows a cardio- and nephroprotective effect and is therefore the most frequent combination in the world recommended for use as the first or second stages of treatment for patients with type 2 diabetes. When initiating a hypoglycemic therapy, immediate release metformin should be preferred.

OBJECTIVE To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA1c, endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS Forty-five patients with poorly controlled (HbA1c 7–11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3-3H]glucose infusion, after which they were randomized to receive 1) liraglutide 1.2 mg/day (LIRA), 2) canagliflozin 100 mg/day (CANA), or 3) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS The mean decrease from baseline to 16 weeks in HbA1c was −1.67 ± 0.29% (P = 0.0001), −0.89 ± 0.24% (P = 0.002), and −1.44 ± 0.39% (P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was −6.0 ± 0.8 kg (P < 0.0001), −3.5 ± 0.5 kg (P < 0.0001), and −1.9 ± 0.8 kg (P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP (P < 0.05), which was accompanied by a 50% increase (P < 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% (P < 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA1c.

Aims/Introduction Sulfonylurea‐related hypoglycemia increases the risk of cardiovascular sequela, such as cardiac arrhythmia. This study aimed to clarify the relationship between the level of glycated hemoglobin (HbA1c) and the duration of hypoglycemia in type 2 diabetes patients treated with sulfonylureas. Materials and Methods Glucose levels in the enrolled patients (n = 300) were investigated with a professional continuous glucose monitoring device in the outpatient setting at six diabetes centers in Japan. Results A total of 269 participants completed the study. The duration of hypoglycemia with glucose values of 10% of the time in daily life (6.8 ± 5.6 min/h). The duration of hypoglycemia with glucose values of, The mean 24‐h glucose profiles over 24 h according to glycated hemoglobin level. The nadir of glucose levels was apparent between 03.00 and 05.00 hours irrespective of glycated hemoglobin level.

Neonatal diabetes is a rare disease, often caused by a monogenic abnormality. A male infant patient developed diabetic ketoacidosis at 2 months‐of‐age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. For >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased. The mutation was transmitted in an autosomal‐dominant fashion across three generations of his family, but the severity of diabetes varied among members from neonatal diabetes to mild diabetes. One family member had normal glucose tolerance despite having the mutation. This case presentation could help in the understanding of neonatal diabetes caused by the ABCC8 gene mutation., A male infant developed diabetic ketoacidosis (DKA) at 2 months‐of‐age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. After that, for >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased.

Neonatal diabetes mellitus (DM) is defined by the onset of persistent hyperglycemia within the first six months of life but may present up to 12 months of life. A gene mutation affecting pancreatic beta cells or synthesis/secretion of insulin is present in more than 80% of the children with neonatal diabetes. Neonatal DM can be transient, permanent, or be a component of a syndrome. Genetic testing is important as a specific genetic mutation can significantly alter the treatment and outcome. Patients with mutations of either KCNJ11 or ABCC8 that encode subunits of the KATP channel gene mutation can be managed with sulfonylurea oral therapy while patients with other genetic mutations require insulin treatment.

Objective To compare the safety of metformin vs sulfonylureas in patients with type 2 diabetes by chronic kidney disease (CKD) stage. Patients and Methods This retrospective cohort study included adults in Manitoba, Canada, with type 2 diabetes, an incident monotherapy prescription for metformin or a sulfonylurea, and a serum creatinine measurement from April 1, 2006, to March 31, 2017. Patients were stratified by estimated glomerular filtration rate (eGFR) into the following groups: eGFR of 90 or greater, 60 to 89, 45 to 59, 30 to 44, or less than 30 mL/min/1.73 m2. Outcomes included all-cause mortality, cardiovascular events, and major hypoglycemic episodes. Baseline characteristics were used to calculate propensity scores and perform inverse probability of treatment weights analysis, and eGFR group was examined as an effect modifier for each outcome. Results The cohort consisted of 21,996 individuals (19,990 metformin users and 2006 sulfonylurea users). Metformin use was associated with lower risk for all-cause mortality (hazard ratio [HR], 0.48; 95% CI, 0.40-0.58; P Conclusion Sulfonylurea monotherapy is associated with higher risk for all-cause mortality, major hypoglycemic episodes, and cardiovascular events compared with metformin. Although the presence of CKD attenuated the mortality benefit, metformin may be a safer alternative to sulfonylureas in patients with CKD.