Sulfonylurea Drugs Research Articles

New-user study design assesses sulfonylurea and warfarin drug interaction

New-user study design assesses sulfonylurea and warfarin drug interaction

Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors

The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1β at 2 μM, with an IC50 value of 0.805 μM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.

9182 Metastatic Extra-Gastrointestinal Stromal Tumor Presenting As Hypoglycemia

Abstract Disclosure: O. faour: None. D. John: None. S.K. Suryanarayanan: None. A.A. Rizvi: None. Introduction: Non islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome seen in association with solid abdominal tumors of mesenchymal and epithelial origin. We report a case of metastatic extra-gastrointestinal stromal tumor (E-GIST) presenting with severe hypoglycemia as its initial manifestation. CASE DESCRIPTION: A 46-year-old patient was found to have a blood glucose of <45 mg/dl during a routine clinic visit with her primary care physician. Although she was asymptomatic, she was sent to the emergency room (ER) for further evaluation. She had a history of prediabetes managed by lifestyle modification. She has been experiencing multiple episodes of hypoglycemia previously which fulfilled the Whipple’s triad in the preceding months. These hypoglycemic episodes included loss of unconsciousness, falls in the shower with head injury, and several hospital visits. Serum glucose in the ER was 14 mg/dl and hypoglycemia persisted despite continuous dextrose solution. Physical examination was notable for a distended, non-tender abdomen and cervical lymphadenopathy. CT scan showed a 15 cm mass in the liver, multiple large masses in the mesentery, and a 11 cm lesion in the left pelvis. There were enlarged lymph nodes in the abdomen, chest, and neck. Serum chemistries drawn when the patient was hypoglycemic revealed potassium level of 2.7 mg/dl (3.5-5.5) an insulin level of <1.0 mIU/L (5-25), C-peptide <0.1 ng/mL (0.5-2), cortisol 13.8 mcg/dL (5-25), and insulin-like growth factor-2 (IGF-2) was 270 ng/mL (38-267). The IGF-2/IGF-1 molar ratio was 3.4 (normal <3:1). The sulfonylurea drug screen came back negative. Upper and lower endoscopies were unrevealing. Biopsy of the liver lesion showed cytology and immunohistochemical findings consistent with a epithelioid metastatic extra-gastrointestinal stromal tumor. A provisional diagnosis of NICTH was made. The patient responded well to intravenous glucose, oral carbohydrate intake and high-dose corticosteroids. She was subsequently started on therapy with the tyrosine kinase inhibitor (TKI) imatinib. Discussion: Paraneoplastic hypoglycemia is often seen in association with metastatic epithelial and mesenchymal tumors. IGF-2 and incompletely processed pro-IGF-2 activates autocrine, paracrine, and endocrine pathways that lead to tumor growth, fasting hypoglycemia, rarely of acromegalic features. Treatment with octreotide, diazoxide, and glucagon is generally ineffective, while glucocorticoid use and surgical intervention are helpful in ameliorating the hypoglycemia. Tumor-directed therapy with TKIs, primarily imatinib, appears promising in achieving remission. Our case is a clinical reminder that hypoglycemia secondary to NICTH can be the predominant presenting feature in patients with underlying E-GIST. Presentation: 6/3/2024

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.

Chinese carrier of the HNF1A p.Gln444fs variant exhibits enhanced response to sulfonylureas

BackgroundWe assessed the response to sulfonylureas and the functional characteristics of HNF1A mutations in patients with maturity-onset diabetes of the young type 3 (MODY3). MethodsWe recruited a family with suspected MODY in this study, and gene sequencing (whole-exome sequencing) was used to screen germline mutations. Luciferase reporter assays were used to evaluate the activity of the mutated genes. ResultsHeterozygous HNF1A variant (NM_000545.8:c.1330_1331del, p.Gln444fs) was identified in the proband and was not found in his father, grandmother, and nonrelated healthy controls. The mutant protein had 552 amino acids, 110 fewer than the wild type protein. Furthermore, the amino acid sequence was completely different between the mutant protein and the wild type protein starting from the 444th amino acid. Luciferase reporter assays revealed that the variant had impaired HNF4A promoter–regulation activity. The patient did not achieve good hypoglycemic effects during long-term treatment with insulin and metformin. The effect of hypoglycemic treatment was highly significant after the addition of sulfonylurea drugs. ConclusionsThe HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.

A Comparison Of Glyburide And Insulin In Women With Gestational Diabetes Mellitus

Background: Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug, because of concern about teratogenicity and neonatal hypoglycemia. There is little information about the efficacy of these drugs in this group of women. Methods: We studied 404 women with singleton pregnancies and gestational diabetes that required treatment. The women were randomly assigned be- tween 11 and 33 weeks of gestation to receive gly- buride or insulin according to an intensified treatment protocol. The primary endpoint was achievement of the desired level of glycemic control. Secondary endpoints included maternal and neonatal complications. Results: The mean (±SD) pretreatment blood glucose concentration as measured at home for one week was 114±19 mg per deciliter (6.4±1.1 mmol per liter) in the glyburide group and 116±22 mg per deciliter (6.5±1.2 mmol per liter) in the insulin group (P=0.33). The mean concentrations during treatment were 105± 16 mg per deciliter (5.9±0.9 mmol per liter) in the glyburide group and 105±18 mg per deciliter (5.9±1.0 mmol per liter) in the insulin group (P=0.99). Eight women in the glyburide group (4 percent) required insulin therapy. There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age (12 percent and 13 percent, respectively); who had macrosomia, defined as a birth weight of 4000 g or more (7 percent and 4 percent); who had lung complications (8 percent and 6 percent); who had hypoglycemia (9 percent and 6 percent); who were admitted to a neonatal intensive care unit (6 percent and 7 percent); or who had fetal anomalies (2 percent and 2 percent). The cord-serum insulin concentrations were similar in the two groups, and glyburide was not detected in the cord serum of any infant in the glyburide group. Conclusion : In women with gestational diabetes, glyburide is a clinically effective alternative to insulin therapy

Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13.

This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets. Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS). Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25. For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic β-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.

Investigating the association between the administration of SGLT-2 inhibitors and the risk of urinary tract infection; a systematic review and meta-analysis

Introduction: Sodium-glucose transporter 2 (SGLT-2) inhibitors induce glycosuria. Therefore, using a meta-analysis study, this study aimed to evaluate the correlation between SGLT2 inhibitor administration and urinary tract infection (UTI) risk. Materials and Methods: In this systematic review and meta-analysis, we conducted searches on Scopus, PubMed, Web of Science, Cochrane, and Google Scholar without time limitations up to October 16, 2023. Data were analyzed using STATA 14 software, and a significance level of P < 0.05 was considered. Results: The combination of 11 studies revealed that the use of SGLT2 inhibitors, when compared to glucagon-like peptide-1 (GLP-1) receptor agonists, reduced the risk of UTI (OR = 0.77; 95% CI: 0.62, 0.95) and when compared to insulin (OR = 0.74; 95% CI: 0.63, 0.87). However, the administration of SGLT2 inhibitors, when compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitors (OR = 1.09; 95% CI: 0.90, 1.32), sulfonylureas (OR = 1.35; 95% CI: 0.88, 2.05), biguanide initiators (OR = 1.14; 95% CI: 1.05, 1.24), thiazolidinediones (OR = 1.19; 95% CI: 0.58, 2.44), and other antidiabetic drugs (OR = 1.20; 95% CI: 0.92, 1.57), did not increase the risk of UTI. The administration of dapagliflozin (OR = 1.51; 95% CI: 0.60, 3.81), canagliflozin (OR = 1.22; 95% CI: 0.47, 3.15), and empagliflozin (OR = 3.22; 95% CI: 2.97, 3.48) showed associations with UTI risk. Furthermore, the correlation between SGLT2 inhibitors use and UTI risk was observed in cohort studies (OR = 1.14; 95% CI: 0.98, 1.32), cross-sectional studies (OR = 0.86; 95% CI: 0.64, 1.14), in males (OR = 1; 95% CI: 0.72, 1.40), and females (OR = 1.17; 95% CI: 0.91, 1.52). Conclusion: Empagliflozin, in contrast to dapagliflozin and canagliflozin, increases the risk of UTI. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023479548) and Research Registry (UIN: reviewregistry1742) Websites

Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 μM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Abstract 318: Glibenclamide May Have a Neuroprotective and Cardioprotective Role Beyond Cerebral Edema in an Asphyxial Model of Cardiac Arrest

Background: Cardiac arrest (CA) is a leading cause of mortality and long-term disability. There are no therapeutics approved for neuro- and cardio-protection. Novel therapeutics are urgently needed to improve patient outcomes. Glibenclamide is a second-generation sulfonylurea drug and inhibitor of SUR1-TRPM4. Little is known about its role in cardioprotection and synaptic density. Aims: To evaluate the effect of glibenclamide on coronary flow reserve (CFR), blood-brain barrier (BBB) permeability, and synaptic density in an asphyxial mouse model of CA. Methods: We used an asphyxial mouse model of CA; potassium chloride was injected into the right internal jugular vein, resulting in asystole. Chest compressions and epinephrine were administered following 12 minutes of no-flow time. Successfully resuscitated mice (n=24) were randomized to receive intravenous glibenclamide or vehicle; the glibenclamide group received a loading dose of 10 μg/kg immediately upon return of spontaneous circulation followed by 1.6 μg every 12 hours up to day 3. Pulse Doppler Velocity (PWV) was used to monitor the CFR and left carotid artery velocity. Synaptic density was quantified with ex vivo autoradiographs after injection of 18 F-SynVesT-2 in the brain (3, 24, and 72 hrs). Evans blue staining and general neurologic deficit scores were assessed 24 hours post-resuscitation. Results: Treatment with glibenclamide resulted in an increase in CFR (1.37±0.11 vs. 1.17±0.06, p=0.01) and carotid peak velocity (61.38±12.81 cm/s vs. 46.83±6.3 cm/s, p<0.05). Whole brain synaptic density was increased in the mice treated with glibenclamide, suggesting a reduction in synaptic density loss. BBB disruption in the cerebrum was significantly lower in Glibenclamide treated mice (0.00022±0.000014/mg vs. 0.000471±0.000088/mg, p<0.01). Mice treated with Glibenclamide had lower neurologic deficit scores (1.83±2.89 vs 4.75±3.84, p<0.05). Conclusions: Glibenclamide given immediately following the return of spontaneous circulation improved CFR, decreased BBB disruption, reduced synaptic density loss, and improved neurologic deficit scores, suggesting both cardio- and neuro-protective effects.

Octreotide Treatment for Hypoglycemic Refractory Case Caused by Sulfonylureas with Impaired Renal Function

Hypoglycemia is an emergency case that is caused by antidiabetic drugs from the sulfonylurea class. Prolonged and refractory hypoglycemia can increase mortality and morbidity. Renal impairment can result in recurrent hypoglycemic symptoms and require special treatment. In this study case, a 47-year-old woman with newly impaired renal function presented in a coma caused by hypoglycemia due to the use of glibenclamide (sulfonylurea drugs) that did not respond to standard hypoglycemic treatment. Treatment of refractory hypoglycemia is a challenge in itself. Octreotide may be considered in cases of refractory hypoglycemia that does not respond to standard glucose treatment, where in this case refractory hypoglycemia is caused by accumulating sulfonylurea because of impaired renal function.

Characterization of binding by sulfonylureas with normal or modified human serum albumin using affinity microcolumns prepared by entrapment

Modification of proteins can occur during diabetes due to the formation of advanced glycation end-products (AGEs) with reactive dicarbonyls such as glyoxal (Go) and methylglyoxal (MGo). Human serum albumin (HSA) is a serum protein that binds to many drugs in blood and that is known to be modified by Go and MGo. This study examined the binding of various sulfonylurea drugs with these modified forms of HSA by using high-performance affinity microcolumns prepared by non-covalent protein entrapment. Zonal elution experiments were employed to compare the retention and overall binding constants for the drugs with Go- or MGo-modified HSA vs normal HSA. The results were compared to values from the literature, such as measured or estimated using affinity columns containing covalently immobilized HSA or biospecifically-adsorbed HSA. The entrapment-based approach provided estimates of global affinity constants within 3–5 min for most of the tested drugs and with typical precisions of ±10–23%. Each entrapped protein microcolumn was stable for over at least 60–70 injections and one month of use. The results obtained with normal HSA agreed at the 95% confidence level with global affinity constants that have been reported for the given drugs in the literature. It was found for HSA that had been modified with clinically-relevant levels of either Go or MGo that an increase in the global affinity constant of up to 2.1-fold occurred for some of the tested drugs. The information acquired in this study can be used in the future to adapt this entrapment-based approach to study and evaluate interactions between other types of drugs and normal or modified binding agents for clinical testing and biomedical research.

Transfer of Proteins from Cultured Human Adipose to Blood Cells and Induction of Anabolic Phenotype Are Controlled by Serum, Insulin and Sulfonylurea Drugs.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are anchored at the outer leaflet of eukaryotic plasma membranes (PMs) only by carboxy-terminal covalently coupled GPI. GPI-APs are known to be released from the surface of donor cells in response to insulin and antidiabetic sulfonylureas (SUs) by lipolytic cleavage of the GPI or upon metabolic derangement as full-length GPI-APs with the complete GPI attached. Full-length GPI-APs become removed from extracellular compartments by binding to serum proteins, such as GPI-specific phospholipase D (GPLD1), or insertion into the PMs of acceptor cells. Here, the interplay between the lipolytic release and intercellular transfer of GPI-APs and its potential functional impact was studied using transwell co-culture with human adipocytes as insulin-/SU-responsive donor cells and GPI-deficient erythroleukemia as acceptor cells (ELCs). Measurement of the transfer as the expression of full-length GPI-APs at the ELC PMs by their microfluidic chip-based sensing with GPI-binding α-toxin and GPI-APs antibodies and of the ELC anabolic state as glycogen synthesis upon incubation with insulin, SUs and serum yielded the following results: (i) Loss of GPI-APs from the PM upon termination of their transfer and decline of glycogen synthesis in ELCs, as well as prolongation of the PM expression of transferred GPI-APs upon inhibition of their endocytosis and upregulated glycogen synthesis follow similar time courses. (ii) Insulin and SUs inhibit both GPI-AP transfer and glycogen synthesis upregulation in a concentration-dependent fashion, with the efficacies of the SUs increasing with their blood glucose-lowering activity. (iii) Serum from rats eliminates insulin- and SU-inhibition of both GPI-APs' transfer and glycogen synthesis in a volume-dependent fashion, with the potency increasing with their metabolic derangement. (iv) In rat serum, full-length GPI-APs bind to proteins, among them (inhibited) GPLD1, with the efficacy increasing with the metabolic derangement. (v) GPI-APs are displaced from serum proteins by synthetic phosphoinositolglycans and then transferred to ELCs with accompanying stimulation of glycogen synthesis, each with efficacies increasing with their structural similarity to the GPI glycan core. Thus, both insulin and SUs either block or foster transfer when serum proteins are depleted of or loaded with full-length GPI-APs, respectively, i.e., in the normal or metabolically deranged state. The transfer of the anabolic state from somatic to blood cells over long distance and its "indirect" complex control by insulin, SUs and serum proteins support the (patho)physiological relevance of the intercellular transfer of GPI-APs.

To the assessment of the use of sugar-reducing drugs from the position of safety

The results and the degree of safety of hypoglycaemic drugs are presented. The current work analyses the safety of the use of sulfonylurea derivatives, biguanides, thiazolidinediones, meglitinides and α-glucosidase inhibitors according to clinical studies published in the scientific literature. Macrovascular complications in diabetes mellitus (DM) develop much earlier than microvascular complications and cause death in 75 % — 80 % of patients. The safety of hypoglycaemic therapy is assessed by the occurrence of hypoglycaemia, changes in body weight, effects on the gastrointestinal tract, and, of course, is associated with the risk of cardiovascular disease. In evaluating the results of numerous clinical studies, the use of sulfonylurea drugs (except gliclazide), meglitinides, alpha-glucosidase inhibitors (acarbose), and thiazolidinediones are not recommended in patients with a very high cardiovascular risk for treating type 2 diabetes due to evidence of an adverse effect on prognosis, or the presence of conflicting data or the lack of sufficient arguments for the cardiovascular safety of drugs. Metformin remains the preferred initial therapy with good tolerability.

Micelle Sensitized Physicochemical Studies on Erbium(III) Complexes with Hypoglycemic Sulfonylurea Drugs

Hypoglycemic sulfonylurea derivatives ligands viz. glimepiride, glibenclamide, gliclazide and glipizide show interaction with lanthanide metal Er (III) in non-micellar and micellar medium. Anionic, cationic and non-ionic surfactant micellar media show great variation in oscillator strength of Er (III) with hypoglycemic sulfonylurea drugs as reflected in UVVisible absorption spectra. Interpretation of UVVisible absorption spectra produced that 4G11/2 ← 4I15/2 and 2H11/2 ← 4I15/2 electronic transition bands show different behavior on account of oscillator strength (P) compared to other electronic f-f transitions, depicted as hypersensitive peaks which are characterized as ratio of Pmicellar / PDMF. Exploitation of different parameters viz: oscillator strength (P), Judd-Ofelt parameter Tλ, nephelauxetic effect 𝛽 and bonding parameter b1/2 from absorption spectra supports the covalency characters in metal ligand Er (III)-drugs doped systems to a greater extent. Thermodynamic exploits of hypersensitive transition correlate the spectroscopic data via Work function A, Thermodynamic efficiency of transition TET and Partition function Q. Thermodynamic parameters notify the microscopic behaviour of Er (III)- sulfonylurea drugs.

Blood glucose control with different treatment regimens in type 2 diabetes patients hospitalized with COVID-19 infection: A retrospective study.

Coronavirus disease (COVID-19) is closely associated with hyperglycemia and a worse prognosis in patients with a previous diagnosis of type 2 diabetes mellitus. A few studies investigated the effects of diabetes treatment regimens in these patients during hospitalization. Here, we evaluate the impact of insulin and non-insulin therapy on glucose control in patients with type 2 diabetes admitted with COVID-19. This is a retrospective study including 359 COVID-19 patients with type 2 diabetes. Patients were divided into 2 groups according to diabetes treatment during hospitalization. The first group included patients treated with insulin only, and the second group patients treated with other antidiabetic agents with or without insulin. Average blood glucose was higher in the insulin-only treatment group (201 ± 66 mg/dL vs 180 ± 71 mg/dL, P = .004), even after excluding mechanically ventilated patients (192 ± 69 vs 169 ± 59 mg/dL, P = .003). In patients with moderate severity of COVID-19, average blood glucose was also significantly higher in the insulin-only treated group (197 ± 76 vs 168 ± 51 mg/dL, P = .001). Most patients (80%) in the combination treatment group received metformin. Moderately affected COVID-19 patients with type 2 diabetes could safely be treated with antihyperglycemic medications with or without insulin.

Роль вітаміну D у розвитку, перебігу та лікуванні артеріальної гіпертензії

The literature review considers the new universal molecule empagliflozin, which managed to change the glucose‑centric approach in endocrinology to an organoprotective one. The results of the pivotal clinical trials conducted with empagliflozin (EMPA‑REG‑OUTCOME, EMPEROR‑REDUCED, EMPEROR‑PRESERVED and EMPULSE) strongly support the ability of empagliflozin to reduce rates of cardiovascular death or hospitalization for heart failure and to slow down the progression of chronic kidney disease. Among the confirmed and potentially favorable metabolic consequences of empagliflozin administration, the following should be emphasized: a selective antihyperglycemic effect only in conditions of hyperglycemia/glucosuria, which does not depend either on insulin production or sensitivity of peripheral tissues to insulin but is limited only by the glomerular filtration rate. This effect allows avoiding hypoglycemia even in patients without diabetes. The drug is one of the most durable among oral hypoglycemic agents and allows to maintain the achieved HbA1c values for 6 — 8 years, delaying the initiation of insulin therapy in patients with type 2 diabetes mellitus. Empagliflozin was superior to placebo in preventing death from cardiovascular disease, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus. This effect resulted from the significant reduction in the risk of cardiovascular mortality without significant changes in nonfatal myocardial infarction or nonfatal stroke. Combination with other oral and injectable hypoglycemic drugs is possible. In case of combination with sulfonylurea drugs or insulin, the dose of the latter needs to be adjusted in the direction of its decrease. Weight loss of up to 2 — 3 kg against the background of empagliflozin is an expected phenomenon that can modify blood pressure indicators and insulin resistance. Empagliflozin has the ability to reduce steatosis and improve liver fibrosis scores in patients with NAFLD without type 2 diabetes mellitus.

Design, optimization, and in-vivo performance of glipizide-loaded O-carboxymethyl chitosan nanoparticles in insulin resistant/type 2 diabetic rat model

Developing an oral nano-based delivery system for diabetes combines the desirable patient compliance of oral delivery with the tunable physicochemical features of nano-systems. Glipizide (GPZ) is a second-generation sulfonylurea drug used for treating type-2 diabetes (T2D). GPZ suffers from poor solubility and a short half-life (2–4 h). GPZ was loaded into O-Carboxymethyl chitosan (O-CMC) nanoparticles (NPs) to obtain a prolonged antidiabetic effect and monitor their effects on different T2D-related biomarkers. Optimized GPZ-O-CMC-NPs showed a particle size of 216 ± 2.5 nm, a zeta potential of −14.2 ± 2.1 mV, and an entrapment efficiency of 80.7 ± 0.8%. Fourier transform-infrared (FTIR) spectroscopy, Differential scanning calorimetry (DSC), and Transmission electron microscopy (TEM) were performed. GPZ-O-CMC-NPs had a superior and prolonged release profile than that of marketed and pure GPZ. Treatment with GPZ-O-CMC-NPs had a more significant impact (P < 0.05) on serum glucose, insulin, lipid profile (3–4 folds), oxidative stress markers (2–3 folds), and inflammatory cytokines (2.5–3.5 folds) than marketed or pure GPZ. These findings corroborate the potential benefits of GPZ-O-CMC-NPs for treating T2D.

PSUN250 Empagliflozin Induced Bladder Cancer in an Adult Patient With Latent Autoimmune Diabetes

Abstract Sodium glucose cotransporter type 2 (SGLT2) inhibitor is a novel class of antidiabetic agent. The association of SGLT2 inhibitors and incidence of bladder cancer has not been well established due to few numbers of cases and not enough length of exposure. Here we describe a case of bladder cancer developed one year after empagliflozin exposure in a patient with latent autoimmune diabetes. Case description A 51-year-old man presented to our endocrine clinic with a one-year diagnosis of type 2 diabetes mellitus. His glycosylated hemoglobin (HbA1c) was 8% on maximum dose metformin and well adherence to diet. The patient had no significant past medical history and his body mass index was 23.6 kg/m2. Empagliflozin 25 mg daily was added to his regimen, in addition to sulfonylurea and dipeptidyl peptidase-4 (DPP-4) inhibitor drugs. The patient continued to have persistent hyperglycemia despite medical therapy with HbA1c ranged between 7.5-7.9%. After one year, he presented with fatigue, unintentional 7-kg weight loss and perianal pain. A transrectal ultrasound of the pelvis showed a 10-mm solid lesion in the urinary bladder. He underwent transurethral resection of bladder tumor; pathology showed a low grade papillary urothelial carcinoma with focal areas of high grade. Empagliflozin was discontinued and due to persistent hyperglycemia, further labs were requested. Fasting blood glucose of 265 mg/dl, HA1c of 7.9%, anti-GAD antibody was positive 37.52 u/ml (&amp;lt;10.0), C-peptide of 0.51 ng/ml (0.37-1.47), insulin of 2.0 mu/ml (2.6-24.9). These findings suggested latent autoimmune diabetes with mild pancreatic reserve. Patient was then started on insulin therapy of Glargine and Aspart. Conclusion The use of SGLT2 inhibitors in patients with autoimmune diabetes may have a higher risk of bladder cancer as compared to patients with type 2 diabetes. An individualized selection of antidiabetic agent with consideration of proper diagnosis is recommended to prevent a serious consequence. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Systematic review and meta-analysis of head-to-head trials comparing sulfonylureas and low hypoglycaemic risk antidiabetic drugs

BackgroundSafety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes.MethodsSystematic review and meta-analysis of randomised controlled trials. Data sources: MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs.Study selectionRandomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.OutcomesThe primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia. Synthesis of results: Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780).ResultsOur final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07–1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17–2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20–6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules.ConclusionOur meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.