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Cisplatin (CDDP) can combat various types of cancers, employing a multifaceted approach against these malignant diseases. Despite its efficacy, resistance to CDDP remains a significant clinical challenge, often resulting in treatment failure and disease progression. Currently, efforts are underway to unravel the mechanisms of CDDP drug resistance in cancer treatment. The elevated presence of glutathione S‐transferase pi‐1 (GSTP1‐1) within tumor cells plays a pivotal role in the development of resistance toward the effects of CDDP. GSTP1‐1 contributes to detoxification by conjugating glutathione (GSH) to CDDP, reducing its accumulation and effectiveness in the tumor cells. In this study, the efficacy of gliquidone, an antidiabetic drug, demonstrated its capacity to impede tumor cell proliferation in both lung cancer A549 cell lines and A549/CDDP cell lines. This was achieved by suppressing the expression of GSTP1‐1 within tumor cells (IC50: 16.8 ± 0.8 μM). Furthermore, through the establishment of a nude mouse model featuring lung adenocarcinoma A549/CDDP cell transplantation tumors, gliquidone demonstrated a significant therapeutic effect on the mice tumors, while avoiding discernible side effects. These findings suggest that gliquidone could potentially be repurposed as an adjunct therapy in CDDP‐resistant lung cancer. [ABSTRACT FROM AUTHOR]

Insulin treatment should be introduced in patients with slowly progressive type 1 diabetes (SPIDDM; definite), according to the revised diagnostic criteria of SPIDDM (2023). In contrast, SPIDDM (probable) patients are in a non‐insulin‐dependent state; therefore, a more flexible treatment can be considered, although sulfonylurea agents should be avoided. Insulin treatment has been shown to maintain endogenous insulin secretion capacity in SPIDDM (probable); however, this does not mean that all SPIDDM (probable) patients should use insulin from the early phase. Dipeptidyl peptidase‐4 inhibitors and biguanides might be the treatment of choice for SPIDDM (probable), but no evidence exists for other hypoglycemic agents. In any case, careful monitoring of the endogenous insulin secretion capacity should be carried out, and if a decrease in insulin secretion capacity is suspected, a change in treatment should be considered to prevent progression to an insulin‐dependent state. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia. Materials and Methods: This retrospective cross‐sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20–100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated. Results: Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase‐4 inhibitor, an sodium–glucose transporter 2 inhibitor and a biguanide in patients aged 65 to <75 years, and dual therapy with a sulfonylurea and a dipeptidyl peptidase‐4 inhibitor in patients aged ≥75 years. Unfortunately, glinide was coprescribed for 338 (0.5%) of elderly patients. Insulin was coprescribed for 3,682 (5.6%) of elderly patients. Conclusions: Analysis of real‐world sulfonylurea prescription data found guideline non‐adherence, namely, excessive prescription of glimepiride, use of glibenclamide in elderly patients, and common coprescription with dipeptidyl peptidase‐4 inhibitors. These findings might provide an opportunity to reconsider the treatment of patients with type 2 diabetes mellitus who are over‐prescribed sulfonylureas to reduce residual risks, such as hypoglycemia. [ABSTRACT FROM AUTHOR]

The article focuses on the use of SGLT2 inhibitors in patients with HNF1A-MODY, a type of monogenic diabetes. Topics include the typical treatment regimen for HNF1A-MODY, the observed clinical outcomes from adding SGLT2 inhibitors to existing therapies, and the specific HNF1A genetic variants found in the study participants.

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Sulfonylurea (SU) are an effective class of oral hypoglycemic drugs that have been used in clinical practice for more than 70 years. Despite the common mechanism of action, members of the class have significant intraclass differences in hypoglycemic activity, safety, and the presence of extrapancreatic effects. This review examines the features of gliclazide modified release (MR), its differences from other representatives of the SU and its place in modern recommendations for the treatment of type 2 diabetes mellitus. Gliclazide MR belongs to the modern 2nd generation SU with high hypoglycemic activity, low risk of hypoglycemia due to reversible binding to the SUR1 receptor and no effect on the Epac2 pathway, generally neutral effect on weight, proven nephroprotective properties and cardiovascular safety, which makes it possible to highlight it among representatives of the SU class. International and national clinical guidelines indicate the place of SU when it is necessary to intensify glucose-lowering therapy and glycemic control in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) significantly increases the risk of cardiovascular diseases. Despite advances in glycemic control, managing cardiovascular risk remains a critical challenge. This systematic review aims to assess and compare the cardiovascular outcomes associated with three classes of antidiabetic medications: sulfonylureas, Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM. A systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases, including PubMed, Embase, Cochrane Library, and Google Scholar, were searched for relevant studies published between 2019 and 2023. Inclusion criteria were adults (≥18 years) with T2DM, studies assessing cardiovascular outcomes with the specified medications, randomized controlled trials, observational studies, or meta-analyses. Two independent reviewers performed data extraction and risk of bias assessments. From the initial 1,543 records, 12 studies were included involving 61,534 patients. As a result, GLP-1 RAs demonstrated favorable cardiovascular safety and efficacy, particularly in reducing major adverse cardiovascular events and all-cause mortality. DPP-4 inhibitors were associated with neutral cardiovascular outcomes but indicated an elevated risk of cardiac failure in some studies. In recent studies, sulfonylureas, previously associated with cardiovascular concerns, showed no consistent evidence of increased cardiovascular risk. These findings highlight the importance of personalized treatment strategies to optimize cardiovascular outcomes in patients with T2DM.

Background: Medication utilization has been increasing in the U.S. year‐over‐year for several decades. As older adults take more medications, there is a higher risk of them being exposed to drug–drug or drug‐disease interactions. The American Geriatrics Society in 2019 updated their Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults. The objective of this study was to assess the prevalence of utilization of medications included in the 2019 Beers Criteria. Methods: An analysis was conducted using the Medicare Part D Provider Utilization and Payment Data Public Use File for calendar‐year 2020. Medications identified in the 2019 Beers Criteria were applied to the analysis. Two categories of medications were assessed: (1) "Avoid" and (2) "Use With Caution." Results: In 2020, 56 million prescriptions were dispensed to Medicare patients 65 years and older that are recommended to be avoided without exception (4.7% of all prescriptions) totaling $957 million in medication costs. The most utilized medication classes in this category were benzodiazepines (25,949,994 prescriptions), "Z‐drugs" (6,204,909 prescriptions), long‐acting sulfonylureas (5,306,577 prescriptions), 1st‐generation antihistamines (5,049,289 prescriptions), and tricyclic antidepressants (4,190,062 prescriptions). Additionally, 135 million prescriptions were dispensed to Medicare beneficiaries 65 years and older for medications which the Beers Criteria states to use caution (11.3% of all prescriptions) exceeding $2.85 billion in medication costs. The most utilized medications for this category were diuretics (74,599,126 prescriptions), selective serotonin reuptake inhibitors (30,033,121 prescriptions), serotonin and norepinephrine reuptake inhibitors (11,858,968 prescriptions), tramadol (11,450,878 prescriptions), and mirtazapine (5,737,304 prescriptions). Conclusion: Even with the existence of the AGS Beers Criteria for PIM Use in Older Adults and its continued updated versions, 16% of medications dispensed to Medicare Part D were potentially inappropriate. Future studies are needed to assess if this has led to worsened outcomes among older adults who utilized these PIM. [ABSTRACT FROM AUTHOR]

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 60 years 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sodium‐glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain. METHODS: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016–2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all‐cause dementia. RESULTS: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all‐cause dementia over a 3.2‐year follow‐up, yielding a lower risk for SGLT2 inhibitors (RD, –2.5%; 95% CI, –3.0% to –2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from –4.3% (–5.5 to –3.2) to –0.9% (–1.9 to 0.2). DISCUSSION: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all‐cause dementia, but the association varied among different subgroups. Highlights: New users of sodium‐glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all‐cause dementia as compared to those of sulfonylureas.The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease.A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas. [ABSTRACT FROM AUTHOR]

The American Diabetes Association (ADA) guidelines prioritize Sodicum-glucose transporter-2-inhibitors (SGLT2i) given cardio-renal and glycemic benefits. This study was conducted to observe clinical factors associated with initial SGLT2i prescription in type 2 diabetes patients eligible for SGLT2i by the ADA. Methods. A retrospective case-control study was performed in a safety-net clinic and consisted of the initial SGLT2i prescriptions group and the group without. The data from the electronic medical records between July 2021 and December 2022 were analyzed in the regressional models. Results. There was a significant association between A1c ≥8% (OR 3.7, p=.01), heart failure (OR 19.3, p<.0001), a history of hypotension (OR 11.9, p=.01), and sulfonylureas (OR 6.5, p=.003) with the SGLT2i prescription. Conclusion. Patients with high A1c levels, heart failure, a history of hypotension, and sulfonylureas were more likely than their counterparts to receive SGLT2i prescriptions. Future research should investigate adherence and provider prescribing behaviors related to SGLT2i to further assess optimal drug use. [ABSTRACT FROM AUTHOR]

Context Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. Objective To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. Methods Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. Results SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P <.001). Glucose sensitivity mirrored the additive effect (pmol min−1 m−2 mM−1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P =.04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P =.65). Conclusion Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU. [ABSTRACT FROM AUTHOR]

Monogenic diabetes (MD) represents a cluster of different types of diabetes produced by a mutation of a single gene. The commonest type of MD is maturity-onset diabetes of the young (MODY) which has several subtypes, and neonatal diabetes mellitus (NDM). With improved diagnostic facilities, more cases of monogenic diabetes are being described, and pregnancy is being reported in different forms of monogenic diabetes as these patients enter the reproductive age group. The treatment of monogenic diabetes may change once pregnancy sets in. For example, some forms of monogenic diabetes which respond to oral antidiabetic drugs (OHA), particularly the sulfonylurea agents (SUs), may need insulin during pregnancy. However, this depends on the fetal inheritance of mutation from the mother. This review attempts to put together published reports of pregnancy in various types of monogenic diabetes focussing on the most frequently seen forms of MD. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is a chronic metabolic disease with a steadily increasing prevalence worldwide. Diabetes affects the function of many organs, including the skin. Pharmacotherapy for T2DM is mainly based on oral hypoglycemic drugs. The therapeutic strategy is chosen taking into account the individual patient's characteristics, among other comorbidities. Antidiabetic drugs can induce cutaneous adverse reactions (CADRs) ranging in severity from mild erythema to serious disorders such as DRESS or Stevens–Johnson syndrome. CADRs can result from hypersensitivity to the drug but can also be related to the mechanism of action of the drug or cross-reactivity with drugs of similar structure. This paper reviews CADRs induced by oral antidiabetic drugs, considering their dermatological manifestations and possible pathomechanisms. Particular attention was paid to specific dermatological conditions such as dipeptidylpeptidase 4 inhibitor-associated bullous pemphigoid or Fournier's gangrene associated with sodium-glucose cotransporter 2 inhibitor therapy. Knowledge of the dermatological manifestations of CADRs is important in clinical practice. Recognition of a skin lesion resulting from an adverse drug reaction allows for appropriate management, which in this case is primarily related to drug discontinuation. This is particularly important in the treatment of T2DM since this disease has a high prevalence in the elderly, who are at higher risk of adverse drug reactions. [ABSTRACT FROM AUTHOR]

PURPOSE We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with insulin-treated or sulfonylurea-treated type 2 diabetes in Taiwan. METHODS A total of 898 patients (41.0% insulin users, 65.1% sulfonylurea users; mean [SD] age = 59.9 [12.3] years, 50.7% female) were enrolled in pharmacies, clinics, and health bureaus of Tainan City, Taiwan. Presence of IAH was determined with Chinese versions of the Gold questionnaire (Gold-TW) and Clarke questionnaire (Clarke-TW). Sociodemographics, disease and treatment histories, diabetes-related medical care, and health status were collected. We used multiple logistic regression models to assess the relationship between duration of medication use and IAH. RESULTS Overall IAH prevalence was 41.0% (Gold-TW) and 28.2% (Clarke-TW) among insulin users, and 65.3% (Gold-TW) and 51.3% (Clarke-TW) among sulfonylurea users. Prevalence increased with the duration of sulfonylurea use, whereas it decreased with the duration of insulin use. After controlling for potential confounders, 5 or more years of sulfonylurea use was significantly associated with 3.50-fold (95% CI, 2.39-5.13) and 3.06-fold (95% CI, 2.11-4.44) increases in the odds of IAH based on the Gold-TW and Clarke-TW criteria, respectively. On the other hand, regular blood glucose testing and retinal examinations were associated with reduced odds in both insulin users and sulfonylurea users. CONCLUSIONS The prevalence of IAH was high among patients using sulfonylureas long term, but the odds of this complication were attenuated for those who received regular diabetes-related medical care. Our study suggests that long-term sulfonylurea use and irregular follow-up increase risk for IAH. Further prospective studies are needed to confirm the observed associations. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 1 (TRPV1) is a non‐selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L‐21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L‐21 exhibited low risk of hyperthermia side effect. These results indicated that L‐21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain. [ABSTRACT FROM AUTHOR]

Distributed network studies and multisite studies assess drug safety and effectiveness in diverse populations by pooling information. Targeting groups of clinical or policy interest (including specific sites or site combinations) and applying weights based on effect measure modifiers (EMMs) prior to pooling estimates within multisite studies may increase interpretability and improve precision. We simulated a 4-site study, standardized each site using inverse odds weights (IOWs) to resemble the 3 smallest sites or the smallest site, estimated IOW-weighted risk differences (RDs), and combined estimates with inverse variance weights (IVWs). We also created an artificial distributed network in the Clinical Practice Research Datalink (CPRD) Aurum consisting of 1 site for each geographic region. We compared metformin and sulfonylurea initiators with respect to mortality, targeting the smallest region. In the simulation, IOWs reduced differences between estimates and increased precision when targeting the 3 smallest sites or the smallest site. In the CPRD Aurum study, the IOW + IVW estimate was also more precise (smallest region: RD = 5.41% [95% CI, 1.03-9.79]; IOW + IVW estimate: RD = 3.25% [95% CI, 3.07-3.43]). When performing pharmacoepidemiologic research in distributed networks or multisite studies in the presence of EMMs, designation of target populations has the potential to improve estimate precision and interpretability. This article is part of a Special Collection on Pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Background: Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus. Methods: All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies. Discussion: With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults. Systematic review registration: PROSPERO CRD42021272686. [ABSTRACT FROM AUTHOR]

Purpose: The current umbrella review aimed to evaluate the effect of metformin on all-cause mortality (ACM), cardiovascular mortality, and cardiovascular disease (CVD) incidence in DM patients. Methods: PubMed, Scopus, Cochrane, Google Scholar, and Web of Science databases were searched with special keywords. Related studies were included after screening by two independent investigators based on title and full texts. The AMSTAR2 checklist was used to assess the quality of studies, and Cochran tests were used to assess the heterogeneity between studies. Overall, seventeen systematic reviews and meta-analysis studies were included. The results revealed that the risk of ACM in patients who received metformin was lower than in patients who did not receive metformin. (OR: 0.80, 95% CI:0.744,0.855); also, the risk of CVD mortality in metformin patients was lower than in the other two groups (placebo and other anti-diabetic drugs) (OR: 0.771, 95% CI:0.688,0.853, P:0.001). The risk of CVD in metformin users was also lower than in the other two groups (OR: 0.828, 95% CI:0.781,0.785). Summary: This comprehensive review showed that the risk of ACM, death due to CVD, and incidents of CVD in DM who use metformin was lower than the patients who received a placebo only or other diabetic drugs, which can guide clinicians in medical decision-making. [ABSTRACT FROM AUTHOR]

The contamination of groundwater by herbicides depends on their mobility in soil, which is related to the organic carbon to water partition coefficient, KOC. Because the log KOC values of widely used sulfonylurea herbicides do not correlate with easily accessible log P estimations, multivariate image analysis (MIA) descriptors were employed to build structure-property models to classify these compounds according to their soil sorption capability. In addition, a deeper analysis based on MIA contour maps of PLS regression coefficients and variable importance in projection scores was performed to obtain insight into the chemical features responsible for the log KOC behavior. A multiple linear regression model obtained from selected descriptors demonstrated high predictability (r2 = 0.95, q2 = 0.84, and r2pred = 0.71) and also provided chemical insight into the log KOC values. It has been found that triazine rather than pyrimidine derivatives are less prone to leach out, but substituents attached to the sulfonyl group play an important role in modulating the log KOC values. Consequently, useful guidance for environmental risk assessment is provided for the development of new sulfonylurea herbicides. [ABSTRACT FROM AUTHOR]

Purpose: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically—from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to determine whether the use of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. Methods: Using the United Kingdom Clinical Practice Research Datalink (2007–2019), we assembled two new‐user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP‐1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP‐1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. Results: Compared with sulfonylureas, GLP‐1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person‐years, respectively; HR 0.96, 95% CI 0.53–1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person‐years, respectively; HR 1.03, 95% CI 0.80–1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. Conclusions: In this population‐based cohort study, GLP‐1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas. [ABSTRACT FROM AUTHOR]

BackgroundSulfonylureas have been a longstanding pharmacotherapy in the management of type 2 diabetes, with potential benefits beyond glycemic control. Although sulfonylureas are effective, interindividual variability exists in drug response. Pharmacometabolomics is a potent method for elucidating variations in individual drug response. Identifying unique metabolites associated with treatment response can improve our ability to predict outcomes and optimize treatment strategies for individual patients. Our objective is to identify metabolic signatures associated with good and poor response to sulfonylureas, which could enhance our capability to anticipate treatment outcome.MethodsIn this cross-sectional study, clinical and metabolomics data for 137 patients with type 2 diabetes who are taking sulfonylurea as a monotherapy or a combination therapy were obtained from Qatar Biobank. Patients were empirically categorized according to their glycosylated hemoglobin levels into poor and good responders to sulfonylureas. To examine variations in metabolic signatures between the two distinct groups, we have employed orthogonal partial least squares discriminant analysis and linear models while correcting for demographic confounders and metformin usage.ResultsGood responders showed increased levels of acylcholines, gamma glutamyl amino acids, sphingomyelins, methionine, and a novel metabolite 6-bromotryptophan. Conversely, poor responders showed increased levels of metabolites of glucose metabolism and branched chain amino acid metabolites.ConclusionThe results of this study have the potential to empower our knowledge of variability in patient response to sulfonylureas, and carry significant implications for advancing precision medicine in type 2 diabetes management.

Objective: Sulfonylureas (SUs) are still among the mostly prescribed antidiabetic drugs with an established mode of action: release of insulin from pancreatic β-cells. In addition, effects of SUs on adipocytes by activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) have been described, which might explain their insulin-sensitizing potential observed in patients. However, there is a discrepancy between the impact of SUs on antidiabetic action and their rather moderate in vitro effect on PPARγ transcriptional activity. Recent studies have shown that some PPARγ ligands can improve insulin sensitivity by blocking PPARγ Ser-273 phosphorylation without having full agonist activity. It is unknown if SUs elicit their antidiabetic effects on adipocytes by inhibition of PPARγ phosphorylation. Here, we investigated if binding of SUs to PPARγ can interfere with PPARγ Ser-273 phosphorylation and determined their antidiabetic actions in vitro in primary human white adipocytes and in vivo in high-fat diet (HFD) obese mice. Methods: Primary human white preadipocytes were differentiated in the presence of glibenclamide, glimepiride and PPARγ ligands rosiglitazone and SR1664 to compare PPARγ Ser-273 phosphorylation, glucose uptake and adipokine expression. Transcriptional activity at PPARγ was determined by luciferase assays, quantification of PPARγ Ser-273 phosphorylation was determined by Western blotting and CDK5 kinase assays. In silico modelling was performed to gain insight into the binding characteristics of SUs to PPARγ. HFD mice were administered SUs and rosiglitazone for 6 days. PPARγ Ser-273 phosphorylation in white adipose tissue (WAT), body composition, glucose tolerance, adipocyte morphology and expression levels of genes involved in PPARγ activity in WAT and brown adipose tissue (BAT) were evaluated. Results: SUs inhibit phosphorylation of PPARγ at Ser-273 in primary human white adipocytes and exhibit a positive antidiabetic expression profile, which is characterized by up regulation of insulin-sensitizing and down regulation of insulin resistance-inducing adipokines. We demonstrate that SUs directly bind to PPARγ by in silico modelling and inhibit phosphorylation in kinase assays to a similar extend as rosiglitazone and SR1664. In HFD mice SUs reduce PPARγ phosphorylation in WAT and have comparable effects on gene expression to rosiglitazone. In BAT SUs increase UCP1 expression and reduce lipid droplets sizes. Conclusions: Our findings indicate that a part of SUs extra-pancreatic effects on adipocytes in vitro and in vivo is probably mediated via their interference with PPARγ phosphorylation rather than via classical agonistic activity at clinical concentrations.

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. [ABSTRACT FROM AUTHOR]

Background and Aims: Given treatment‐related hypoglycaemia in hospitals can lead to adverse outcomes, the Australian Commission on Safety and Quality in Health Care has included hypoglycaemia as a reportable hospital‐acquired complication (HAC) with financial disincentives. However, the designation of a hypoglycaemia HAC relies on clinical coding without a defined glucose threshold or clinical context. We assessed the biochemical validity and clinical relevance of a hypoglycaemia HAC. Methods: We performed a retrospective review on patients discharged from the Northern Health hospitals between March and August 2021 who were designated as experiencing a hypoglycaemia HAC. We assessed cases for biochemical validity (glucose <4.0 mmol), clinical context and whether they were treatment‐related (treatment with insulin or sulphonylurea). We then compared this cohort with a hospital‐wide glucometric survey based on a point‐prevalence study to determine the proportion of individuals with hypoglycaemic events that were designated as hypoglycaemia HAC. Results: Two hundred fifty‐six admissions were coded as hypoglycaemia HAC. Eleven (4%) did not have a biochemically valid episode. Of the valid cases, 34 (14%) were not treated with any glucose‐lowering medication and 11 (4%) were treated with noninsulin, nonsulphonylurea glucose‐lowering medication. Two hundred admissions (78%) were considered treatment‐related HAC. Of 139 individuals with diabetes identified in the hospital‐wide point‐prevalence study, 25 (18%) had biochemical evidence for hypoglycaemia: 22 were treatment‐related, of which 68% were not coded as HAC. Conclusion: Given safety and cost implications, the designation of hypoglycaemia HAC requires a standardised definition incorporating a biochemical threshold and clinical context. We propose a clinically relevant definition of hypoglycaemia HAC to promote safe diabetes care. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardiovascular benefits, whereas thiazolidinediones (TZDs) and sulfonylureas (SUs) increase cardiovascular risk. The objective of this study was to describe the use of SGLT-2is, GLP-1RAs, TZDs, and SUs before and after a heart failure (HF)-related hospitalization in nursing home (NH) residents with type 2 diabetes (T2D). This was a cohort study using a 20% sample of Medicare claims linked with Minimum Data Set resident assessments. The study population was long-stay NH residents with T2D and an HF-related hospitalization between January 1, 2013, and August 31, 2018. For individuals with multiple HF hospitalizations, 1 hospitalization was randomly selected. We ascertained diabetes medications using Medicare Part D claims during the 120 days before and after hospital discharge (or skilled nursing facility discharge, where applicable). We calculated (1) the proportion of study participants who received a medication class of interest during pre- and posthospitalization periods; (2) the proportion of continuous users; and (3) the proportion of posthospitalization users who were new users. A total of 12,990 NH residents with T2D and an HF-related hospitalization were included (mean age 78 years, 66% female, 19% Black). Before hospitalization, 1.5% received TZDs, 14.1% received SUs, 1.2% received GLP-1RAs, and 0.3% received SGLT-2is. Among prehospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 49%, 62%, 60%, and 40% continued the medications, respectively. Among posthospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 37%, 10%, 28%, and 11%, respectively, were new users. Among NH residents with hospitalized HF, GLP-1RAs and SGLT-2is were seldom used. TZDs and SUs were still used by many residents with T2D after HF hospitalizations. Barriers may exist in the use of newer diabetes medications to prevent heart failure in NH residents with T2D, which warrants further studies in older adults with multimorbidity. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is characterized by insulin resistance and β-cell failure. The latter involves impaired insulin secretion and β-cell dedifferentiation. Sulfonylurea (SU) is used to improve insulin secretion in diabetes, but it suffers from secondary failure. The relationship between SU secondary failure and β-cell dedifferentiation has not been examined. Using a model of SU secondary failure, we have previously shown that functional loss of oxidoreductase Cyb5r3 mediates effects of SU failure through interactions with glucokinase. Here we demonstrate that SU failure is associated with partial β-cell dedifferentiation. Cyb5r3 knockout mice show more pronounced β-cell dedifferentiation and glucose intolerance after chronic SU administration, high-fat diet feeding, and during aging. A Cyb5r3 activator improves impaired insulin secretion caused by chronic SU treatment, but not β-cell dedifferentiation. We conclude that chronic SU administration affects progression of β-cell dedifferentiation and that Cyb5r3 activation reverses secondary failure to SU without restoring β-cell dedifferentiation. [ABSTRACT FROM AUTHOR]

The simultaneous determination of trace pesticides in complex matrices containing high concentrations of natural pigments remains challenging. In this study, quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation together with high-performance liquid chromatography with ultraviolet detection (HPLC–UV) was applied for the multi-residue analysis of seven sulfonylurea herbicides (SUHs) in tomatoes. SUH residue was extracted using the QuEChERS procedure, followed by solid-phase extraction (SPE) and dispersive SPE (d-SPE). To reduce the amount of carotenoids in tomato extracts, several d-SPE clean-up procedures were compared, and octadecylsilane (C18) provided the best color removal rate (%) of tomato extracts and recoveries (%) for all the tested SUHs. The validation results indicate good linearity (R2 > 0.9970), accuracy, and precision. Recoveries of 70–120% and relative standard deviations < 20% were achieved for all analytes at three spiked concentrations. The limits of detection and quantification for the 7 SUHs were 0.003 mg kg−1 and 0.008–0.009 mg kg−1, respectively. The developed method was subsequently used to quantify multi-residue SUHs during real sample analysis. None of the tested samples had SUH residue levels higher than the maximum residue limits established by the Korean Ministry of Food and Drug Safety. The results suggest that QuEChERS sample preparation employing a combination of C18 is a high-throughput and rapid clean-up procedure for the multi-residue analysis of SUHs in tomatoes. [ABSTRACT FROM AUTHOR]

Simple Summary: Diabetes affects patients with breast cancer. Women with diabetes and the comorbidities related to diabetes tend to receive less aggressive breast cancer treatments primarily because of the potential side effects of the treatment. Managing proper antidiabetic treatment should affect the patient's breast cancer prognosis in patients with both conditions. This review explores the link between diabetes and an elevated risk of breast cancer, highlighting the global prevalence of these conditions. It delves into the impact of antihyperglycemic therapy, including insulin, metformin, and novel groups: incretins and SGLT-2 inhibitors, on the prognosis of breast cancer in diabetic patients. The review also underscores the increased incidence and mortality rates of breast cancer in individuals with diabetes, along with the role of obesity and its connection to the metastasis process in those undergoing antidiabetic treatment. The role of obesity as a confounding variable is confirmed, highlighting the importance of considering obesity during hypoglycemic therapy selection in breast cancer patients. Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Super bacterial infection caused by metallo‐β‐lactamases (MβLs) has posed a serious public health threat, while developing inhibitors of MβLs is an ideal strategy to combat drug‐resistance. Here, seventeen sulfonylureas were synthesized and confirmed. Biological assay shown that these molecules effectively inhibited MβL ImiS, with an IC50 value in the range of 29.5–188.2 μM, and the best inhibitor competitively and irreversibly inhibited ImiS with a Ki value of 15.2 μM. Structure‐activity relationship analysis revealed that the chlorine‐substituted phenyl significantly raised inhibitory activity of sulfonylureas on ImiS. Antibacterial and chessboard dilution assays shown that the most sulfonylureas tested enhanced antimicrobial effect of meropenem (MER) on E. coli‐ImiS, and the two inhibitors with best effect resulted in an 8‐fold reduction in MIC of MER. Mice tests shown that the best inhibitor synergizing MER virtually diminished the load of E. coli‐ImiS in spleen and liver. Docking study revealed that the sulfonylurea reacts with ImiS mainly through the sulfonyl group, in which one of oxygen atoms coordinates to Zn(II), and forms two hydrogen bonds with Lys224 (2.1 Å) and His263 (3.1 Å). This work revealed the sulfonylureas are promising candidates for the development of ImiS inhibitors. [ABSTRACT FROM AUTHOR]

Background: Assessing a patient with Type 2 Diabetes (T2DM) involves a comprehensive evaluation of their medical history, current symptoms, physical examination, and laboratory tests. Here's a structured approach to assessing a patient with T2DM. Evaluate the patient's current diabetes management plan, including diet, exercise, medication adherence, self-monitoring of blood glucose, and insulin administration if applicable. Assess barriers to effective diabetes management, such as socioeconomic factors, access to healthcare, health literacy, and psychosocial support. Collaborate with the patient to set individualized goals for glycemic control, blood pressure, lipid levels, weight management, and prevention of diabetes-related complications. Materials and methods: A six-month longitudinal study was conducted at a tertiary care facility. Those with type 2 diabetes who were receiving insulin and oral hypoglycemics were included in the trial. Laboratory investigations and a sociodemographic profile were gathered using a pretested, structured questionnaire. EPI Info, Open EPI, and SPSS 22 version software were used for the statistical analysis. The statistical tests were the Students t-test and the Chi-square test. Result: There were ninety-nine diabetic individuals in the oral group. Oral hypoglycemics were 46.8±7.6 years old on average. Our research indicates that type II diabetes can be treated with both monotherapy and combination medications. According to the results of this study, the majority of doctors first prescribed monotherapy (25%) consisting of Metformin, Glipizide, Glimepiride, and Gliclazide to control hyperglycemia. Then came triple treatment (40%) including Metformin + Glimepiride + Pioglitazone and dual therapy (35%) comprising FDC of Metformin + Pioglitazone, Metformin + Glipizide, Metformin + Glimepiride, Metformin + Saxagliptin, and Metformin + Voglibose. Conclusion: The most often given medications in our research were biguanide, metformin, and sulfonylureas, such as glimepiride, glibenclamide, glipizide, and gliclazide. [ABSTRACT FROM AUTHOR]

Objective: Using non-geriatric type 2 diabetic patients with and without diabetic foot ulcers (DFUs), this study investigated the frequency of poor handgrip strength and examined the association between handgrip strength and diabetic foot disorder. Methods: The study comprised a total of 525 patients with type 2 diabetes who visited the endocrinology outpatient clinic between August 2020 and June 2022; 242 of them had DFUs. Patients were selected according to inclusion and exclusion criteria. Data on medications used, as well as demographic and clinical information, were taken from hospital archives. The severity of ulcers was assessed using the Wagner score. Using a portable digital dynamometer, a test of handgrip strength was conducted. Low handgrip strength was defined as less than 16 kg for females and 27 kg for males. Results: Patients with DFUs exhibited lower handgrip strength, older age, a longer duration of diabetes diagnosis, a lower body mass index, and higher fasting plasma glucose and hemoglobin A1c levels. Comorbidities such as peripheral artery disease and ischemic heart disease were more frequent in patients with DFUs and low handgrip strength. Diabetic foot ulcer frequency was 3.149 times higher among those with poor hand grip strength than those with good strength (odds ratio = 3.149; 95% CI, 2.118-4.672; P < .001). Conclusion: Non-geriatric type 2 diabetes patients with DFUs had a higher frequency of low handgrip strength. Low handgrip strength was independently associated with the presence of DFUs. This study emphasizes the importance of addressing low handgrip strength as a potential risk factor in managing diabetic foot disease in non-geriatric type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

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Illicit drug supply adulteration can heighten the risk for adverse health outcomes. Sulfonylurea medications are widely used in the treatment of diabetes mellitus (DM). Unintentional or intentional overdose of sulfonylureas can cause refractory hypoglycemia. This case report describes a 62-year-old male patient who presented to the emergency department (ED) after being found on the ground with signs of mild trauma. He was noted to be persistently hypoglycemic despite boluses of intravenous dextrose, a dextrose infusion, and oral nutrition. The patient did report purchase and oral ingestion of pills sold as oxycodone and that the pill shape and color were different from his usual supply. The patient was empirically treated with octreotide resulting in normalization of his serum glucose. Testing demonstrated a serum glipizide concentration six times the reporting range. This case represents unintentional sulfonylurea exposure in the setting of non-prescribed oxycodone use, resulting in hypoglycemia refractory to intravenous dextrose and oral nutrition. Octreotide is an additional potential treatment for this condition. As in this case, ingestion of street drugs may present a potential source of sulfonylurea exposure. Opioid contamination with sulfonylureas has not been widely reported in the literature and knowledge about this potential exposure is important for the prompt recognition and treatment of these patients by emergency physicians. [ABSTRACT FROM AUTHOR]

Ukraine is one of the world’s guarantors of food security and has the potential to further increase agricultural production. However, the vast majority of herbicides used on crops are acetolactate synthase (ALS) inhibitors, which poses a threat of herbicide-resistant weed species. The emergence and spread of herbicide-resistant weed biotypes can significantly increase the cost of growing crops to the point of loss of profitability. Herbicide resistance in barnyardgrass (Echinochloa crus-galli var. crus-galli) has been studied in long-term field and greenhouse experiments. Resistance of E. crus-galli to the ALS herbicide triazolopyrimidine derivative ‒ penoxsulam was identified. Expressed resistance was observed in weed plants grown from seeds collected under production conditions in Kherson region in 2015–2016 and 2020–2021. Cross resistance was observed for imidazolinone and sulfonylurea derivatives. It should be noted that the level of cross resistance to ALS herbicides was slightly higher for plants derived from weed seeds harvested in 2020–2021 compared to those harvested in 2015–2016. The introduction of a herbicidal composition of a herbicide mixture ‒ an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD) (an enzyme in plants in the chain of carotenoid synthesis) ‒ mesotrione with an ALS-inhibitor (nicosulfuron) allowed effective control of the weed, which indicates the absence of multiple resistance to herbicides ‒ inhibitors of carotenoid synthesis. The high efficiency of E. crus-galli control was established by the application of herbicides ‒ inhibitors of fatty acid synthesis (graminicides). The highest level of efficiency in the experiments was observed with the application of fluazifop-butyl and somewhat less ‒ with pinoxaden. A tendency to reduce phytotoxicity to barnyardgrass from the south of Ukraine was observed with the introduction of tepraloxydim and quizalofop-ethyl. A lower level of phytotoxicity of fenoxaprop-p-ethyl on E. crus-galli should be noted compared to the effect of pinoxaden. No multiple resistance was observed with glyphosate (5-enolpyruvylshikimate-3-phosphate synthase inhibitor) and reglone (photosystem I inhibitor), allowing control of vegetative weeds at the beginning and end of the growing season. It has been established that monocot weed species have significantly increased their presence and harmfulness in agrophytocenoses in Ukraine and in the world since the 1950s with the widespread introduction of selective dicotyledonous species control with aryloxyphenoxyacetic, propionic and benzoic acid derivatives. This trend has been maintained until recently ‒ barnyardgrass is one of the dominant weed species in modern agrophytocenoses of Ukraine. Therefore, the identification of the ALS-resistant biotype of barnyardgrass complicates weed control in the following crops in rotations in the southern regions of the country: in maize crops with cross resistance to nicosulfuron, in sunflower ‒ to imidazolinones (imazamox, imazapyr), and also makes it impossible to use penoxsulam in rice production. Traditionally, the use of synthetic auxins, phenoxyacetic acid derivatives, etc. is used to control ALS-resistance. However, in Kherson region of Ukraine, already in the third year of application of rinskor (florpyrauxifen-benzyl), some weed plants were found on rice fields affected by ALS-resistant barnyardgrass, which recovered after the use of synthetic auxin. Therefore, the control of ALS-resistance (penoxsulam, etc.) in E. crus-galli with the application florpyrauxifen-benzyl in the Kherson region of Ukraine is already limited. An obvious and economically feasible preventive measure against the emergence of resistant weed biotypes is the implementation of GAP (Good Agricultural Practice, FAO) approaches: in particular, the use of high quality seeds without weed impurities, increasing the proportion of agrotechnical weed control measures, restoring and expanding crop rotations with mandatory rotation of herbicides with different modes of action, introducing dicotyledonous/leguminous crops into rotations, and using herbicides with different modes of action in crops separately or in mixtures. At the same time, agrotechnical measures and the preservation of biodiversity in agrophytocenoses should be the main factor in controlling resistance in weeds. The use of herbicides and their mixtures with different modes of action is of secondary importance. The identification of highly damaging ALS-resistant E. crus-galli in southern Ukraine indicates the insufficient effectiveness of weed control exclusively with herbicides with a single mechanism of action and requires a significant revision of the principles of crop rotation and ways of weed control in the country to maintain high levels of profitability and productivity of agrophytocenoses. Solving this problem is urgent for the preservation of Ukraine's potential as one of the guarantors of global food security.

Ramadan fasting, a religious practice observed by Muslims worldwide, involves abstaining from eating, drinking, smoking, and using oral medications from dawn to dusk during the ninth lunar month. Studies have demonstrated that fasting during Ramadan has been shown to increase HDL cholesterol, leptin, adiponectin, and insulin sensitivity, as well as lower several hemostatic risk factors for cardiovascular diseases. Additionally, it may result in a drop in blood sugar levels, especially in diabetics who are also on blood sugar-lowering medicine. Hypoglycemia, characterized by low blood sugar levels, could also result from fasting during Ramadan. The GLP-1 (glucagon-like peptide-1) hormone plays a significant role in regulating glucose metabolism and insulin secretion, and Ramadan fasting can affect its production and release in the gut. Research contributes to our understanding of the utilization of GL-1 medications during Ramadan among patients, broadening therapy alternatives and offering insightful information for well-informed decision-making. Therefore, this narrative review aims to explore the current evidence that studies the safety and efficacy of GLP-1 agonists during Ramadan for nondiabetic and diabetic patients to ensure healthy fasting during Ramadan. [ABSTRACT FROM AUTHOR]

Background: Hypoglycemia from overtreatment is a serious but underrecognized complication among older adults with type 2 diabetes. However, diabetes treatment is seldom deintensified. We assessed the effectiveness of a Clinical Decision Support (CDS) tool and shared decision‐making (SDM) in decreasing the number of patients at risk for hypoglycemia and reducing the impact of non‐severe hypoglycemic events. Methods: HypoPrevent was a pre‐post, single arm study at a five‐site primary care practice. We identified at‐risk patients (≥65 years‐old, with type 2 diabetes, treated with insulin or sulfonylureas, and HbA1c < 7.0%). During three clinic visits over 6 months, clinicians used the CDS tool and SDM to assess hypoglycemic risk, set individualized HbA1c goals, and adjust use of hypoglycemic agents. We assessed the number of patients setting individualized HbA1c goals or modifying medication use, changes in the population at risk for hypoglycemia, and changes in impact of non‐severe hypoglycemic events using a validated patient‐reported outcome tool (TRIM‐HYPO). Results: We enrolled 94 patients (mean age—74; mean HbA1c (±SD)—6.36% ± 0.43), of whom 94% set an individualized HbA1c goal at either the baseline or first follow‐up visit. Ninety patients completed the study. Insulin or sulfonylurea use was decreased or eliminated in 20%. An HbA1c level before and after goal setting was obtained in 53% (N = 50). Among these patients, the mean HbA1c increased 0.53% (p < 0.0001) and the number of patients at‐risk decreased by 46% (p < 0.0001). Statistically significant reductions in the impact of hypoglycemia during daily activities occurred in both the total score and each functional domain of TRIM‐HYPO. Conclusions: In a population of older patients at risk for hypoglycemia, the use of a CDS tool and SDM reduced the population at risk and decreased the use of insulin and sulfonylureas. Using a patient‐reported outcome tool, we demonstrated significant reductions in the impact of hypoglycemia on daily life. [ABSTRACT FROM AUTHOR]

Sulfonylureas (SU) continue to be a vital therapeutic category of oral hypoglycemic agents (OHAs) for the management of type 2 diabetes mellitus (T2DM). Physicians consider modern SU (gliclazide and glimepiride) as "safe and smart" choices for T2DM management. The presence of multiple international guidelines and scarcity of a national guideline may contribute to the challenges faced by few physicians in choosing the right therapeutic strategy. The role of SU in diabetes management is explicit, and the present consensus aims to emphasize the benefits and reposition SU in India. This pragmatic, practical approach aims to define expert recommendations for the physicians to improve caregivers' knowledge of the management of T2DM, leading to superior patient outcomes. [ABSTRACT FROM AUTHOR]

We previously developed, synthesized and tested light‐activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light‐dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push‐pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine‐tuned, light‐activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine‐, pyrrolidine‐ and piperidine‐based sulfonylureas all increased beta cell Ca2+‐spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine‐based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine‐azobenzenes as chemical photoswitches across drug classes. [ABSTRACT FROM AUTHOR]

This work presents a series of successive vegetation experiments in biotesting of samples of sod-podzolic cultivated soil after its treatment with herbicides of the class of sulfonylureas—Magnum, water-dispersable granules (metsulfuron-methyl (600 g/kg) manufactured by August) and Alister Grand, MD (diflufenican 180 g/L + mesosulfuronmethyl 6.0 g/L + iodosulfuron-methyl-sodium 4.5 g/L + antidote mephenpyrdiethyl 27 g/L) manufactured by Bayer. The residual phytotoxicity of these preparations for seedlings of sensitive crops of white lupine (Lupinus albus) and mung bean (Vigna radiata) was studied. The initial soil samples were taken in the field on day 5 after the application of herbicides in winter wheat crops grown using two different tillage technologies: traditional moldboard plowing and zero tillage. The results of biotesting of samples at 20°C and humidity of 60% of field capacity showed that the half-life of herbicides (DT50) comprised 40 ± 3 days after the incubation start, and detoxification to the level of 70–80% occurred 200–240 days after the introduction of herbicides into the sod-podzolic. Regardless of the tillage method and the applied herbicide, the suppression of test crops at the level of >10% relative to the control was detected 2 years after the application of herbicides. White lupine and mung bean are highly sensitive to the effect of microquantities of herbicides of the sulfonylurea group; therefore, it is recommended to use these test crops to determine the residual phytotoxicity of soil. The shown residual effect of sulfonylureas on legumes is important for special crop rotations elaborated for zero tillage. [ABSTRACT FROM AUTHOR]

In this study, some new sulfonylurea derivatives based on the sulfanilamide compound were synthesized. IR, 1H-NMR, 13C-NMR spectroscopic methods and elemental analysis data were used to confirm the structures of the synthesized compounds. ABTS, DPPH, Cuprac and β-Carotene/linoleic acid assays were performed to evaluate the antioxidant activities of sulphonylurea derivatives. The activities of these compounds against some enzymes (acetylcholinesterase, butrylcholinesterase, tyrosinase, α-amylase and α-glucosidase) were also investigated. Compounds S7, S8, S13 and S14 showed inhibitory activity against α-amylase enzyme with IC50 values of 227.84±1.48- 298.27±8.61 µM. In addition, the drug-likeness properties and solubility of the compounds were determined by computational programs. [ABSTRACT FROM AUTHOR]

Background and purpose: Multidrug and toxin extrusion transporter 1 (MATE1), encoded by the SLC47A1 gene and single nucleotide polymorphisms of organic cation transport 1, may impact metformin's responsiveness and side effects. Inward-rectifier potassium channel 6.2 (Kir 6.2) subunits encoded by KCNJ11 may affect the response to sulfonylurea. This study aimed to evaluate the association between SLC22A1 rs72552763 and rs628031, SLC47A1 rs2289669 and KCNJ11 rs5219 genetic variations with sulfonylurea and metformin combination therapy efficacy and safety in Egyptian type 2 diabetes mellitus patients. Experimental approach: This study was conducted on 100 cases taking at least one year of sulfonylurea and metformin combination therapy. Patients were genotyped via the polymerase chain reaction-restriction fragment length polymorphism technique. Then, according to their glycated hemoglobin level, cases were subdivided into non-responders or responders. Depending on metformin-induced gastrointestinal tract side effects incidence, patients are classified as tolerant or intolerant. Findings/Results: KCNJ11 rs5219 heterozygous and homozygous mutant genotypes, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and AG), and mutant alleles of both polymorphisms were significantly related with increased response to combined therapy. Individuals with the SLC22A1 (rs72552763) GAT/del genotype and the SLC22A1 (rs628031) AG and AA genotypes were at a higher risk for metformin-induced gastrointestinal tract adverse effects. Conclusion and implications: The results implied a role for SLC47A1 rs2289669 and KCNJ11 rs5219 in the responsiveness to combined therapy. SLC22A1 (rs628031) and (rs72552763) polymorphisms may be associated with increased metformin adverse effects in type 2 diabetes mellitus patients. [ABSTRACT FROM AUTHOR]

Background: Sulfonylureas are oral glucose‐lowering medications positioned as a second‐line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase‐4 (DPP4) inhibitor use. Methods: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population‐based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity‐score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention‐to‐treat exposure definition. A separate propensity‐score weighted analysis was conducted to explore within‐class differences in dementia risk among sulfonylurea new users selected from the primary cohort. Results: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person‐years; aHR [95% CI] = 1.09 [1.04–1.15]) over a mean follow‐up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03–1.32]). Conclusion: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes. See related Editorial by Lee et al. in this issue. [ABSTRACT FROM AUTHOR]

Background: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently thought to have 14 subtypes. Patients with MODY are easily misdiagnosed with type 1 diabetes. Case presentation: We report a 25-year-old male patient with diabetes regarding a heterozygous missense mutation in the ABCC8 gene (c.2473C > T, p.Arg825Trp). Based on the genetic test results, the patient was diagnosed with MODY12 and treated with glimepiride with improved glycemic control. Conclusion: This case report highlights an ABCC8 gene mutation in MODY12 that responds to sulfonylurea treatment. [ABSTRACT FROM AUTHOR]