Class Of Antidiabetic Drugs Research Articles

Unlocking the power of empagliflozin: Rescuing inflammation in hyperglycaemia- exposed human cardiomyocytes through comprehensive multi-level analysis.

Hyperglycaemic conditions increase cardiac stress, a common phenomenon associated with inflammation, aging, and metabolic imbalance. Sodium-glucose cotransporter 2 inhibitors, a class of anti-diabetic drugs, showed to improve cardiovascular functions although their mechanism of action has not yet been fully established. This study investigated the effects of empagliflozin on cardiomyocytes following high glucose exposure, specifically focusing on inflammatory and metabolic responses. A three-part strategy was formulated: (i) a meta-analysis of selected randomized clinical trials was carried out to assess the anti-inflammatory effects of empagliflozin in diabetic patients; (ii) the impact of empagliflozin on human cardiomyocyte AC16 cells exposed to normal (5 mM) and high (33 mM) glucose concentrations for 2 and 7 days was explored by evaluating gene expression and protein levels of pivotal markers associated with cardiac inflammation, stress, endoplasmic reticulum damage, and calcium modulation; (iii) in silico data from bioinformatic analyses were exploited to construct an interaction map delineating the potential mechanism of action of empagliflozin on cardiac tissue. Empagliflozin reversed high-glucose mediated alterations at the transcriptional level, decreasing inflammatory, metabolic, and aging signatures. Specifically, in vitro experiments on human cardiomyocytes, meta-analyses of clinical data on inflammatory biomarkers from diabetic peripheral blood samples, and sequencing of pathological human heart tissues, all support that empagliflozin exerts anti-inflammatory effects both systemically and directly in cardiac tissue, on cardiomyocytes. Our study provides insights based on robust mechanistic data for optimizing heart failure management and highlights the intricate interplay between diabetes, inflammation, aging, and cardiovascular health.

Impact of Sodium-Glucose Co-Transporter 2 Inhibitors on Atrial Fibrillation Recurrence Post-Catheter Ablation Among Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Atrial fibrillation (AF) is the most common cause of arrhythmia-induced cardiomyopathy. Effective management strategies include medical therapy for rate and rhythm control, catheter ablation (CA), and goal-directed medical therapy. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), a novel class of antidiabetic drugs, have shown a promising impact in reducing cardiovascular events in diabetic and nondiabetic heart failure (HF) patients. It is unclear what impact SGLT2i use may have on AF recurrence following CA. To evaluate the effects of SGLT2i on preventing AF recurrence following CA and its impact on other cardiovascular outcomes. We performed a comprehensive literature search through multiple search engines (PubMed, Scopus, Web of Science, and Cochrane) to include eligible studies using the appropriate keywords until 10 April 2024. Our search yielded nine eligible studies with 16 857 patients. Our analysis reveals a significant reduction in AF recurrence after CA among patients receiving SGLT2i compared to non-SGLT2i medications (RR = 0.72, 95% CI [0.67-0.78], p < 0.00001). Additionally, SGLT2i therapy was associated with decreased all-cause hospitalizations and reduced risk of ischemic stroke. However, no significant difference in all-cause mortality was observed between SGLT2i and non-SGLT2i groups. Our study found that SGLT2 inhibitors significantly reduced AF recurrence post-CA in diabetic patients. Moreover, SGLT2i use was associated with lowered hospitalization and ischemic stroke risk. Though no significant difference in mortality was noted, the decrease in hospitalization suggests a possible favorable effect on cardiovascular events.

Analysis of the Endocrine Responses to Anti-Diabetes Drugs: An Issue of Elevated Plasma Renin Concentration in Sodium-Glucose Co-Transporter 2 Inhibitor.

Glucose metabolism is associated with several endocrine disorders. Anti-diabetes drugs are crucial in controlling diabetes and its complications; nevertheless, few studies have been carried out involving endocrine function. This study aimed to investigate the association between anti-diabetes drugs and endocrine parameters. We performed a study of 180 consecutive patients with type 2 diabetes who attended a medical center. Laboratory measurements of metabolic values and endocrine parameters were assessed after a stable treatment regimen of more than 12weeks. The differences in various endocrine parameters were compared between subjects with or without certain anti-diabetes drugs, with the administrated anti-diabetes drugs being analyzed to find independent risks associated with elevated endocrine parameters. After maintaining stable treatment, acceptable glycemic control was noted with an average HbA1c of 7.55% in females and 7.43% in males. Participants taking sulfonylurea (55.8 vs 26.34 ng/L, P=0.043), dipeptidyl peptidase-4 inhibitor (DPP4i) (47.14 vs 32.26 ng/L, P=0.096), or sodium-glucose co-transporter 2 inhibitor (SGLT2i) (64.58 vs 28.11 ng/L, P=0.117) had higher plasma renin concentrations compared to those without this drug but the aldosterone levels did not differ, as well as for other adrenal tests and thyroid function. Under linear regression modeling, SGLT2i was found to be independently associated with a risk of high renin level (beta coefficient: 30.186, 95% confidence interval: 1.71─58.662, P=0.038), whereas sulfonylurea only had borderline associations (B: 21.143, 95% CI: -2.729─45.014, P=0.082). Additionally, renin-angiotensin-aldosterone system (RAAS) blockade (B: 36.728, 95% CI: 12.16─61.295, P=0.004) or diuretics (B: 47.847, 95% CI: 2.039─93.655, P=0.041) was also independently associated with increased renin levels. SGLT2i was the only class of anti-diabetes drugs independently associated with elevated renin levels, with results similar to RAAS blockade and diuretics. Although SGLT2i appears to protect reno- and cardio-function, the clinical impact of increased renin warrants further precise study for verification.

A Mechanism-Based Comparative Review on Functional Food with Phytomolecules and Marketed Formulation for Type II Diabetes Mellitus

Abstract: Type II diabetes mellitus is a chronic disorder characterized by pancreatic beta cell dysfunction, insulin resistance, and hyperglycemia. Administration of different classes of anti-diabetic drugs over the long term is essential to maintain normoglycemic levels in affected individuals. This study is focused on natural analogs as substitutes for the most marketed synthetic and semi-synthetic anti-diabetic drugs. This study aimed to review phytoconstituents with their mechanism of action, which are comparatively equivalent to that of the allopathic anti-diabetic marketed drugs, like biguanides, sulphonylurea, and thiazolidinediones. The methodology used for the review involved using the keywords collected from online sites, like PubMed, ScienceDirect, and Google Scholar. At present, different drugs are available for the treatment of diabetes and work with different mechanisms, like metformin induces the AMPK pathway in hepatocytes and muscle fibers with increased glucose uptake in peripheral tissues, whereas the phytoconstituents, like quercetin (flavonoid), mahanimbine, and koenidine (carbazole alkaloids) involve same mechanism as metformin. Sulfonylureas drugs bind to specific receptors in hepatocytes, resulting in glucose-independent insulin release. The phytomolecule amyrins (pentacyclic triterpenoid) and kaempferol (flavonoid) have similar effects as that of sulphonylureas. Thiazoglinediones target adipocytes and cause GLUT-4 translocation and up-regulation of PPAR and adiponectin gene expression. Phytoconstituents, like cyanidin-3-glucoside (anthocyanin) and protocatechuic acid (tannin), exhibit a similar mechanism of action to that of thiazolidinediones. In this review, it can be concluded that the selected compounds have the same antidiabetic activity as the synthetic drugs. In the future, a new polyherbal formulation can be developed with these selected molecules having the same mechanisms of action, with significant therapeutic value without side effects.

Positive impact of DPP-4 or SGLT2 inhibitors on mild cognitive impairment in type 2 diabetes patients on metformin therapy: A metabolomic mechanistic insight.

Mild cognitive impairment is increasingly recognized as a complication of type 2 diabetes (T2D). Although currently no disease-modifying treatments for cognitive disorders exist, interest surged in potential neuroprotective effects of newer anti-diabetic drugs. This study investigates the impact of newer anti-diabetic drug classes, dipeptidyl peptidase-4 (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) - on cognitive decline in T2D patients on metformin therapy. A prospective observational cohort study was conducted, with a follow-up duration of 6 months. The study compared the cognitive performance of T2D patients on metformin monotherapy to those on a combination of metformin with DPP-4i or SGLT2i, using the Montreal Cognitive Assessment Battery. A group of healthy volunteers served as a reference. At baseline, patients receiving combination therapy had a cognitive performance comparable to that of healthy volunteers, while those on metformin monotherapy scored lower. These differences persisted for patients who completed the follow-up, though there was no change within group. Baseline differences were independent of glycemic control, blood lipids, renal function, and serum inflammatory markers. Comprehensive metabolomics and lipidomics revealed that T2D patients on metformin monotherapy exhibited enriched purine, glutathione and sphingolipid metabolism, with alterations in xanthine, L-pyroglutamic acid, and several sphingomyelins. These changes suggest increased oxidative stress in T2D, mitigated in the combination therapy group, as evidenced by total serum antioxidant capacity. As such, we conclude that the combination of DPP-4i or SGLT2i with metformin positively impacts cognitive function in T2D patients by modulating metabolic pathways rather than improving glycemic control, peripheral diabetic complications, or systemic inflammation.

Long-term benefit of SGLT2 inhibitors to prevent heart failure hospitalization in patients with diabetes, with potential time-varying benefit.

SGLT2 inhibitors show promise in reducing hospitalization for heart failure in diabetics, but their long-term effects and time-dependency remain unclear. We conducted a retrospective nested case-control study within a large type 2 diabetic cohort (n = 11,209) using electronic health records. Cases (heart failure hospitalization, n = 352) were matched to controls (n = 1372) based on age, sex, cohort entry date, and diabetes duration. Matched-set conditional logistic regression was used to estimate hazard ratios (HRs) for antidiabetic drug class and heart failure hospitalization risk. SGLT2 inhibitors were associated with a significant reduction in heart failure hospitalization risk (adjusted HR 0.56, 95% CI 0.38-0.82, p = 0.028). This protective effect appeared more pronounced with a longer duration of treatment, suggesting a potential cumulative benefit. Time-varying analysis within propensity score-matched cohorts revealed a progressive decrease in hospitalization risk with continued SGLT2 inhibitor use, indicating a strengthening effect over time (greedy nearest neighbor: HR 0.52, CI 0.31-0.87, p = 0.015; optimal matching: HR 0.54, CI 0.34-0.85, p = 0.008). While promising, further investigation with larger datasets is warranted to definitively confirm these findings.

Evaluating the appropriateness and the factors associated with sodium-glucose co-transporter 2 inhibitors prescribing in a Middle Eastern country: a cross-sectional study.

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are a novel class of oral antidiabetic drugs (ADDs). Studies evaluating the appropriateness of SGLT2is prescribing, and the factors associated with their initiation in the Middle East region are lacking. This study aimed to evaluate the appropriateness of prescribing SGLT2is based on indication, dosing, and contraindication and determine the factors associated with their initial prescribing. In this cross-sectional study, a cohort of 650 patients newly prescribed SGLT2is (n = 400) and/or any other oral ADDs (n = 250) during 2020 were included. Data were extracted from an electronic medical record system. Multivariate logistic regression was conducted to investigate factors associated with prescribing SGLT2is. SGLT2is were prescribed for appropriate indication in 400 patients (100%), while inappropriately prescribed in relation to contraindication and dosing in 14 patients (3.5%). Male patients were more likely to be prescribed SGLT2is (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.02-2.82). Patients with a baseline glycated hemoglobin (HbA1c) above 7% and atherosclerotic cardiovascular disease (ASCVD) were more likely to be prescribed SGLT2is (OR, 3.22; 95% CI, 1.84-5.64) and (OR, 2.18; 95% CI, 1.05-4.52), respectively. Patients receiving metformin (OR, 7.56; 95% CI, 4.46-12.80), sulfonylureas (OR, 2.30; 95% CI, 1.16-4.56), and dipeptidyl peptidase 4 inhibitors (OR, 3.43; 95% CI, 2.00-5.87) were more likely to be prescribed SGLT2is. SGLT2is were found to be typically prescribed for the appropriate indication. Among the most important factors associated with prescribing SGLT2is are having uncontrolled HbA1c, history of ASCVD, and using other ADDs.

Sodium-glucose cotransporter 2 inhibitor attenuates left ventricular dysfunction in post-myocardial infarction in rats via reducing cardiac mitochondrial impairment

Abstract Background Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a class of antidiabetic drugs that has demonstrated cardiovascular benefits in heart failure patients, regardless of diabetic status. Although current evidence regarding the role of SGLT2i in myocardial infarction (MI) is still limited, a recent randomized study reported the favorable effects of dapagliflozin on cardiometabolic outcomes in post-MI patients. Nevertheless, the evidence of the underlying mechanism of SGLT2i in post-MI is still unclear. Purpose We aimed to investigate the cardioprotective effects and cellular mechanisms of SGLT2i in post-MI rats. Methods 72 male Wistar rats were divided into two groups: the MI group, which underwent surgery involving permanent ligation of the left anterior descending coronary artery to induce MI (n=58), and the sham group, which underwent a sham operation (n=14). One-week post-surgery, echocardiography was performed. For inclusion in the MI group, only rats exhibiting anterior wall akinesia and a left ventricular ejection fraction (LVEF) &amp;lt; 50% were considered. Subsequently, MI rats were stratified into three groups to receive different interventions: 1) MI+VEH (distilled water, PO, n=13), 2) MI+DAPA (dapagliflozin, 1 mg/kg, PO, n=11), and 3) MI+ENA (enalapril, 10 mg/kg, PO, n=14). After 8 weeks of treatment, echocardiography was performed again. Then, the rats were sacrificed, and heart tissues were used to determine mitochondrial function and protein expressions. Results After 8 weeks of treatment, the MI+VEH group exhibited a decrease in LVEF compared to the sham group (Fig. 1A). The MI+VEH group was associated with cardiac mitochondrial dysfunction, as indicated by increased mitochondrial oxidative stress, mitochondrial membrane depolarization, and mitochondrial swelling, and impaired mitochondrial biogenesis, as indicated by decreasing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expressions (Fig. 1B-F). Treatment with dapagliflozin and enalapril effectively attenuated left ventricular (LV) systolic dysfunction, reversed mitochondrial dysfunction, and restored mitochondrial biogenesis induced by MI (Fig. 1A-F). Conclusion SGLT2i could attenuate LV dysfunction and restore mitochondrial dysfunction in post-MI rats. These findings demonstrate SGLT2i as a novel cardioprotection against post-MI complications.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

Application of Fabric Phase Sorptive Extraction as a Green Method for the Analysis of 10 Anti-Diabetic Drugs in Environmental Water Samples

Due to the increased prevalence of diabetes, the consumption of anti-diabetic drugs for its treatment has likewise increased. Metformin is an anti-diabetic drug that is commonly prescribed for patients with type 2 diabetes and has been frequently detected in surface water and wastewaters, thus representing an emerging contaminant. Metformin can be prescribed in combination with other classes of anti-diabetic drugs; however, these drugs are not sufficiently investigated in environmental samples. Fabric phase sorptive extraction (FPSE) has emerged as a simple and green method for the extraction of analytes in environmental samples. In this study, FPSE coupled with a high-performance liquid chromatography diode array detector (HPLC-DAD) was employed for the simultaneous analysis of different classes of anti-diabetic drugs (metformin, dapagliflozin, liraglutide, pioglitazone, gliclazide, glimepiride, glargine, repaglinide, sitagliptin, and vildagliptin) in environmental water samples. Four different fabric membranes were synthesized but the microfiber glass filter coated with sol-gel polyethylene glycol (PEG 300) was observed to be the best FPSE membrane. The parameters affecting the FPSE process were optimized using a combination of one-factor-at-a-time processes and the design of experiments. The FPSE was evaluated as a green extraction method, based on green sample preparation criteria. The FPSE-HPLC-DAD method achieved acceptable validation results and was applied for the simultaneous analysis of anti-diabetic drugs in surface and wastewater samples. Glimepiride was detected below the quantification limit in both lake and river water samples. Dapagliflozin, liraglutide, and glimepiride were detected at 69.0 ± 1.0 μg·L−1, 71.9 ± 0.4 μg·L−1, and 93.9 ± 1.3 μg·L−1, respectively, in the city wastewater influent. Dapagliflozin and glimepiride were still detected below the quantification limit in city wastewater effluent. For the hospital wastewater influent, metformin and glimepiride were detected at 1158 ± 21 μg·L−1 and 28 ± 0.8 μg·L−1, respectively, while only metformin (392.6 ± 7.7 μg·L−1) was detected in hospital wastewater effluent.

EMMY trial: What we know and what we need to know

ABSTRACT SGLT-2 inhibitors are a class of antidiabetic drugs with additional cardiovascular benefits. Though initially developed for glycemic control, subsequent studies in the heart failure (HF) population also demonstrated positive outcomes. Currently, they are approved for use in HF with both reduced and preserved ejection fraction. More recently, encouraging data have emerged on acute HF. Following an episode of acute myocardial infarction, patients are also at high risk for developing HF and experiencing recurrent events despite optimal therapy. The PARADISE MI study failed to demonstrate any benefits of ARNI in this scenario. The EMMY trial explored the role of SGLT-2i in &gt;450 odds patients with acute MI. At 26 weeks SGLT-2i (empagliflozin) use led to a higher fall in NT-pro-BNP levels compared to standard treatment. There was additional improvement in left ventricular echocardiographic parameters with empagliflozin too. However, it was a small trial, had a short follow-up and there were no clinical endpoints. But none the least, it attested to the safety of SGLT-2i in the post-MI scenario. Because the primary care physician frequently encounters patients in the post-MI scenario, the manuscript provides insights into their practice. Based on contemporary evidence, the universal use of SGLT-2 inhibitors in patients following acute MI is not warranted. A further role of these drugs in post-MI HF will be clarified in ongoing trials.

The potential adverse effects of hypodermic glucagon-like peptide -1 receptor agoniston patients with type 2 diabetes: A population-based study.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of injectable antidiabetic drugs, have shown significant efficacies in improving glycemic and weight control in patients with type 2 diabetes (T2D). However, the long-term safety of GLP-1 RAs remains insufficiently studied. This study aimed to provide real-world evidence on potential adverse outcomes associated with GLP-1 RAs use in T2D patients without major chronic diseases including impaired cardiac or renal function. We conducted a retrospective cohort study involving 7746 T2D patients on GLP-1 RAs in Shenzhen, China. They were compared with 124 371 metformin-only users and 36 146 insulin-only users, forming two therapy control groups. GLP-1 RAs users were also further 1:2 paired with the control groups. Competing risk survival analyses were conducted to assess the incidence risks, presenting subdistributional hazard ratios (sHRs) with 95% confidence intervals (CIs) for various adverse outcomes associated with GLP-1 RAs use. Compared with metformin-only users, GLP-1 RAs use was associated with increased risks of various adverse outcomes (sHRs with 95% CIs), including pancreatitis (2.01, 1.24-3.24), acute nephritis (3.20, 2.17-4.70), kidney failure (3.73, 2.74-5.08), thyroid cancer (2.25, 1.23-4.10), and thyroid dysfunction (1.27, 1.00-1.63), respectively; Similar results were also found when compared with insulin-only users. Importantly, long-term (≥12 months) GLP-1 RAs use may further elevate the incidence risks of pancreatitis, acute nephritis, thyroid cancer, and thyroid dysfunction. Compared with traditional T2D treatments, GLP-1 RAs use may be associated with increased risks of various adverse outcomes in a Chinese population. Cautions were strongly warranted in the use of GLP-1 RAs. Further validation is crucial across diverse populations.

SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 μmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.

Elucidating the role of weight loss and glycaemic control in patients with type 2 diabetes.

To investigate the independent contributions of glycated haemoglobin (HbA1c) reduction and weight loss to clinical outcomes in patients with type 2 diabetes (T2D) treated with antidiabetic drugs, including glucagon-like peptide-1 receptor agonists (GLP-1RAs). This observational, retrospective cohort study used deidentified electronic health record-derived data from patients evaluated at the Cleveland Clinic (1 January 2000-31 December 2020). Cohort A included 8876 patients with newly diagnosed T2D treated with any of six antidiabetic drug classes. Cohort B included 4161 patients with T2D initiating GLP-1RA treatment. The effects of body mass index (BMI) and HbA1c reduction, variability, and durability on clinical outcomes were investigated. In Cohort A, each 1% BMI reduction was associated with 3%, 1%, and 4% reduced risk of heart failure (p = 0.017), hypertension (p = 0.006), and insulin initiation (p = 0.001), respectively. Each 1% (~11 mmol/mol) HbA1creduction was associated with 4% and 29% reduced risk of hypertension (p = 0.041) and insulin initiation (p = 0.001), respectively. In Cohort B, each 1% BMI reduction was associated with 4% and 3% reduced risk of cardiovascular disease (p = 0.008) and insulin initiation (p = 0.002), respectively. Each 1% (~11 mmol/mol) HbA1c reduction was associated with 4% and 16% reduced risk of chronic kidney disease (p = 0.014) and insulin initiation (p = 1 × 10-4), respectively. Lower BMI variability and greater BMI durability were associated with decreased risk of clinical outcomes in both cohorts. Antidiabetic medication-associated, and specifically GLP-1RA-associated, weight loss and HbA1c reductions independently reduce real-world clinical outcome risk.

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.

Therapeutic Potential of Sodium-glucose Co-transporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists for Patients with Acute Coronary Syndrome: A Review of Clinical Evidence.

Atherosclerotic Cardiovascular Disease (ASCVD) is still one of the leading causes of death globally, with Coronary Artery Disease (CAD) being the most prevalent form of ASCVD. Patients with type 2 Diabetes Mellitus (DM) experience an increased risk for ASCVD during the disease course, with CAD being the most common cause of death among affected individuals, resulting in shorter life expectancy and increased morbidity among survivors. Recently, 2 novel classes of anti-diabetic drugs, namely Sodium-Glucose Co-Transporter- 2 (SGLT-2) inhibitors and Glucagon-Like Peptide-1 (GLP-1) receptor agonists, have shown impressive cardio-renal benefits for patients with type 2 DM, while they might decrease cardio-renal risk even in the absence of baseline DM. However, there is no evidence to date regarding their safety and efficacy in the setting of an acute coronary syndrome (ACS) event, regardless of concomitant DM. This study aims to provide a detailed, updated presentation of currently available clinical evidence concerning the potential role of SGLT-2 inhibitors and GLP-1 receptor agonists in the setting of an ACS, and to highlight whether those drug classes could be utilized as adjuncts to standard-of-care treatment in this specific patient population, along with a presentation of the potential short- and long-term cardiovascular benefits.

Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets.

Fagonia indica from Zygophyllaceae family is a medicinal specie with significant antidiabetic potential. The present study aimed to investigate the in vitro antidiabetic activity of Fagonia indica crude extract followed by an in silico screening of its phytoconstituents. For this purpose, crude extract of Fagonia indica was prepared and divided in three different parts, i.e., n-hexane, ethyl acetate, and methanolic fraction. Based on in vitro outcomes, the phytochemical substances of Fagonia indica were virtually screened through a literature survey and a screening library of compounds (1-13) was prepared. The clinical potential of these novel drug candidates was assessed by applying an ADME screening profile. Findings of SwissADME indicators (Absorption, Distribution, Metabolism, and Excretion) for the compounds (1-13) presented relatively optimal physicochemical characteristics, drug-likeness, and medicinal chemistry. The antidiabetic action of these leading drug candidates was optimized through molecular docking analysis against 3 different human pancreatic α-amylase macromolecular targets with (PDB ID 1B2Y), (PDB ID 3BAJ), and (PDB ID: 3OLI) by applying Virtual Docker (Molegro MVD). Metformin was taken as a reference standard for the sake of comparison. In vitro antidiabetic evaluation gave good results with promising α-amylase inhibitory action in the form of IC50 values, as for n-hexane extract = 206.3µM, ethyl acetate = 41.64µM, and methanolic extract = 9.61µM. According to in silico outcomes, all 13 phytoconstituents possess the best binding affinity with successful MolDock scores ranging from - 97.2003 to - 65.6877kcal/mol and show a great number of binding interactions than native drug metformin. Therefore, the current work concluded that the diabetic inhibition prospective of extract and the compounds of Fagonia indica may contribute to being investigated as a new class of antidiabetic drug or drug-like candidate for further studies.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors: Antidiabetics Medications for Treating Diabetes

Type 2 diabetes (T2D) is a progressive disease, and most patients need to treat with monotherapy and combinations of oral hypoglycaemic drugs. At present about 500 million people worldwide are suffering from T2D. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel antidiabetic drug class that mediates epithelial glucose transport at the renal proximal tubules, inhibiting glucose absorption that result in glycosuria, modest weight loss and improve glycaemic control with a low risk of hypoglycaemia. These are used by T2D patients together with diet and exercise, either alone or in combination with other diabetes medicines. The main side-effects of SGLT-2 inhibitors are urinary tract and genital infections, as well as euglycemic diabetic ketoacidosis. Some other probable adverse effects are lower limb amputations, risk of bone fractures, Fournier gangrene, male bladder cancer, female breast cancer, orthostatic hypotension, and acute kidney injury. This mini review explains aspects of SGLT-2 inhibitors with treatment procedures and side-effects.

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors and Cardiovascular Outcomes: A Review of Literature.

Coronary arterial diseases are a major contributor to disease and death worldwide and are most often compounded by several other underlying medical conditions. A key concern is type 2 diabetes mellitus (T2DM). Despite progress in medical advancements, these life-threatening illnesses are still underdiagnosed and undermanaged. A relatively newer class of anti-diabetic drugs, the sodium-glucose cotransporter-2 inhibitors (SGL2-Is), also termed gliflozins, have shown promising results in reducing cardiovascular risk, regardless of diabetic status. These drugs have on-target (promoting renal glycosuria and diuresis by acting on the SGLT-2 channels in the proximal convoluted tubule) and off-target effects contributing to the reported cardiovascular benefit. Some emerging theories about its impact on myocardial energetics, calcium balance, and renal physiology exist. In this review article, we explored three major cardiovascular outcome trials: the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, the CANagliflozin cardioVascular Assessment Study (CANVAS) program, and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 DiabetesMellitus Patients-Removing Excess Glucose(EMPA-REG OUTCOME) trial to evaluate the cardiovascular effects of SGLT2-Is.

Semaglutide in Chronic Kidney Disease: Great Enthusiasm. But How Does It Work?

Chronic Kidney Disease (CKD) is a clinical condition characterized by the progressive loss of kidney function. 10% of the world's population is affected by this condition, which represents the fifth leading cause of death globally. Furthermore, CKD is associated with increased risk of fatal and non-fatal cardiovascular events, and progression to end-stage renal disease. Over the last twenty years, an exponential growth in its prevalence and incidence has been observed. For this reason, various drugs have been developed and implemented in clinical practice, with various mechanisms, with the aim of reducing and minimizing this dramatic "cardio-renal" risk. These include SGLT2 inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists. However, a large proportion of CKD patients do not respond sufficiently to these treatments. GLP-1 receptor agonists represent a class of antidiabetic and nephroprotective drugs that are very promising in improving the prognosis of patients with CKD, especially if associated with one of the above-mentioned classes. In this article, we discuss the direct and indirect mechanisms through which one of the GLP-1 agonists, semaglutide, ensures nephro- and cardioprotection in patients with CKD and type 2 diabetes.