Antihyperglycemic Agents Research Articles

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Drug-drug interactions of empagliflozin and dapagliflozin

Abstract Introduction The sodium glucose co-transporter2-inhibitors dapagliflozin (Dapa) and empagliflozin (Empa), initially developed as antihyperglycemic agents, are increasingly also prescribed for non-diabetic patients with heart failure (HF). Glucuronidation by uridine-diphosphate glucuronosyltransferase (UGT)1A9 is the main mechanism of metabolism of Dapa, whereas Empa is eliminated mainly by excretion. Both Dapa and Empa are substrates of P-glycoprotein. The risk for drug-drug interactions (DDI) of Empa and Dapa is assumed to be low. Aim of this study was to summarize reports of DDI of Empa and Dapa from the literature. Methods Search-terms in PubMed were "drug-drug interaction" and AND "sodium glucose co-transporter2-inhibitors" OR "SGLT2" OR "dapagliflozin" OR "empagliflozin". The drugs were classified according the Anatomical Therapeutic Chemical (ATC) system. Included were randomized trials, pharmacovigilance studies, case series, case reports, studies in healthy subjects and in vivo data. The funding of the study and the disclosures of the authors were registered. Results In 45 reports DDI of Empa and Dapa with 29 drugs were described (Table). According to the ATC system, these were drugs for the alimentary tract and metabolism (n=5), blood and blood forming organs (n=2), cardiovascular system (n=11), genitourinary system and sex hormones (n=2), antiinfectives (n=2), antineoplastic and immunomodulating agents (n=3), musculo-skeletal system (n=2) and nervous system (n=2). The reports comprised studies in healthy subjects (n=28), case reports (n=7), case series (n=6), pharmacovigilance studies (n=2), a subgroup analysis of a randomized trial (n=1) and in vivo data (n=1). Most of the reports found no clinically relevant DDI (n=32). Dapa and Empa both had a synergistic diuretic effect with bumetanide, and led to severe infections when combined with the interleukin-17-inhibitors secukinumab or ixekizumab. Empa administered with intravenous iron was reported to increase cell-iron availability, with lithium to reduce lithium exposure and with valproate to increase valproate exposure. Dapa administered with sacubitril-valsartan was reported to lead to severe hypotension, with linezolid to pancytopenia, with donafenib to an increased exposure to donafenib, with rifampicin to a reduction and mefenamic acid to an increase in Dapa exposure. Of the 45 reports, 33 were funded by a pharmaceutical company marketing Dapa or Empa and 33 had authors with conflicts of interest with pharmaceutical companies marketing Dapa or Empa. Conclusions Most data about DDI of Empa and Dapa derive from studies in healthy subjects and from the marketing companies. The clinical relevance DDI of Empa and Dapa in polymorbid patients with polymedication is largely unknown. There is an urgent need for independent studies on DDI of these drugs in diabetic and non-diabetic patients with HF.Table

Anti-Hyperglycemic Medication Management in the Perioperative Setting: A Review and Illustrative Case of an Adverse Effect of GLP-1 Receptor Agonist

A host of anti-hyperglycemic agents are currently available and widely prescribed for diabetes and weight loss management. In patients undergoing surgery, use of these agents poses a clinical challenge to surgeons, anesthesiologists, and other perioperative care providers with regard to optimal timing of discontinuation and resumption of use, as well as possible effects of these agents on physiology and risk of postoperative complications. Here, we provide a comprehensive review of anti-hyperglycemic medications’ effects on physiology, risks/benefits, and best practice management in the perioperative setting. Additionally, we report an illustrative case of small bowel obstruction in a patient taking semaglutide for 6 months prior to an otherwise uncomplicated laparoscopic hysterectomy and bilateral salpingo-oophorectomy. This review is meant to serve not as a replacement of, but rather as a consolidated complement to, various society guidelines regarding perioperative anti-hyperglycemic agent management.

6630 Crooke Cell Pituitary Adenoma Without a Cushingoid Appearance

Abstract Disclosure: J. Hodge: None. S. Idriss: None. I. Jamal: None. R. Panta: None. Background: Crooke cell pituitary adenomas are corticotroph adenomas with Crooke’s cell changes, which are cytoplasmic accumulation of cytokeratin filaments in response to glucocorticoid excess. They are aggressive, invasive tumors, typically macroadenomas, with a high rate of Cushing’s disease and post -treatment (surgery and/or radiotherapy) recurrence. We present a case of Crooke cell pituitary adenoma without a Cushingoid appearance. Clinical Case: A 66-year-old Hispanic male with a 16-year history type II diabetes mellitus with retinopathy, presented with a pituitary macroadenoma at age 60. This was found incidentally when he had a brain CT for evaluation of vertigo. Subsequent brain MRI demonstrated a large 2.4 x 2.0 x 1.7 cm pituitary macroadenoma with extension into the suprasellar cistern and the left cavernous sinus. He was asymptomatic, without Cushingoid features. Hormonal evaluation revealed central hypogonadism and hypothyroidism, mildly elevated prolactin of 39.3 (4-15.2 ng/mL) and morning cortisol level of 12.7 (6-18.4 ug/dL). A 24-hour urine cortisol was normal. He was started on testosterone and thyroid hormone replacement therapy. His diabetes mellitus became progressively difficult to control with a peak HbA1C of 10.1%, about 7 years prior the macroadenoma finding. His HbA1C remained persistently elevated in the 8.1-9.5% range despite being on 6 anti-hyperglycemic agents, including basal insulin. A morning ACTH level 4 years after the initial visit, was 115 (6-50 pg/mL) with a cortisol level of 13.7 (6-18.4 ug/dL). Repeat morning ACTH and cortisol levels 7 months later were very similar. 5 years after the macroadenoma finding, he was noted to have worsening glaucoma, which was believed to be due to optic nerve compression. Therefore, he underwent endoscopic transphenoidal resection for tumor debulking. Pathology supported the diagnosis of Crooke cell corticotroph pituitary adenoma. Repeat brain MRI 3-months post-surgery demonstrated residual tumor, but normal optic chiasm and optic tracts. He had an abnormal dexamethasone suppression test prior to surgery (cortisol 6.4 ug/dL) and continued to do so post-operatively (cortisol 3.7 ug/dL with persistently elevated ACTH). Just prior to his surgery, testosterone replacement therapy was held. Total testosterone level after surgery was normal 309.6 (280-800 ng/dL) and free testosterone 7 (5-21 ng/dL); he remained off replacement therapy. Conclusion: Crooke cell pituitary adenomas are rare with limited data on prognosis and guidance for clinical management. Some patients may have subtle features of hypercortisolism, such as difficult to control diabetes mellitus, without an overt Cushingoid appearance. Presentation: 6/1/2024

6779 The Diversity of Immune Checkpoint Inhibitor Associated Diabetes

Abstract Disclosure: V.A. Mendpara: None. M. Lansang: None. M. Caromori: None. L. Kennedy: None. K. Zhou: None. Immune checkpoint inhibitor (ICI) treatment has become a first-line therapy for a variety of cancers, including use of nivolumab (a programmed death 1 [PD-1] inhibitor) for metastatic melanoma. Though able to prolong survival, ICIs cause immune-related adverse events (irAE) through down-regulation of immune control pathways. One irAE is diabetes mellitus (DM), referred to as ICI-induced DM. Despite its low incidence (2%), ICI-induced DM carries with it high morbidity, with need for hospitalization in up to 25% of patients, and burden as patients are typically committed to multiple daily insulin injections (MDII). Here we report diverse presentations of four patients treated with ICI for metastatic melanoma who developed ICI-induced DM. The median age at DM presentation was 60.5 years (range 59-78 years). All patients received nivolumab and one patient was also treated with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 inhibitor). The median time from start of ICI to development of ICI-induced DM was 32.5 wks, ranging from 27-46 wks. Three of the 4 patients previously developed hypothyroidism at median of 15 wks from starting ICI. Two patients presented in DKA and the other 2 with severe hyperglycemia (glucose >300 mg/dL). Median HbA1c was 7.05% (range 6.4%-7.4%) at presentation. GAD Ab was negative in 3 of 4 patients, including one who had DKA. C-peptide was undetectable (<0.2 ng/mL) in the 2 patients with DKA, 0.4 ng/mL in one other patient, and not measured in the fourth. All patients were immediately started on MDII. However, the two patients without DKA on presentation were eventually initiated on non-insulin agents. One of them was started on a DPP-4 inhibitor and discontinued fast-acting insulin, and the other started a GLP-1 receptor agonist and reduced their fast-acting insulin requirement. The heterogeneity of DM presentation and its clinical course reported here highlights a few important points. The first is that the onset of ICI-induced DM is often much later than that of the most common endocrine irAE, hypothyroidism, which has an onset around 10 weeks in average. Second, DM often presents as severe hyperglycemia incidentally detected on blood work. GAD Ab positivity is relatively less common, suggesting a different underlying etiology than classic type 1 DM. Onset of severe hyperglycemia can occur over many weeks (as indicated by higher HbA1c), making it important to monitor for hyperglycemia in those with no previous history of prediabetes or DM. Finally, it may be possible to use a combination of non-insulin antihyperglycemic agents to provide better glycemic management. No widely validated strategies for the surveillance of irAEs are currently available, and a better understanding in the propensity of patients to develop irAEs is clearly required. Importantly, optimal management of irAEs relies on early recognition and frequently demands a multidisciplinary approach. Presentation: 6/2/2024

Whiteness and greenness assessments of a sensitive HPLC method with fluorimetric detection for dapagliflozin quantitation in human plasma: Application to a healthy human volunteer.

The evident ecological impact of human actions, like air pollution, global warming, and ozone depletion, underscores the need for environmentally friendly approaches across various domains, including analytical chemistry. This study aimed to establish a validated, eco-friendly, and sustainable approach utilizing a fluorescence detector coupled with high-performance liquid chromatography for quantifying the antihyperglycemic agent dapagliflozin (DAPA), in human plasma. This method employed a C18 Microsorb MV (4.5 × 250 mm, 5 μm [particle size]) column at 40°C, with 40:60% v/v isocratic elution of acetonitrile and (0.1%) orthophosphoric acid as the mobile phase at 1 mL/min flow rate. DAPA and the internal standard demonstrated their greatest response by performing excitation at 225 nm (λex) and recording chromatograms at an emission wavelength (λem) equal to 305 nm. The presented approach demonstrated high linearity between 50 and 2000 ng/mL and full adherence to the guidelines of the US Food and Drug Administration regarding the validation of bioanalytical methods. The described technique was effectively used for quantification of DAPA in human plasma samples from a healthy male participant who received a tablet of 10 mg DAPA. Analytical Eco-Scale, Analytical GREEnness metric, and the recently created ChlorTox Scale were utilized for greenness assessment. Additionally, the "Red, Green, and Blue 12" model was used in whiteness evaluation.

Novel 3,5‐Dimethylpyrazole‐Linked 1,2,4‐Triazole‐3‐thiols as Potent Antihyperglycemic Agents: Synthesis, Biological Evaluation, and In Silico Molecular Modelling Investigations

AbstractIn this work, a series of pyrazole‐linked 1,2,4‐triazole‐3‐thiol derivatives (3a–i) were prepared and identified by 13C NMR, 1H NMR, and mass spectrometry (ESI‐MS) data. The newly synthesized molecules were also evaluated in vitro for their α‐amylase and α‐glucosidase inhibitory potential. All newly synthesized compounds exhibited potent α‐glucosidase inhibition activity with IC50 in the range of 1.016 ± 0.70 to 24.40 ± 0.02 µM and good α‐amylase inhibitory with IC50 in the range of 49.91 ± 0.32 to 500 µM, as compared to acarbose. The most potent compound among this series is derivative 3e, with IC50 value of 1.016 ± 0.70 µM, which is many folds more than that of acarbose. In addition, in docking studies, both compounds exhibited good interactions at the active region of target proteins. Therefore, this study may lead via structural modifications to the discovery of new potent α‐amylase and α‐glucosidase inhibitors useful in the diabetes treatment.

Elevated HbA1c Levels Are Associated with a Risk of Pancreatic Cancer: A Case-Control Study.

Background: The early diagnosis of pancreatic cancer (ICD-10 C25) can improve the patient's prognosis. The association between pancreatic cancer and type 2 diabetes (T2D) is known, but not yet fully understood. It is, therefore, necessary to investigate the impact of hemoglobin A1c (HbA1c) serum levels on pancreatic cancer development and the potential intervention options. Methods: In the case-control study, patients from the German IQVIATM Disease Analyzer database aged ≥18 years with a diagnosis of pancreatic cancer (ICD-10 C25) and a diagnosis of T2D (ICD-10: E11) were included. The patients' propensity score matched 1:5 with individuals without pancreatic cancer. Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Results: An elevated serum HbA1c prior to the index date was found to be significantly associated with an increased risk of a subsequent pancreatic cancer diagnosis for the mean HbA1c values of 6.5-8.4% (OR: 1.38; 95% CI: 1.22-1.57) as well as for mean HbA1c values ≥8.5% (OR: 1.41; 95% CI: 1.16-1.73). The only antihyperglycemic agent negatively associated with the subsequent pancreatic cancer diagnosis was the sodium-glucose cotransporter-2 (SGLT-2) inhibitor, with an odds ratio of 0.80 (95% confidence interval: 0.74-0.87 per year of therapy). This correlation was observed in both age- and sex-stratified subgroups. Conclusions: The data indicate that elevated serum HbA1c levels in patients with T2D are associated with an increased risk of pancreatic cancer development. It is possible that SGLT2 therapy may prove an effective means of reducing the risk of pancreatic cancer, thereby offering a potential avenue for the future reduction in pancreatic cancer incidence in patients with T2D.

Clinical outcomes in type 2 diabetes patients with chronic heart failure treated with metformin: a meta-analysis.

To explore outcomes of metformin (Met) as an antihyperglycemic agent in patients with type 2 diabetes mellitus (T2DM) combined with chronic heart failure (CHF). This article employed a meta-analysis approach to systematically search several databases. Stata 15.1 software was employed for statistical analysis. This meta-analysis encompassed 15 randomized controlled trials, involving 20,595 patients with T2DM and CHF. The results revealed that in comparison to the non-Met group, the Met group exhibited a significantly reduced risk of all-cause mortality (RR = 0.72, 95%CI: 0.60-0.87) and a notably lower risk of cardiovascular mortality (RR = 0.52, 95%CI:0.29-0.92). However, there was no significant difference in the risk of hospitalization due to heart failure (RR = 0.85, 95%CI: 0.70-1.04). Furthermore, the Met group demonstrated significant improvements in NT-proBNP levels compared to the non-Met group (WMD = -132.91, 95%CI: -173.03, -92.79). Regarding the enhancement of Left Ventricular Ejection Fraction and Left Ventricular End-Diastolic Dimension levels, no statistically significant differences were observed between the two groups. In individuals with T2DM and CHF, the use of Met is linked to a decreased likelihood of all-cause mortality and cardiovascular-related mortality. Furthermore, it can enhance cardiac function in CHF patients without elevating the risk of hospitalization due to heart failure, establishing its safety and potential benefits.

Glucagon-Like Peptide-1 Receptor Agonists are Not Associated with an Increased Risk of Progressing to Vision-Threatening Diabetic Retinopathy

ABSTRACT Purpose Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used to treat type 2 diabetes mellitus (DM) by augmenting insulin release and sensitivity. We assessed the overall risk for development of vision-threatening diabetic retinopathy (VTDR), proliferative diabetic retinopathy (PDR), and diabetic macular edema (DME), among GLP-1RA users. Methods A retrospective cohort of patients with NPDR newly started on a GLP-1RA from a national insurance claims database was compared to a cohort of patients treated with other oral anti-diabetic agents and matched for age, sex, race, index year, and number of active diabetic medications. Exclusions occurred for < 2 years in the database before diagnosis; prior diagnoses of PDR, DME, vitreous hemorrhage, and/or other retinal vascular diseases; and prior intraocular treatment for VTDR. Results A total of 6093 users of GLP-1RA were matched to 14,122 controls. In the GLP-1RA cohort, 632 (10.1%), 76 (1.2%), and 544 (8.9%) patients progressed to VTDR, PDR, or DME, respectively. This is compared to 1332 (9.5%) VTDR, 165 (1.2%) PDR, or 1148 (8.1%) DME in the control group. Accounting for underlying DM severity with IPTW, no difference in hazard was seen in the GLP-1RA cohort compared to controls for progression to VTDR (HR = 1.02, 95%CI: 0.92–1.14 p = 0.69), DME (HR = 1.06, 95%CI: 0.95–1.1.9, p = 0.31), or PDR (HR = 0.81, 95%CI: 0.58–1.12, p = 0.20). Conclusion We found no difference in the risk for vision-threatening diabetic retinopathy, nor for its component diseases, DME or PDR, with GLP-1RA use compared to other oral anti-hyperglycemic agents in patients with NPDR.

Use of SGLT-2 Inhibitors in Adults (Age ≥ 65) with Type 2 Diabetes and Cardiovascular Disease is Lower in Alberta and Manitoba than in Ontario (2018-2020): A Cross-Sectional Study of Different Drug Funding Policies

ObjectivesSodium-glucose cotransporter 2 inhibitors (SGLT2i) provide heart and kidney benefit in adults with diabetes and cardiovascular disease (CVD). Public drug coverage policies for SGLT2i differ by province in Canada. Our study aimed to describe the potential effects of prior authorization / step therapy (PA/ST) and relatively high income-based deductibles, compared to regular benefit status with modest co-pay, on SGLT2i prescriptions in high-risk adults. MethodsCross-sectional study of individuals age ≥ 65 years with type 2 diabetes and CVD, taking ≥ 1 antihyperglycemic agent from 2019 to 2020, using electronic medical record data from primary care practices. We compared SGLT2i use (2019-2020) in Alberta (PA/ST, modest co-pay), and Manitoba (PA/ST, relatively high income-based deductible), to Ontario (regular benefit status, modest co-pay). Poisson regression was used to adjust for confounders, including age, sex, glycated hemoglobin, and other medication use. Other diabetes medications were estimated as control cases. ResultsWe included 3,191 adults (average age 75 years, 31% female). SGLT2i use was lowest in Manitoba (15.6%), then Alberta (25.9%), and highest in Ontario (31.9%). After adjustment, compared to Ontario, SGLT2i prescriptions were lower in Alberta (prevalence ratio [PR] 0.80, 95% CI [0.71-0.91], p < 0.001) and Manitoba (PR 0.48 [0.39-0.59], p < 0.001). ConclusionsPA/ST and relatively high deductibles are associated with reduced SGLT2i prescribing – PA/ST by approximately 20% in Alberta and Manitoba, and relatively high deductibles by an additional relative reduction of 40% in Manitoba. PA/ST and cost-sharing policies should be flexible and responsive to changing evidence of clinical benefit.

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

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

Fabrication of novel vildagliptin loaded ZnO nanoparticles for anti diabetic activity

Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV–vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV–visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC50 values of 24.11 μg/per ml and 42.94 μg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.

Extraction of anti-hyperglycaemic bioactive compounds from Phyllanthus niruri L. through solvent mixture design: In vitro and in vivo evaluation

BackgroundSpecies within Phyllanthus genus exhibit a diverse range of experimentally validated pharmacological activities. Notably, Phyllanthus niruri Linneo(Phyllanthaceae), commonly referred to as stonebreaker, is a native Central and South American species with a rich history of use in traditional ethnomedicine for treating gastrointestinal and renal disorders. PurposeThe aim of this study was to investigate the application of various solvent mixtures to optimize the extraction of anti-hyperglycemic secondary metabolites from P. niruri. MethodsTo optimize the extraction of anti-hyperglycemic compounds from P. niruri, a solvent mixture design strategy was employed. The optimized extracts were subjected to chemical characterization using spectrophotometric methods and HPLC-DAD analysis. Also, the influence of edaphoclimatic conditions on the composition of extracts was investigated. The anti-hyperglycaemic potential of the extracts was evaluated through both in vitro and in vivo assays. The in vitro studies included enzyme inhibition assays targeting α-glucosidase from two sources (yeast and pig). For in vivo studies, a rat model with oral starch overload was used to confirm the anti-hyperglycaemic activity of the extracts. ResultsAn optimal solvent mixture (70 % methanol and 30 % ethyl acetate) was found as effective for extracting compounds with anti-hyperglycemic potential from P. niruri. All the extracts obtained using this solvent inhibited both, yeast and pig α-glucosidase, with greater selectivity for inhibiting the yeast-derived enzyme. Extracts from aerial parts (AP) exhibited the strongest inhibitory activity. These extracts contained phenolic compounds, specifically flavonoids, but no condensed tannins were detected. Chromatographic analysis of profile revealed a major peak consistent with corilagin. In vivo studies using a dose of 500 mg kg-1 demonstrated that this extract significantly reduced blood sugar levels after starch overload in rats. ConclusionThis study demonstrates the importance of selecting appropriate solvent mixtures to extract bioactive compounds with anti-hyperglycemic properties from P. niruri. Our findings support the traditional use of this plant as a anti-hyperglycaemic agent in ethnomedicine.

Impact of Selected Glucagon-like Peptide-1 Receptor Agonists on Serum Lipids, Adipose Tissue, and Muscle Metabolism-A Narrative Review.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are novel antihyperglycemic agents. By acting through the central nervous system, they increase satiety and reduce food intake, thus lowering body weight. Furthermore, they increase the secretion of insulin while decreasing the production of glucagon. However, recent studies suggest a more complex metabolic impact through the interaction with various other tissues. In our present review, we aim to provide a summary of the effects of GLP-1 RA on serum lipids, adipose tissue, and muscle metabolism. It has been found that GLP-1 RA therapy is associated with decreased serum cholesterol levels. Epicardial adipose tissue thickness, hepatic lipid droplets, and visceral fat volume were reduced in obese patients with cardiovascular disease. GLP-1 RA therapy decreased the level of proinflammatory adipokines and reduced the expression of inflammatory genes. They have been found to reduce endoplasmic reticulum stress in adipocytes, leading to better adipocyte function and metabolism. Furthermore, GLP-1 RA therapy increased microvascular blood flow in muscle tissue, resulting in increased myocyte metabolism. They inhibited muscle atrophy and increased muscle mass and function. It was also observed that the levels of muscle-derived inflammatory cytokines decreased, and insulin sensitivity increased, resulting in improved metabolism. However, some clinical trials have been conducted on a very small number of patients, which limits the strength of these observations.

Dapagliflozin improves skeletal muscle insulin sensitivity through SIRT1 activation induced by nutrient deprivation state

Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. β-hydroxybutyric acid (β-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after β-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.

Croton gratissimus Burch Herbal Tea Exhibits Anti-Hyperglycemic and Anti-Lipidemic Properties via Inhibition of Glycation and Digestive Enzyme Activities.

Over the years, the world has continued to be plagued by type 2 diabetes (T2D). As a lifestyle disease, obese individuals are at higher risk of developing the disease. Medicinal plants have increasingly been utilized as remedial agents for managing metabolic syndrome. The aim of the present study was to investigate the in vitro anti-hyperglycemic and anti-lipidemic potential of Croton gratissimus herbal tea infusion. The inhibitory activities of C. gratissimus on carbohydrate (α-glucosidase and α-amylase) and lipid (pancreatic lipase) hydrolyzing enzymes were determined, and the mode of inhibition of the carbohydrate digestive enzymes was analyzed and calculated via Lineweaver-Burk plots and Michaelis Menten's equation. Its effect on Advanced Glycation End Product (AGE) formation, glucose adsorption, and yeast glucose utilization were also determined. High-performance liquid chromatography (HPLC) was used to quantify the possible phenolic compounds present in the herbal tea infusion, and the compounds were docked with the digestive enzymes. C. gratissimus significantly (p < 0.05) inhibited α-glucosidase (IC50 = 60.56 ± 2.78 μg/mL), α-amylase (IC50 = 35.67 ± 0.07 μg/mL), as well as pancreatic lipase (IC50 = 50.27 ± 1.51 μg/mL) in a dose-dependent (15-240 µg/mL) trend. The infusion also inhibited the non-enzymatic glycation process, adsorbed glucose effectively, and enhanced glucose uptake in yeast cell solutions at increasing concentrations. Molecular docking analysis showed strong binding affinity between HPLC-quantified compounds (quercetin, caffeic acid, gallic acid, and catechin) of C. gratissimus herbal tea and the studied digestive enzymes. Moreover, the herbal tea product did not present cytotoxicity on 3T3-L1 cell lines. Results from this study suggest that C. gratissimus herbal tea could improve glucose homeostasis and support its local usage as a potential anti-hyperglycemic and anti-obesogenic agent. Further in vivo and molecular studies are required to bolster the results from this study.

Development and Validation RP-HPLC Method for Estimation of Antidiabetic Drugs in Pharmaceutical Dosage Form

This study details the development and validation of an RP-HPLC method for estimating Canagliflozin and Metformin in pharmaceutical dosage forms. Canagliflozin, an SGLT2 inhibitor, and Metformin, an antihyperglycemic agent, were obtained from Arti Drug Pvt. Ltd. Marketed formulation Invokamet was sourced locally. Chromatographic separation was achieved on a C18 column (250 x 4.6 mm, 5 µm) using a mobile phase of Methanol: Water (80:20) with 0.1% ortho phosphoric acid at a 1.0 ml/min flow rate and detection at 254 nm. The retention times for Canagliflozin and Metformin were 8.183 min and 3.633 min, respectively. Method validation parameters included system suitability, accuracy, precision, and robustness. System suitability tests confirmed adequate resolution and repeatability. Accuracy was evaluated through recovery studies at 80%, 100%, and 120% concentration levels, yielding satisfactory results. Precision was demonstrated with intra-day and inter-day % RSD values below 2. Robustness was assessed by varying mobile phase composition and flow rate, showing consistent retention times and tailing factors. The method proved selective, accurate, precise, and robust, with a short run time, facilitating rapid quantification of samples. It is suitable for routine quality control analysis of Canagliflozin and Metformin in pharmaceutical formulations

Metformin and Atrial Fibrillation: A Systematic Review of Their Association.

Atrial fibrillation (AF) is a common cardiac arrhythmia with a significant impact on patient outcomes and healthcare systems. Given the rising incidence of AF with age and its association with conditions, such as diabetes, there is growing interest in exploring pharmacological interventions that might mitigate AF risk. Metformin, a widely prescribed antihyperglycemic agent for type 2 diabetes mellitus (T2DM), has demonstrated various cardiovascular benefits, including anti-inflammatory and antioxidative properties, leading to speculations about its potential role in AF prevention. This systematic review synthesizes findings from five studies examining the association between metformin use and AF risk in patients with T2DM. The review included a dynamic cohort study, three retrospective cohort studies, and a case report, all sourced from databases, such as PubMed, Embase, and the Cochrane Library. The results are mixed; while some studies suggest that metformin use is linked to a reduced incidence of AF, others report no significant association, particularly in postoperative settings. The largest cohort study highlighted a dose-response relationship, suggesting prolonged metformin use correlates with lower AF risk. Conversely, a case report raised concerns about metformin-induced lactic acidosis potentially triggering AF episodes. The review underscores the heterogeneity in study designs and outcomes, pointing to the need for more robust research to establish causality and clarify underlying mechanisms. Future studies should prioritize prospective designs and explore the pleiotropic effects of metformin on atrial remodeling and electrophysiology to better understand its potential role in AF prevention.

Management of Metabolic-Associated Fatty Liver Disease/Metabolic Dysfunction-Associated Steatotic Liver Disease: From Medication Therapy to Nutritional Interventions.

Non-alcoholic fatty liver disease (NAFLD) is a common long-lasting liver disease that affects millions of people around the world. It is best identified with a hepatic fat build-up that ultimately leads to inflammation and damage. The classification and nomenclature of NAFLD have long been a controversial topic, until 2020 when a group of international experts recommended substituting NAFLD with MAFLD (metabolic dysfunction-associated FLD). MAFLD was then terminologically complemented in 2023 by altering it to MASLD, i.e., metabolic dysfunction-associated steatotic liver disease (MASLD). Both the MAFLD and the MASLD terminologies comprise the metabolic element of the disorder, as they offer diagnostic benchmarks that are embedded in the metabolic risk factors that underlie the disease. MASLD (as a multisystemic disease) provides a comprehensive definition that includes a larger population of patients who are at risk of liver morbidity and mortality, as well as adverse cardiovascular and diabetes outcomes. MASLD highlights metabolic risks in lean or normal weight individuals, a factor that has not been accentuated or discussed in previous guidelines. Novel antihyperglycemic agents, anti-hyperlipidemic drugs, lifestyle modifications, nutritional interventions, and exercise therapies have not been extensively studied in MAFLD and MASLD. Nutrition plays a vital role in managing both conditions, where centralizing on a diet rich in whole vegetables, fruits, foods, healthy fats, lean proteins, and specific nutrients (e.g., omega-3 fatty acids and fibers) can improve insulin resistance and reduce inflammation. Thus, it is essential to understand the role of nutrition in managing these conditions and to work with patients to develop an individualized plan for optimal health. This review discusses prevention strategies for NAFLD/MAFLD/MASLD management, with particular attention to nutrition and lifestyle correction.