Antidiabetic drug administration prevents bone mineral density loss: Evidence from a two-sample Mendelian randomization study.

The aim of this study was to investigate the effect of common antidiabetic drugs on BMD by two-sample Mendelian randomization (MR). The single nucleotide polymorphisms that were strongly associated with insulin, metformin, rosiglitazone and gliclazide were extracted as instrumental variables (IVs) for MR analysis. The inverse variance weighted (IVW) method was used as the primary MR method to assess the causal effect of antidiabetic drugs on BMD, and other MR methods, including Weighted median, MR Egger and Weighted mode, were used for complementary analysis. Reliability and stability were assessed by the leave-one-out test. In the present work, IVW estimation of the causal effect of insulin on heel BMD demonstrated that there was a null effect of insulin on heel BMD (ß = 0.765; se = 0.971; P = 0.430), while metformin treatment had a positive effect on heel BMD (ß = 1.414; se = 0.460; P = 2.118*10-3). The causal relationship between rosiglitazone and heel BMD analysed by IVW suggested that there was a null effect of rosiglitazone on heel BMD (ß = -0.526; se = 1.744; P = 0.763), but the causal effect of gliclazide on heel BMD evaluated by IVW demonstrated that there was a positive effect of gliclazide on heel BMD (ß = 2.671; se = 1.340; P = 0.046). In summary, the present work showed that metformin and gliclazide have a role in reducing BMD loss in patients with diabetes and are recommended for BMD loss prevention in diabetes.

Real-world evidence on the effectiveness and safety of gliclazide MR 60 mg in Bangladeshi patients with Type II diabetes during fasting: a sub-analysis from the global DIA-RAMADAN study.

Aim: Many Muslims with Type II diabetes (T2DM) fast during Ramadan, which can put them at increased risk of hypoglycemia. This sub-analysis of the global DIA-RAMADAN study assessed the effectiveness and safety of gliclazide modified release (MR) 60 mg in the Bangladeshi cohort. Materials & methods: DIA-RAMADAN was an international, prospective, observational study conducted in adult T2DM patients intending to fast and receiving gliclazide MR 60 mg once daily for ≥90 days before Ramadan. Dosing was switched from morning to evening at the start of Ramadan. The primary outcome was the proportion of patients with ≥1 symptomatic hypoglycemic event. Secondary outcomes included changes between inclusion (V0) and end of study visit (V1) in glycated hemoglobin (HbA1c), body weight and fasting plasma glucose (FPG). Results: Among the 98 Bangladeshi patients, 80 (81.6%) were at moderate/low-risk (category 3) for fasting and 18 (18.4%) were high-risk (category 2), as per International Diabetes Federation and Diabetes and Ramadan International Alliance (IDF-DAR) guidelines. Gliclazide MR was being prescribed as monotherapy to 59 (60.2%) patients and in combination with metformin to 39 (39.8%). There was no incidence of severe hypoglycemic events. Mean (±SD) HbA1c change from V0 was -0.1 ± 0.8% (p = 0.159). Mean (±SD) changes in FPG and body weight were -0.8 ± 39.7 mg/dl (p = 0.876) and -0.0 ± 1.5 kg (p = 0.810), respectively. Conclusion: In a real-world setting, this sub-analysis in Bangladeshi patients shows that patients with T2DM treated with gliclazide MR 60 mg can fast safely during Ramadan with a very low risk of hypoglycemia, while maintaining glycemic control and body weight.

ADVANCE to ADVANCE-ON: Unfolding the "Legacy Story" in Diabetes.

Type 2 diabetes mellitus (T2DM) is a progressive disease. The importance of early intensive glucose lowering in preventing vascular complications in diabetes is well established. Sulfonylureas (SU) is recommended by most guidelines and widely used for the management of T2DM. However, there has been ambiguity around the long-term benefits with regard to microvascular and macrovascular outcomes with SUs. The United Kingdom Prospective Diabetes Study (UKPDS) provided evidence of sustained cardiovascular (CV) and microvascular benefits of previous intensive glycemic control with SUs or insulin in T2DM patients. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release (MR) Controlled Evaluation (ADVANCE) trial, another landmark study in T2DM patients and its posttrial observational follow-up (FU) study [ADVANCE-Observational Study (ADVANCE-ON)] together provide definite evidence for sustained renal benefits of gliclazide MR based intensive glucose control initiated early during the course of diabetes. These effects, however, may be specific to gliclazide. Evidence from other studies and reviews also suggests that gliclazide MR may hold a distinct place among currently available SUs and reinforce its utility in diabetes management.

Real-world evidence on health-related quality of life in patients with type 2 diabetes mellitus using sulphonylureas: An analysis of the Joint Asia Diabetes Evaluation (JADE) Register.

AIMS: To describe health-related quality of life (HRQoL) and identify associated factors in patients with type 2 diabetes mellitus (T2DM) treated with oral glucose-lowering drugs (OGLDs). METHODS: This retrospective, cross-sectional analysis included adults with T2DM from 11 Asian countries/regions prospectively enrolled in the Joint Asian Diabetes Evaluation (JADE) Register (2007-2019) with available EuroQol-5D (EQ-5D-3L) data. RESULTS: Of 47,895 included patients, 42,813 were treated with OGLDs + lifestyle modifications (LSM) and 5,082 with LSM only. Among those treated with OGLDs, 60% received sulphonylureas (SUs), of whom 47% received gliclazide. The OGLD + LSM group had a lower mean EQ-5D-3L index score than the LSM-only group (p < 0.001). The most affected EQ-5D-3L dimensions in OGLD + LSM-treated patients were pain/discomfort (26.2%) and anxiety/depression (22.6%). On multivariate analysis, good HRQoL was positively associated with male sex, education level, balanced diet and regular exercise, and negatively with complications/comorbidities, self-reported hypoglycaemia, smoking, HbA1c, age, body mass index and disease duration. Patients receiving gliclazide vs non-gliclazide SUs had lower HbA1c and better HRQoL in all dimensions (p < 0.001). CONCLUSIONS: Demographic, physical and psychosocial-behavioural factors were associated with HRQoL in patients with T2DM. Our real-world data add to previous evidence that gliclazide is an effective OGLD, with most treated patients reporting good HRQoL. A plain language summary of this manuscript is available here.

Genetic Variants Associated with Poor Responsiveness to Sulfonylureas in Filipinos with Type 2 Diabetes Mellitus.

Introduction: Sulfonylureas (SUs) are commonly used drugs for type 2 diabetes mellitus (T2DM) in the Philippines. This study aimed to associate genetic variants with poor response to gliclazide and glimepiride among Filipinos. Methodology: Two independent, dichotomous longitudinal substudies enrolled 139 and 113 participants in the gliclazide and glimepiride substudies, respectively. DNA from blood samples underwent customized genotyping for candidate genes using microarray. Allelic and genotypic features and clinical associations were determined using exact statistical methods. Results: Three months after sulfonylurea monotherapy, 18 (13%) were found to be poorly responsive to gliclazide, while 7 (6%) had poor response to glimepiride. Seven genetic variants were nominally associated (p<0.05) with poor gliclazide response, while three variants were nominally associated with poor glimepiride response. For gliclazide response, 3 carboxypeptidase-associated variants (rs319952 and rs393994 of AGBL4 and rs2229437 of PRCP) had the highest genotypic association; other variants include rs9806699, rs7119, rs6465084 and rs1234315. For glimepiride response, 2 variants were nominally associated: CLCN6-NPPA-MTHFR gene cluster - rs5063 and rs17367504 - and rs2299267 from the PON2 loci. Conclusion: Genetic variants were found to have a nominal association with sulfonylurea response among Filipinos. These findings can guide for future study directions on pharmacotherapeutic applications for sulfonylurea treatment in this population.

Preparation and evaluation of radiolabeled gliclazide parenteral nanoemulsion as a new tracer for pancreatic ß-cells mass.

PURPOSE: The present investigation aims to develop and evaluate a radiopharmaceutical for targeting and assessing ß-cells mass based on gliclazide, an antidiabetic drug that specifically binds the sulfonylurea receptor unique to the ß-cells of the pancreas. METHODS: Conditions were optimized to radiolabel gliclazide with radioiodine via electrophilic substitution reaction. Then, it was formulated as a nanoemulsion system using olive oil and egg lecithin by hot homogenization followed by ultrasonication. The system was assessed for its suitability for parenteral administration and drug release. Then, the tracer was evaluated in silico and in vivo in normal and diabetic rats. RESULTS AND CONCLUSIONS: The labeled compound was obtained with a high radiochemical yield (99.3 ± 1.1%) and good stability (>48 h). The radiolabeled nanoemulsion showed an average droplet size of 24.7 nm, a polydispersity index of 0.21, a zeta potential of -45.3 mV, pH 7.4, an osmolality of 285.3 mOsm/kg, and viscosity of 1.24 mPa.s, indicating suitability for parenteral administration. In silico assessment suggested that the labeling did not affect the biological activity of gliclazide. The suggestion was further supported by the in vivo blocking study. Following intravenous administration of nanoemulsion, the pancreas uptake was highest in normal rats (19.57 ± 1.16 and 12 ± 0.13% ID) compared to diabetic rats (8.51 ± 0.16 and 5 ± 0.13% ID) at 1 and 4 h post-injection, respectively. All results supported the feasibility of radioiodinated gliclazide nanoemulsion as a tracer for pancreatic ß-cells.

Analytical Method Capable of Quantifying Eight Nitrosamine Impurities from Five Different Commercially Available Metformin Formulations with Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride by Ultra High Performance Liquid Chromatography Tripple Quadrupole Mass Spectrometry.

Metformin and its combinations are widely used to treat type 2 diabetes. The drugs commonly used in combination with Metformin are Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride. Combination therapy is preferred over monotherapy of Metformin in most diabetics. About eighteen pharmaceutical manufacturers have lately recalled metformin formulation batches from the U.S. market due to N-nitrosodimethylamine (NDMA) impurities based on the food and drug administration (USFDA) guideline "Control of Nitrosamine in Human Drugs." European Medicines Agency (EMA) and Health Canada have also established guidelines for nitrosamine impurities. Nitrosamines are well-known mutagenic impurities and probable human carcinogens found in pharmaceutical formulations. Thus, global regulatory agencies require pharmaceutical and formulation manufacturers to complete risk assessments for nitrosamine impurities for patient safety. Therefore, drug manufacturers must develop analytical techniques for monitoring trace nitrosamine impurities. Quantifying nitrosamine impurities in formulations requires modern equipment like LC-MS/MS and great intellect. The present study intends to give a single pre-packaged LC-MS/MS method parameters, including liquid chromatography and triple quadrupole mass spectrometer configuration. This method could quantify eight nitrosamine impurities from five different Metformin combinations (Metformin with Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride). The atmospheric pressure chemical ionisation (APCI) was used as an ionisation source, and the mass spectrometer was set to multiple reaction monitoring (MRM) mode for all eight nitrosamine impurities. A unified pre-packaged analytical setup allows analytical chemists to develop a reliable, sensitive, robust, and precise method for quantifying eight nitrosamine impurities from five different Metformin formulations of varying manufacturers. This analytical method saves time, money, and the environment using fewer pharmaceutical chemicals.

Crude extract from Euphorbia prostrata extended curative period of glibenclemide in alloxan-induced diabetic rats.

OBJECTIVES: Euphorbia prostrata is traditionally used alongside antidiabetic agents to manage diabetes. Bioactive ingredients of medicinal herbs may alter the overall pharmacokinetics of antidiabetic agents. METHODS: We assessed hypoglycemic activities of ethanolic plant extract (EPE) singly and its effects on antidiabetic properties of gliclazide, glibenclemide and metformin in allaxonized rats. Varying concentrations of EPE (250 and 500 mg/kg) with or without metformin (10 mg/kg), glibenclemide (2 mg/kg) and gliclazide (5 mg/kg) were orally administered to evaluate herb-drug interaction. RESULTS: The levels of blood glucose declined significantly after treatment with metformin, glibenclemide and gliclazide singly (p<0.01) or concomitantly with EPE (p<0.001). Concentration dependent mild to moderate reduction (5.2 and 10.0%) was registered in blood glucose for 250 and 500 mg/kg of EPE respectively. The overall reduction in blood glucose due to combined treatment with EPE and standard agents was additive. On the other hand, synergistic herb-drug interaction was registered for insulin levels in rats that received glibenclamide and gliclazide alongside EPE. Extract with metformin had antagonistic insulin outcome. Regarding the duration of hypoglycemic activities, periodical changes were similar in case of glibenclamide and gliclazide separately or in combination with EPE. However, in case of metformin with extract, the blood glucose continued to decline for 14 h and retained at 15.0% below the baseline values even after 24 h of treatment. CONCLUSIONS: In conclusion, the extract itself had weak hypoglycemic effects but prolonged the therapeutic duration of metformin to more than 24 h when administered combinedly.

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

BACKGROUND AND OBJECTIVES: Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). RESULTS: During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). CONCLUSIONS: Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

Randomized Comparison of Initiating the Fixed-Ratio Combination of iGlarLixi or Biosimilar Insulin Glargine Together With Gliclazide in Participants of South Asian Origin With Type 2 Diabetes: VARIATION 2 SA Trial.

OBJECTIVES: The objective of this study was to compare initiation of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) vs insulin glargine U100 (iGlar) along with gliclazide, exclusively in people of South Asian origin with type 2 diabetes (T2D). METHODS: The Variability of glucose Assessed in a Randomized trial comparing the Initiation of A Treatment approach with biosimilar basal Insulin analog Or a titratable iGlarLixi combinatioN in type 2 diabetes among South Asian participants (VARIATION 2 SA) trial (ClinicalTrials.gov identifier: NCT03819790) randomized insulin-naïve adults with T2D having glycated hemoglobin (A1C) 7.1% to 11% to initiate either iGlarLixi or iGlar + gliclazide. Insulin doses were titrated similarly to a prebreakfast glucose target of 4.0 to 5.5 mmol/L. Average time in range (TIR) on a masked continuous glucose monitor (CGM), A1C, fasting plasma glucose (FPG) and weight were assessed at the end of the 12-week treatment period. RESULTS: Mean baseline characteristics for the 104 randomized participants were similar between treatment groups, including the following: age, 59±11 years; diabetes duration, 13.7±7.3 years; and A1C, 8.5%±1.2%. Coprimary outcomes of average TIRs within 24- and 12-h (6 am to 6 pm) periods at the end of trial were 70.5%±16.8% and 72.9%±17.6% for iGlarLixi, whereas these TIRs were 65.6%±21.6% and 67.3%±20.7% for the iGlar + gliclazide regimen, respectively, with no significant differences between groups (p=0.35 for 24-h TIR and p=0.14 for 12-h TIR). No significant difference in secondary outcomes was observed between treatment groups. Self-reported hypoglycemic events throughout the trial period and CGM-reported hypoglycemia (<4 and <3 mmol/L) were similar between randomized treatments. CONCLUSIONS: Initiation of iGlarLixi resulted in similar TIR, A1C, FPG, weight and hypoglycemia compared with the more affordable option of starting iGlar + gliclazide in adults of South Asian origin with T2D.

Indonesia DIA-RAMADAN Study: A Real-life, Prospective and Observational of Gliclazide MR in Type-2 Diabetes Patients During Ramadan Fasting.

BACKGROUND: Sulfonylureas (SUs) have been widely used in many countries for T2DM treatment. Gliclazide is one of the SUs with the lowest risk of hypoglycemia; however, the safety and effectiveness of gliclazide MR during Ramadan has not yet been reported in Indonesia. This study aimed to assess safety, efficacy, and tolerability of gliclazide modified release (MR) during Ramadan fasting. METHODS: The study was a part of DIA-RAMADAN study, a prospective observational study with subjects of T2DM patients aged >18 years, who had either controlled or sub-optimally controlled blood glucose level, performed Ramadan fasting. Subjects had been treated with gliclazide MR for at least 90 days prior the study, and were examined for their body mass index (BMI), fasting plasma glucose (FPG) and HbA1c levels 6 to 8 weeks before Ramadan (V0) and 4 to 6 weeks after the end of Ramadan (V1). RESULTS: Out of 198 subjects participating in the study, there were only two subjects (1.0%) who reported symptomatic HEs (either confirmed or not confirmed) and no severe HEs had been reported. There were no significant changes in HbA1c and FPG levels (p>0.05). Interestingly, there was a reduction of bodyweight (-0.4kg) from pre- to post-Ramadan (p < 0.001). Almost no subjects reported discontinuation of gliclazide MR throughout the entire study; however, there was one subject who reported a change of diabetic treatment into diet only. CONCLUSION: gliclazide MR is safe, well tolerated and can maintain glycemic control effectively for Indonesian patients with T2DM who perform Ramadan fasting.

Sodium-Glucose Cotransporter-2 (SGLT-2) Attenuates Serum Uric Acid (SUA) Level in Patients with Type 2 Diabetes.

BACKGROUND: Hyperuricemia has a strong association with diabetes mellitus. Hyperuricemia can lead to cardiovascular and renal complications in patients with diabetes. The goal of this study was to compare the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on serum uric acid (SUA) levels in patients with type 2 diabetes against traditional oral antihyperglycemic drugs (OADs). METHODS: In this double-blind randomized controlled trial, 70 patients with type 2 diabetes and elevated SUA levels were assigned to two treatment groups. Patients in group A received SGLT-2 inhibitors tablet dapagliflozin 5 mg to 10 mg and empagliflozin 10 mg to 25 mg. Group B patients received OADs such as glimepiride, metformin, sitagliptin, gliclazide, and glibenclamide as monotherapy or combination therapy. The changes in SUA level were primary end points while changes in body weight and body mass index (BMI) from baseline to end point were secondary end points. RESULTS: After four weeks of treatment, we noted a significant reduction of mean SUA levels in the SGLT-2 inhibitor group from 7.5 ± 2.5 to 6.3 ± 0.8 mg/dl versus comparator group from 7.1 ± 1.8 to 6.8 ± 2.2 mg/dl (p = 0.001). Mean body weight was significantly reduced in the SGLT-2 group from 82 ± 10.4 to 78 ± 12.5 kg versus comparator group from 78 ± 13.2 to 79.2 ± 9.7 kg (p = 0.001). Similarly, the mean BMI of patients in the SGLT-2 group was significantly reduced from 25.7 ± 3.2 to 24.2 ± 3.2 kg/m2 versus comparator group from 27.5 ± 4.2 to 28 ± 3.6 kg/m2 (p = 0.002). CONCLUSION: SGLT-2 inhibitors have a strong potential to decrease SUA levels in patients with type 2 diabetes.

Alleviation of cisplatin-induced hepatotoxicity by gliclazide: Involvement of oxidative stress and caspase-3 activity.

AIMS: Cisplatin (CP), as an effective alkylating agent, is widely used in cancer treatment, while hepatotoxicity is one of its side effects. Gliclazide (GLZ), as an oral hypoglycemic drug, has antioxidant and anti-inflammatory properties. This study was designed to investigate the protective effect of GLZ against CP-induced hepatotoxicity in mice. METHODS: In this experimental study, 64 adult male mice randomly were allocated into eight groups (8 mice/group). Control, GLZ (5, 10, and 25 mg/kg, orally), CP (10 mg/kg, single dose, intraperitoneally), and CP+GLZ (in three doses). GLZ was administrated for 10 consecutive days. CP was injected on the 7th day of the study. At the end of the experiment, hepatotoxicity was evaluated by serum and tissue biochemical, histopathological, and immunohistochemical assessments. RESULTS: The data were revealed that CP increased oxidative stress (increased MDA and reduced GSH), liver damage enzymes (ALT, AST, and ALP), and immunoreactivity of caspase-3 in liver tissue of CP-injected mice. Also, CP induced histopathological changes such as eosinophilic of hepatocytes, dilatation of sinusoids, congestion, and proliferation of Kupffer cells. GLZ administration significantly ameliorated serum functional enzyme and hepatic oxidative stress markers in CP-injected mice. In addition, the histological and immunohistochemical alterations were ameliorated in GLZ-treated mice. Of the three doses, 10 and 25 mg/kg were more effective. CONCLUSIONS: In conclusion, GLZ with its antioxidant, anti-inflammatory, and anti-apoptotic activities, can be suggested as a promising drug in the treatment of CP-induced hepatotoxicity.

Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care.

AIM: Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI. METHODS: We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs. RESULTS: MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide. CONCLUSION: About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

Cost-Effectiveness of Gliclazide-Based Intensive Glucose Control vs. Standard Glucose Control in Type 2 Diabetes Mellitus. An Economic Analysis of the ADVANCE Trial in Vietnam.

Introduction: ADVANCE was a large, multinational clinical study conducted over 5 years in type 2 diabetes mellitus (T2DM). In all, 11,140 patients were randomly assigned to receive gliclazide-based intensive glucose control (IGC) or standard glucose control (SGC). IGC was shown to significantly reduce the incidence of major macrovascular and microvascular events (composite endpoint) or major microvascular events compared with SGC, primarily by enhancing renal protection. We assessed the cost-effectiveness of IGC vs. SGC, based on the ADVANCE results, from a Vietnamese healthcare payer perspective. Materials and Methods: A partitioned survival times model across five health states (no complications, myocardial infarction, stroke, end-stage renal disease [ESRD], and diabetes-related eye-disease) was designed. Time-to-event curves were informed by the cumulative incidence of events and corresponding hazard ratios from the ADVANCE study. Health outcomes were expressed in terms of ESRD avoided and quality-adjusted life years (QALYs). Costs (in US $) comprised treatment costs and health state costs. Utility weights and costs were documented from literature reporting Vietnamese estimates. For sensitivity analyses, all parameters were individually varied within their 95% confidence interval bounds (when available) or within a ±30% range. Results: Over a 5-year horizon, IGC avoided 6.5 additional ESRD events per 1,000 patients treated compared with SGC (IGC, 3.5 events vs. SGC, 10.0 events) and provided 0.016 additional QALYs (IGC, 3.570 QALYs vs. SGC, 3.555 QALYs). Total costs were similar for the two strategies (IGC, $3,786 vs. SGC, $3,757). Although the total drug costs were markedly higher for IGC compared with SGC ($1,703 vs. $873), this was largely offset by the savings from better renal protection with IGC (IGC, $577 vs. SGC, $1,508). The incremental cost-effectiveness ratio (ICER) of IGC vs. SGC was $1,878/QALY gained, far below the threshold recommended by the World Health Organization (i.e., 1-3 × gross domestic product per inhabitant ≈$7,500 in Vietnam). The ICER of IGC vs. SGC per ESRD event avoided was $4,559/event. The findings were robust to sensitivity analysis. Conclusion: In Vietnam, gliclazide-based IGC was shown to be cost-effective compared with SGC from a healthcare payer perspective, as defined in the ADVANCE study.

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes.

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 µmol/day (IQR 17-138), and ß-hydroxybutyrate by 59 µmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

Comparative effectiveness of gliclazide modified release versus sitagliptin as second-line treatment after metformin monotherapy in patients with uncontrolled type 2 diabetes.

AIMS: To compare the effectiveness and safety of gliclazide modified release (MR) to sitagliptin as type 2 diabetes mellitus (T2D) treatments in a real-world patient population. MATERIALS AND METHODS: This retrospective cohort study used records from the UK Clinical Practice Research Datalink. The cohort consisted of adult patients with T2D newly treated with either gliclazide MR or sitagliptin as second-line treatment added to metformin and with a glycated haemoglobin (HbA1c) level of ≥7.0% (53 mmol/mol). Patients were 1:1 matched using high-dimensional propensity score matching and followed to determine the time taken to reach an HbA1c <7.0%. Secondary outcomes included time to HbA1c ≤6.5% (48 mmol/mol), time to ≥1% (11 mmol/mol) HbA1c reduction from baseline, treatment persistence and durability, and hypoglycaemic events. RESULTS: Among the 1986 patients included, those on gliclazide MR more likely achieved an HbA1c <7.0% [hazard ratio (HR): 1.35; 95% confidence interval (CI): 1.15-1.57], HbA1c ≤6.5% (HR: 1.51; 95% CI: 1.19-1.92) or had an HbA1c reduction ≥1% from baseline (HR: 1.11; 95% CI: 1.00-1.24) compared with patients on sitagliptin. Durability (log-rank P = .135) and persistence (P = .119) were similar between the two groups. Hypoglycaemic events were uncommon (23 total severe and non-severe events; incidence rate, 3.7 per 1000 patient years), with 4.7 and 2.6 events per 1000 patient years with gliclazide MR and sitagliptin treatment, respectively. CONCLUSIONS: In this real-world study, second-line gliclazide MR was more effective than sitagliptin in reducing HbA1c, with similar durability and persistence and low rates of hypoglycaemic events, in individuals with T2D on metformin treatment and HbA1c above the target of 7.0%.

The Effect of CYP2C9 Genotype Variants in Type 2 Diabetes on the Pharmacological Effectiveness of Sulfonylureas, Diabetic Retinopathy, and Nephropathy.

AIM: 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.

Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes.

OBJECTIVES: There is a bidirectional relationship between cardiovascular and renal disease. The drug-class of SGLT2 inhibitors improves outcomes at both ends of this so called cardiorenal axis. We assessed the effects of SGLT2 inhibition and sulfonylurea treatment on systemic hemodynamic function and investigated whether SGLT2 inhibitor-induced changes in systemic hemodynamics correlate with changes in renal hemodynamics. METHODS: Forty-four people with type 2 diabetes were randomized to 12 weeks of dapagliflozin 10 mg/day or gliclazide 30 mg/day treatment. Systemic hemodynamic function, autonomic nervous system activity, and vascular stiffness were measured noninvasively, whereas renal hemodynamics, glomerular filtration rate (GFR) and effective renal plasma flow, were assessed with gold-standard urinary clearances of inulin or iohexol and para-aminohippuric acid, respectively. Correlation analyses were performed to assess relationships between dapagliflozin-induced changes in cardiovascular and renal variables. RESULTS: Dapagliflozin reduced stroke volume by 4%, cardiac output by 5%, vascular stiffness by 11%, and mean arterial pressure by 5% from baseline, without increasing heart rate or sympathetic activity, while simultaneously lowering glomerular filtration rate by 8%. Despite similar improvements in glycemic control by dapagliflozin and gliclazide (-0.5 ±â€Š0.5 versus-0.7 ±â€Š0.5%; P = 0.12), gliclazide did not affect any of these measurements. There was no clear association between the dapagliflozin-induced changes in cardiovascular and renal physiology. CONCLUSION: Dapagliflozin seemingly influences systemic and renal hemodynamics independently and beyond glucose lowering in people with type 2 diabetes.This clinical trial was registered at https://clinicalTrials.gov (ID: NCT02682563).

A real-world study in patients with type 2 diabetes mellitus treated with gliclazide modified-release during fasting: DIA-RAMADAN.

AIMS: To explore the real-world safety and effectiveness of gliclazide modified release (MR) in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan. METHODS: DIA-RAMADAN (NCT04132934) was a prospective, international, observational study conducted in nine countries. Patients >18 years of age with T2DM (N = 1244) were examined at an inclusion visit (V0) occurring 6-8 weeks before the start of Ramadan. Patients received a diary to report treatment changes, hypoglycaemic events (HEs), and other adverse events. Gliclazide MR was taken once daily for 14-18 weeks. A second visit (V1) was conducted 4-6 weeks after the end of Ramadan. The primary endpoint was the proportion of patients reporting ≥1 symptomatic HE. Changes in HbA1c, fasting plasma glucose (FPG), and body weight were secondary endpoints. RESULTS: The proportion of patients reporting ≥1 symptomatic HE during Ramadan was low (2.2%) with no reported severe HEs. There was a significant reduction in HbA1c (-0.3%), FPG (-9.7 mg/dL), body weight (-0.5 kg) and body mass index (-0.2 kg/m2) between V0 and V1 (p < 0.001). CONCLUSIONS: Patients with T2DM treated with gliclazide MR during Ramadan have a low risk of hypoglycaemia and maintain glycaemic control and weight while fasting.