Sulfonylurea Research Articles

Identification and optimisation of a risk stratified cohort of patients with type 2 diabetes through the delivery of a enhanced pharmacist-led service

Abstract Introduction Cardio-renal metabolic (CRM) diseases are each associated with significant morbidity and mortality, and due to their shared pathology, the benefit of managing these diseases holistically is becoming increasingly evident. The East Belfast Federation practices have sought to review patients living with type 2 diabetes (T2D), prioritising those not meeting their 3 Treatment Targets (3TT, HbA1c, blood pressure [BP] and cholesterol) to optimise treatment through a pharmacist-led model of care. Aims and Objectives 1. Improve adherence to latest update of NICE T2D [NG28, 2022], with a focus on patients with Cardiovascular Disease (CVD) & Chronic Kidney Disease (CKD). 2. Upskill diabetes teams, to create a legacy effect and ensure improved holistic management will continue beyond the project period. 3. Use a clinical audit tool to identify, stratify and optimise T2D patients not meeting their 3TTs. 4. Improve identification, coding and recall of patients with non-diabetic hyperglycaemia (NDH) as per QOF Indicator NDH001NI [QOF 2022/23]. 5. Enhanced focus on review of sulphonylureas (SU) in relation to frailty and risk of hypoglycaemia [Strain, 2021]. Method Patients not meeting their 3TTs (HbA1c>58 mmol/mol, BP>140/80mmHg, total cholesterol>5mmol/L) were identified from October 2022 to July 2023. Primary care based clinics created which we tailored to the specific needs of the practices with a focus on optimising patients with CVD & CKD co-morbidities. Dedicated specialist education and clinical support was provided to existing diabetes teams in CRM patient management. Additional searches were created and patients identified to review patients experiencing NDH and on a SU. Results At 9 months from baseline, there was a statistically significant improvement of 8.9% in patients achieving all 3TTs (n=373, P=0.013). This was accompanied by an increase in the number of patients optimised for CV risk reduction, with a 39% and 42% increase in patient receiving sodium glucose co-transporter-2 (SGLT2) inhibitors (n=542) and Glucagon-like peptide-1 receptor agonists (GLP1RA) (n=190), respectively. A 5.5% (n=28) reduction in the number of patients on a SU was observed, as well as a 44% (n=76) increase in the number of referrals into the Diabetes Prevention Programme (DPP). 151 statins and 51 BP medications were started/optimised. Discussion and Conclusion The project further exemplifies the feasibility of a pharmacist-led T2D service in a primary care setting. In addition to improvement in established T2D markers, the role promoted collaboration and facilitated best-practice sharing across multiple diabetes teams. This approach allows for more co-ordinated care for patients who may otherwise be referred to multiple specialists, which often results in fragmented care. Future work should focus on promoting CRM protection as early as possible to reduce disease progression and improve outcomes.Number of patients on antidiabetic meds% attainment of 3TT

Risk of Urinary Tract Infections in Male Veterans With Diabetes Prescribed Sodium-Glucose Cotransporter-2 Inhibitors Versus Sulfonylureas Across the Veterans Health Administration.

Background: Due to their mechanism of action, sodium-glucose cotransporter-2 inhibitors (SGLT2is) carry a presumed increased risk of urinary tract infection (UTI) which is reflected in current prescribing data. As SGLT2i prescribing trends increase, some retrospective studies confirm an increased risk of UTI while conflicting studies find no increased risk of UTI associated with this therapy. Objectives: This study aims to compare the odds of developing a UTI in male Veterans with type 2 diabetes mellitus (T2DM) on metformin taking a SGLT2i vs a sulfonylurea (SU) within the Veterans Health Administration (VHA). Methods: This retrospective cohort study identified male Veterans with T2DM on metformin with a new fill of SGLT2i or SU between January 1, 2020 to December 31, 2022. Patients were then assessed for UTI diagnosis. An adjusted odds ratio (AOR) was calculated. Results: The SGLT2i cohort had 5.2% of patients diagnosed with outpatient UTI and 1.6% of patients diagnosed with inpatient UTI. The SU cohort had 5.3% of patients diagnosed with outpatient UTI and 1.3% of patients diagnosed with inpatient UTI. A logistic regression analysis resulted in a decreased odds of diagnosis of outpatient UTI in the SGLT2i cohort vs the SU cohort ([AOR] = 0.91, 95% CI [0.86 - 0.96], P-value = < 0.001), and no difference in the diagnosis of inpatient UTI ([AOR] = 1.06, 95% CI [0.96 - 1.18], P-value = 0.234). Conclusion: This retrospective study of national VHA data adds to growing literature which finds no excessive risk of UTI associated with SGLT2i therapies.

Photolytic ortho-Selective Amino Pyridylation of Aryl Isocyanates with N-Amino Pyridinium Ylides for the Synthesis of N-Arylsulfonyl Ureas.

Herein, we report an expedient synthesis of aryl sulfonyl ureas 4 and 5 from N-amino pyridinium ylides and aryl isocyanates. N-Aminopyridinium ylides 3 are synthesized via blue light-emitting diode irradiation of pyridine/isoquinoline and appropriate iminoiodinanes. The strategy involved a hitherto unknown carboamination of imine moieties (of aryl isocyanates) via a three-component reaction of pyridine derivatives/isoquinoline 1, N-aryl sulfonyl iminoiodinanes 2, and numerous aryl isocyanates at room temperature in 2-methyl tetrahydrofuran to afford the target compounds in moderate to excellent yields. N-Arylpyridinium ylides 3 (as intermediates) undergo a [3+2] cycloaddition with the aryl isocyanates followed by the aromatization of the pyridine/isoquinoline moiety to afford compounds 4. On the basis of the substitution pattern among the reactants, in some cases pyridine extrusion occurs during the reaction to afford depyridinylated aryl sulfonyl ureas 5. In general, isocyanates are used as dipolarophiles in [3+2] cycloaddition reactions. However, regioselective amino pyridylation of these species is a first. Control experiments and density functional theory calculations elucidate the reaction mechanism. The batch process of the protocol could be seamlessly transferred to the photoflow synthesis.

12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus

Abstract Disclosure: R. Pratibha: None. K. Dummula: None. Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (&amp;gt;250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy. Presentation: 6/3/2024

Synthetic Approaches to Gliclazide: An Antidiabetic Medication

AbstractType 2 diabetes mellitus (T2DM) remains a global health concern, causing a significant threat to world health. Oral anti‐diabetic drugs play a crucial role in effective management of diabetes. Numerous anti‐diabetic medications have been known for a long period, classified according to their chemical groups but because of their low pharmaceutical cost and long‐term efficacy, sulphonylurea (SU) continues to be a well‐positioned medication with a long history of clinical use in treating type 2 diabetes. Among various available SU, Gliclazide stands out due to its significant reduction in cardiovascular mortality and extremely low rate of severe hypoglycaemia. Numerous synthetic methodologies have been developed to create more efficient pathways resulting in less waste and cheaper manufacturing. The present review aims to summarise some recently reported literature for the synthesis of Gliclazide. We have made an effort to highlight their drawbacks and advantages in this comparative analysis. Here we tried to compile different synthetic routes via various methods to synthesise Gliclazide which will serve as a valuable foundation to make potential modifications to the present inventions. This effort ultimately aims to contribute to the enhancement of the society's health and welfare.

Assessment of cardiovascular risk with sulfonylurea use in type 2 diabetes mellitus: A retrospective cohort study

AimsThe utilization of sulfonylurea (SU) for the management of Type 2 Diabetes Mellitus (T2DM) has witnessed a decline, attributed to the rising popularity of alternative medications and uncertainties surrounding the cardiovascular risk profile of SUs. This study aimed to investigate the potential association between SU intake and the incidence of cardiovascular events in patients with T2DM. MethodsA retrospective cohort study, based on a general practice (GP) registry, was designed, encompassing patients diagnosed with T2DM between 2005 and 2014.Follow-up persisted until the occurrence of a cardiovascular event, loss to follow-up, or until December 31, 2022. Comparative analyses were conducted between patients, receiving SU treatment and those without ResultsData from a cohort comprising 5589 patients revealed that 13 % and 13.1 % of individuals in the comparator group and the SU group, respectively, experienced a cardiovascular event. However, no statistically significant elevation in the risk of cardiovascular events was observed after SU usage. Furthermore, the glycated haemoglobin (HbA1c) levels were significantly higher in the SU group (7.0 % vs. 6.4 %,p < 0.001). ConclusionsThe findings from this study indicate that the use of sulfonylureas SUs is not associated with a statistically significant increase in the risk of cardiovascular events among patients with type T2DM. These results contribute to the ongoing discourse on the safety and efficacy of SU therapy in diabetes management.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. ObjectivesThe aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. MethodsAcross the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. ResultsOver 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). ConclusionsIn patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

Live Cell Monitoring of Phosphodiesterase Inhibition by Sulfonylurea Drugs.

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs.

Effect of different hypoglycemic drugs and insulin on the risk of new-onset atrial fibrillation in people with diabetes: a network meta-analysis

ObjectiveDiabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin.MethodWe conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI).ResultAfter searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i.ConclusionSGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.

Precision treatment of beta-cell monogenic diabetes: a systematic review

BackgroundBeta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.MethodsThe search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text.ResultsThere are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU’s effectiveness in lowering HbA1c. Two cross-over trials (each with 15–16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes.ConclusionThere is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Profiles of sulfonylurea use in Diabetes Mellitus type 2: an analysis of clinical practice over the last 10 years

AimsDescribing the evolution over time in the use of sulfonylureas (SUs) and the characteristics of patients at first prescription and at interruption of treatment with SUs. MethodsRetrospective evaluation of data from the Italian Association of Diabetologists (AMD) Annals registry (2010–2020), about T2D patients who started treatment with SUs. The longitudinal probability of remaining on SUs was estimated by Kaplan Meier survival curves. ResultsSU prescription decreased from 30.7 % (2010) to 12.9 % (2020). Patients started on SU were 68.2 ± 11.2 years old, mostly males (55.5 %), with diabetes duration = 10.1 ± 8.3 years, BMI = 29.7 ± 5.5 kg/m2, and HbA1c = 8.3 ± 1.7 % [67 mmol/mol]. After one year, the probability of staying on SU was 85.4 %, 75.9 % after two years, 68.2 % after 3 years, 56.6 % after 5 years. Patients who discontinued SUs had higher BMI and HbA1c, were younger, more often males and treated with insulin. Over time, the percentage of subjects switched to metformin, DPP4i, SGLT2i, and GLP1RA increased, whereas use of glinides, glitazones, acarbose and insulin declined. ConclusionsThese data suggest a consensus, slowly, but increasingly aligning with the current National indications of dismissing SUs for the treatment of T2D. The new drugs for diabetes should represent a preferable choice in all patients who do not have specific contraindications.

Current Position of Gliclazide and Sulfonylureas in the Contemporary Treatment Paradigm for Type 2 Diabetes: A Scoping Review.

The increasing burden of type 2 diabetes (T2D), in relation to alarming rise in the prevalence; challenges in the diagnosis, prevention, and treatment; as well as the substantial impact of disease on longevity and quality of life, is a major concern in healthcare worldwide. Sulfonylureas (SUs) have been a cornerstone of T2D pharmacotherapy for over 60years as oral antidiabetic drugs (OADs), while the newer generation SUs, such as gliclazide modified release (MR), are known to be associated with low risk of hypoglycemia in addition to the cardiovascular neutrality. This scoping review aimed to specifically address the current position of gliclazide MR among other SUs in the contemporary treatment paradigm for T2D and to provide a practical guidance document to assist clinicians in using gliclazide MR in real-life clinical practice. The main topics addressed in this paper include the role of early and sustained glycemic control and use of SUs in T2D management, the properties of gliclazide MR in relation to its effectiveness and safety, the use of gliclazide therapy in special populations, and the place of SUs as a class and gliclazide MR specifically in the current T2D treatment algorithm.

Impact of Gliclazide Modified Release or Glimepiride as Add-on Therapy to Metformin on Glycemic and Oxidative Stress Parameters in Type 2 Diabetic Patients

Background: Type 2 diabetes mellitus is a condition characterized by an elevation of oxidative stress, which has been implicated in diabetic progression and its vascular complications. Aim: Assessing the impact of gliclazide modified release (MR) versus glimepiride on oxidative stress markers, glycemic indices, lipid profile, and estimated glomerular filtration rate in uncontrolled type 2 diabetic patients on metformin monotherapy. Methods: This was an observational comparative study conducted in Thi-Qar specialized diabetic, endocrine, and metabolism center. Sixty-six patients were randomized into two groups based on the addition of the sulfonylureas (SUs). Group 1 (33 patients) was on gliclazide MR, whereas Group 2 (33 patients) was on glimepiride. The measured oxidative stress markers were reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and protein carbonyl (PC) evaluated before and after 16 weeks of SUs addition. Results: There were significant drops in SOD (P &lt; 0.001), MDA (P &lt; 0.001), and PC (P = 0.001) and a significant increase in GSH (p = 0.029) levels after gliclazide MR add-on therapy. There were significant drops in SOD (P = 0.026) and MDA (P &lt; 0.001) levels with non-significant changes in both GSH (P = 0.214) and PC (P = 0.538) after glimepiride add-on therapy. There was a significant difference in improvement of PC level (P = 0.048) in the gliclazide group compared to the glimepiride group, with a non-significant numerically higher improvement of GSH, SOD, and MDA in gliclazide MR than glimepiride. At the end of the study, there were no significant differences in glycemic control, lipid profile, or eGFR improvement between the two groups. Conclusion: Glycemic control plays a pivotal role in decreasing oxidative stress. The control of diabetes with the gliclazide-MR-metformin combination reduced oxidative stress more than the glimepiride-metformin combination, indicating its antioxidant property. Keywords: Oxidative Stress, T2DM, Gliclazide MR, Glimepiride, Metformin.

Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

374-P: Impact of Sulfonylurea (SU) Use on Hypoglycemia and Continuous Glucose Monitoring (CGM) Metrics after 16 Weeks of iGlarLixi in Insulin-Naïve Adults with Type 2 Diabetes (T2D) and Mean A1C &amp;gt;10%

374-P: Impact of Sulfonylurea (SU) Use on Hypoglycemia and Continuous Glucose Monitoring (CGM) Metrics after 16 Weeks of iGlarLixi in Insulin-Naïve Adults with Type 2 Diabetes (T2D) and Mean A1C &amp;gt;10%

Bensulfuron methyl induced multiple stress responses in the field wheat plants: Microbial community and metabolic network disturbance

Sulfonylurea (SU) herbicides are widely used and often detected in environmental matrices and have toxic effects on ecosystems and plant development. However, the interaction between SU and soil-plant metabolism during the whole wheat growth cycle remains poorly investigated. Field trials demonstrated that bensulfuron methyl exposure reduced wheat height and a thousand grains' weight, disrupting the critical metabolic pathways, including linoleic acid and amino acid metabolism in the maturity stage. During different growth processes, bensulfuron methyl exposure decreases wheat soil and plants' defense-related indole alkaloid compounds, such as benzoxazinoids and melatonin. Microbial sequencing results showed that bensulfuron methyl treated decreased the abundance of beneficial microorganisms (Gammaproteobacteria, Bacteroidia, and Blastocatella) in the rhizosphere soil, which positively correlated with the inhibition of soil enzyme activity and the secretion of allelopathic substances (benzoxazinoids and melatonin). Molecular docking further confirmed that bensulfuron methyl affects protein molecular structure by establishing hydrogen bonds, which disequilibrate wheat benzoxazinoids and melatonin metabolism. Therefore, bensulfuron methyl exposure disrupted the interaction between soil microorganisms and indole alkaloid metabolism, hindering plant development. This study provides constructive insights into the environmental risks of herbicides and agricultural product safety throughout wheat development.

A randomized double blind placebo controlled trial to assess the safety and efficacy of a patented fenugreek (Trigonella foenum-graecum) seed extract in Type 2 diabetics.

Fenugreek plant (Trigonella foenum-graecum) constitutes a traditionally acclaimed herbal remedy for many human ailments including diabetes, obesity, neurodegenerative diseases, and reproductive disorders. It is also used as an effective anti-oxidative, anti-inflammatory, antibacterial, and anti-fungal agent. The seed of the plant is especially enriched in several bioactive molecules including polyphenols, saponins, alkaloids, and flavonoids and has demonstrated potential to act as an antidiabetic phytotherapeutic. A novel patented formulation (Fenfuro®) was developed in our laboratory from the fenugreek seeds which contained >45% furostanolic saponins (HPLC). A placebo-controlled clinical compliance study was designed to assess the effects of complementing Fenfuro® on a randomized group of human volunteers on antidiabetic therapy (Metformin and sulphonylurea) in controlling the glycemic index along with simultaneous safety assessment. In a randomized double-blind, placebo-controlled trial, 42 individuals (21 male and 21 female volunteers) in the treatment group (out of 57 enrolled) and 39 individuals (17 male and 22 female volunteers) in the placebo group (out of 47 enrolled), all on antidiabetic therapy with Metformin/Metformin with sulphonyl urea within the age group of 18-65 years were administered either 1,000 mg (500 mg × 2) (Fenfuro®) capsules or placebo over a period of 12 consecutive weeks. Fasting and postprandial glucose along with glycated hemoglobin were determined as primary outcomes to assess the antidiabetic potential of the formulation. Moreover, in order to evaluate the safety of the formulation, C-peptide and Thyroid Stimulating Hormone (TSH) levels as well as immunohematological parameters were assessed between the treatment and placebo groups at the completion of the study. After 12 weeks of administration, both fasting as well as postprandial serum glucose levels decreased by 38 and 44% respectively in the treatment group. Simultaneously, a significant reduction in glycated hemoglobin by about 34.7% was also noted. The formulation did not have any adverse effect on the study subjects as there was no significant change in C- peptide level and TSH level; liver, kidney, and cardiovascular function was also found to be normal as assessed by serum levels of key immunohematological parameters. No adverse events were reported. This clinical compliance study re-instated and established the safety and efficacy of Fenfuro® as an effective phytotherapeutic to treat hyperglycemia.

Efficacy and Safety of DPP-4 Inhibitors and Metformin Combinations in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis.

Several oral antidiabetic regimens are available for treating type 2 diabetes mellitus (T2DM), dipeptidyl peptidase-4 inhibitors (DPP4i) being one of them. We conducted a network meta-analysis (NMA) comparing DPP4i plus metformin (Met) combination with other Met-based oral antidiabetic drug (OAD) combinations used in treating patients with T2DM. We searched PubMed and Embase from inception until 19th April, 2022 for phase II and phase III trials in patients with T2DM on Met-based traditional OADs. The primary outcome was assessed by change in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour post-prandial blood glucose (2h-PPG). The secondary safety outcomes assessed were hypoglycemic events, serious adverse events (SAEs), cardiovascular (CV) events, and gastrointestinal (GI) events. Sixty-two trials were included in the analysis. The combination of DPP4i + Met revealed a comparable mean reduction in HbA1c levels to the glinides (Gli) + Met combination (mean difference [MD]: -0.03%, 95% CI: 0.69, -0.65), although the difference was not statistically significant. The mean HbA1c reduction with DPP4i + Met was greater than with sulfonylureas (SU) + Met (MD: -0.05, 95% CI: -0.29, 0.39), thiazolidinedione (TZD) + Met (MD: -0.69, 95% CI: -1.39, -0.02), and SU + TZD (MD: 0.21; 95% CI: -1.30, 1.71), with no statistical significance. DPP4i + Met demonstrated a non-significant lower incidence of CV events in comparison to TZD + Met (RR: 1.01, 95% CI: 0.46, 2.45) and SU + Met (RR: 1.06, 95% CI: 0.61, 2.06). DPP4i in combination with Met was efficacious and had a well-tolerated safety profile compared with other traditional OADs. This combination can be considered as a suitable treatment option for patients with T2DM.

Review on sulphonamide analogues for the perspective of antibacterial and antidiabetic activity

Several facets of sulphonamides are covered in this overview, including their chemistry, history, structure-activity relationship, classification systems, and contemporary synthesis techniques. The review also covers the range of sulphonamides pharmacological effects as antibacterial and antidiabetic agents. Sulphonamides work by competitively limiting microorganisms' ability to produce vitamin Bc, which stops bacteria from proliferating but does not actually kill them and need to be used against a range of fungi and gram-positive and gram-negative bacteria. According to the International Diabetes Federation's global cartographic image of diabetes (http://www.diabetesatlas.org/), type 2 diabetes mellitus (T2DM) is a pandemic that affects people worldwide. Hyperglycemia is the primary symptom of diabetes mellitus, a chronic, progressive, and poorly understood metabolic disease and discussed the mechanisms of metformin, glitazones, sulphonyl urea’s and other agents. Worldwide, copious research has been conducted on molecular targets associated with type 2 diabetes, including PPAR-γ, incretin, GLP-1, DPP-4, and SGLT2, DPP-IV, GSK-3, Aldose-reductase, fructose-bisphosphatases, and β3 adrenoceptor are used to treat type 2 diabetes.

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.