Class Of Antidiabetic Drugs Research Articles

The clinical efficacy, outcomes and quality of life of diabetic disease patients treated with dapagliflozin

Introduction: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and a common serious complication that affects 1/3rd of type-1 and half of type-2 diabetes mellitus patients. In the early stages of DKD-RAAS blockades (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) and antihyperglycemic agents such as sodium-glucose transport protein (SGLT) 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors may help prevent DKD by lowering blood glucose levels and through intrinsic renal protection. SGLT2 inhibitors are a new class of oral antidiabetic drugs, which delay the progression of DKD. Dapagliflozin is a drug of choice when the estimated glomerular filtration rate (eGFR) is 25–75 mL/min/1.73 m2 and urine albumin–creatinine ratio ≥≥30 mg/mmol. Aim and Objectives: The aim of the study was to evaluate the clinical outcomes of dapagliflozin in DKD and to check the complications and quality of life of the patients after treatment. Methodology: It was a prospective observational study conducted for a period of 6 months in a tertiary care hospital. The data were collected from the 49 patients with DKD who underwent treatment with dapagliflozin, after approval of the protocol by the IEC. The statistical analysis was done using SPSS software, V.22.(1) 1. SPSS I. IBM SPSS Statistics Version 22 Statistical Software: Core System Users’ Guide. SPSS Inc. 2014. Results and Discussion: The majority of patients enrolled were males (81.63%) compared to females (18.36%) and most of them were geriatrics > 60 years. The majority of patients received dapagliflozin 10 mg, followed by few patients with 5 mg. The effectiveness of dapagliflozin was observed by statistically significant improvement in serum creatinine (P < 0.05), BUN (P < 0.05), and blood urea (P ≤ 0.05). Clinically significant improvement was observed in eGFR, creatinine clearance, serum sodium, potassium, chlorides, glycated hemoglobin levels, and body mass index (P > 0.05), which was statistically insignificant. Statistically significant improvement in the quality of life (P < 0.001) of patients was observed. Out of 49, two patients reported with UTI which may be a suspected drug-related side effect. Conclusion: The study concludes that dapagliflozin has a positive impact on treating DKD. The overall quality of life of the patients was moderately improved. These outcomes suggest that dapagliflozin may become the main line therapy in patients suffering from DKD.

Multifunctional host-defense peptides isolated from skin secretions of the banana tree dwelling frog Boana platanera (Hylidae; Hylinae)

Five host-defense peptides (figainin 2PL, hylin PL, raniseptin PL, plasticin PL, and peptide YL) were isolated from norepinephrine-stimulated skin secretions of the banana tree dwelling frog Boana platanera (Hylidae; Hylinae) collected in Trinidad.Raniseptin PL (GVFDTVKKIGKAVGKFALGVAKNYLNS.NH2) and figainin 2PL (FLGTVLKLGKAIAKTVVPMLTNAMQPKQ. NH2) showed potent and rapid bactericidal activity against a range of clinically relevant Gram-positive and Gram-negative ESKAPE + pathogens and Clostridioides difficile. The peptides also showed potent cytotoxic activity (LC50 values < 30 μM) against A549, MDA-MB-231 and HT29 human tumor-derived cell lines but appreciably lower hemolytic activity against mouse erythrocytes (LC50 = 262 ± 14 μM for raniseptin PL and 157 ± 16 μM for figainin 2PL). Hylin PL (FLGLIPALAGAIGNLIK.NH2) showed relatively weak activity against microorganisms but was more hemolytic. The glycine-leucine-rich peptide with structural similarity to the plasticins (GLLSTVGGLVGGLLNNLGL.NH2) and the non-cytotoxic peptide YL (YVPGVIESLL.NH2) lacked antimicrobial and cytotoxic activities. Hylin PL, raniseptinPL and peptide YL stimulated the rate of release of insulin from BRIN-BD11 clonal β-cells at concentrations ≥100 nM. Peptide YL was the most effective (2.3-fold increase compared with basal rate at 1 μM concentration) and may represent a template for the design of a new class of incretin-based anti-diabetic drugs.

The role of sodium – glucose cotransporter-2 inhibitors in the treatment of different phenotypes of chronic heart failure

The number of patients with chronic heart failure syndrome is steadily increasing worldwide and Ukraine is not an exception. About 50 % of patients with heart failure have preserved ejection fraction of left ventricle. Recently, there has been significant progress in the diagnosis of this phenotype of heart failure, many diagnostic scales and practice-oriented algorithms have been developed, but the issue of treatment of chronic heart failure remains open. Aim of the study. To summarize and analyze the results of large-scale randomized trials and to discuss the possible pathophysiological mechanisms underlying the “pleiotropiс” effects of sodium-glucose cotransporter-2 inhibitors. Sodium-glucose cotransporter-2 inhibitors are the first class of antidiabetic drugs that have demonstrated improved cardiovascular prognosis in patients with chronic heart failure with preserved ejection fraction regardless of the presence of diabetes mellitus. Conclusions. The necessity of prescribing sodium-glucose cotransporter-2 inhibitors in a cohort of patients with heart failure, regardless of left ventricular ejection fraction, has the highest level of evidence. The pathophysiological mechanisms underlying these effects are not fully understood. Further trials will allow us to identify new mechanisms of action and establish potential relationships between them.

Sodium-glucose cotransporter-2 inhibitors and the risk of atrial fibrillation in patients with type 2 diabetes: a population-based cohort study.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have a direct cardiac effect that is likely to be independent of its glucose lowering renal effect. Previous research has shown that SGLT2-is mitigate heart failure and prevent arrhythmic cardiac death. Our objective is to determine whether SGLT-2is reduce atrial fibrillation (AF) in comparison to other second-to third-line antidiabetic drugs in type 2 diabetes. We conducted a population-based, new-user active comparator cohort study using data from the UK Clinical Practice Research Datalink. We identified a cohort of patients initiating a new antidiabetic drug class between January 2013 and September 2020. This cohort included patients initiating their first ever non-insulin antidiabetic drug, as well as those who switched to or added-on an antidiabetic drug class not previously used in their treatment history. Individuals with a diagnosis of AF or atrial flutter at any time before cohort entry were excluded. Cox regression analysis with time-dependent covariates was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF comparing SGLT-2-is with other second-line to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or≥5 years), body mass index (BMI), HbA1c, and presence of heart failure.The cohort comprised 142447 patients. SGLT-2is were associated with a statistically significant reduced hazard of AF compared to other second-line to third-line antidiabetic drugs (adjusted HR: 0.77 [95% CI: 0.68-0.88]). This reduced risk was present in both sexes but was more prominently among women (adjusted HRwomen: 0.60 [95% CI: 0.45-0.79]; HRmen: 0.85 [95% CI: 0.73-0.98]; P-value interaction: 0.012). There was no evidence for effect modification when stratifying on duration of diabetes, BMI, HbA1c, or presence of heart failure. SGLT-2is were associated with a reduced risk of AF in patients with type 2 diabetes compared to other second-line to third-line antidiabetic drugs. This reduced risk occurs in both sexes but more prominently among women.

Causal Estimation of Long-term Intervention Cost-effectiveness Using Genetic Instrumental Variables: An Application to Cancer.

This article demonstrates a means of assessing long-term intervention cost-effectiveness in the absence of data from randomized controlled trials and without recourse to Markov simulation or similar types of cohort simulation. Using a Mendelian randomization study design, we developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate, and thyroid cancers on health care costs and quality-adjusted life-years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used these estimates in a simulation model to estimate the cost-effectiveness of a hypothetical population-wide preventative intervention based on a repurposed class of antidiabetic drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. Genetic liability to prostate cancer and breast cancer had material causal impacts on either or both health care costs and QALYs. Mendelian randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anticancer indication. Our new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision-analytic models of cancer interventions such as screening programs or simulations of longer-term outcomes associated with therapies investigated in randomized controlled trials with short follow-ups. Our method allowed us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anticancer intervention to inform and complement other means of assessing long-term intervention value. The article demonstrates a novel method of assessing long-term intervention cost-effectiveness without relying on randomized controlled trials or cohort simulations.Mendelian randomization was used to estimate the causal effects of certain cancers on health care costs and quality-adjusted life-years (QALYs) using data from the UK Biobank cohort.Given causal data on the association of different cancer exposures on costs and QALYs, it was possible to simulate the cost-effectiveness of an anticancer intervention.Genetic liability to prostate cancer and breast cancer significantly affected health care costs and QALYs, but the hypothetical intervention using SGLT2 inhibitors for prostate cancer may not be cost-effective, depending on the drug's price for the new anticancer indication. The methods we propose and implement can be used to efficiently estimate intervention cost-effectiveness and to inform decision making in all manner of preventative and therapeutic contexts.

Comparative analysis of newer classes of antidiabetics and the concept of pharmaceutical care – dealing with therapeutic problems

The prevalence of obesity is increasing rapidly. The latest World Health Organization – WHO report declares the disease as an epidemic. After pharmacodynamic, pharmacokinetic, clinical and pharmacoepidemiologic data analysis and comparison of the three classes of antidiabetic medicinal products: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors, a literature review of the topic, patient education and the concept of pharmaceutical care emerged as methods for dealing with the most common adverse drug reactions, safety concerns, and drug interactions.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease

Several oral antidiabetic drug (OAD) classes can potentially improve patient outcomes in nonalcoholic fatty liver disease (NAFLD) to varying degrees, but clinical data on which class is favored are lacking. To investigate which OAD is associated with the best patient outcomes in NAFLD and type 2 diabetes (T2D). This retrospective nonrandomized interventional cohort study used the National Health Information Database, which provided population-level data for Korea. This study involved patients with T2D and concomitant NAFLD. Receiving either sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, each combined with metformin for 80% or more of 90 consecutive days. The main outcomes were NAFLD regression assessed by the fatty liver index and composite liver-related outcome (defined as liver-related hospitalization, liver-related mortality, liver transplant, and hepatocellular carcinoma) using the Fine-Gray model regarding competing risks. In total, 80 178 patients (mean [SD] age, 58.5 [11.9] years; 43 007 [53.6%] male) were followed up for 219 941 person-years, with 4102 patients experiencing NAFLD regression. When compared with sulfonylureas, SGLT2 inhibitors (adjusted subdistribution hazard ratio [ASHR], 1.99 [95% CI, 1.75-2.27]), thiazolidinediones (ASHR, 1.70 [95% CI, 1.41-2.05]), and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.31-1.59]) were associated with NAFLD regression. SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression when compared with thiazolidinediones (ASHR, 1.40 [95% CI, 1.12-1.75]) and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.30-1.62]). Only SGLT2 inhibitors (ASHR, 0.37 [95% CI, 0.17-0.82]), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas. The results of this cohort study suggest that physicians may lean towards prescribing SGLT2 inhibitors as the preferred OAD for individuals with NAFLD and T2D, considering their potential benefits in NAFLD regression and lower incidences of adverse liver-related outcomes. This observational study should prompt future research to determine whether prescribing practices might merit reexamination.

Peran SGLT2i terhadap Risiko Kardiorenal Pasien dengan atau Tanpa Diabetes Melitus Tipe 2

Sodium-glucose Co-transporter 2 inhibitor (SGLT2i) is one of the antidiabetic classes recommended for patients with heart and kidney problems. Evidence-based studies show the benefits of SGLT2i extend to heart, kidney, or other metabolic diseases in patients without diabetes mellitus.

Comparative effects of canagliflozin and sitagliptin in chronically ischemic myocardium.

Recent studies demonstrate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i), two classes of antidiabetic drugs, are cardioprotective. However, the mechanisms of these benefits and their comparative efficacy remain unclear. We aimed to compare the effects of these antidiabetic agents on cardiac function, perfusion, and microvascular density using a swine model of chronic myocardial ischemia. Chronic myocardial ischemia was induced in Yorkshire swine by ameroid constrictor placement to the left circumflex artery. Two weeks later, pigs were administered vehicle ("CON", 8 pigs), 300 mg SGLT2i canagliflozin, ("CANA", 8 pigs), or 100 mg DPP4i sitagliptin ("SIT", 5 pigs) daily. Five weeks later, pigs were euthanized. Cardiac function, perfusion, collateralization, and protein expression were determined by pressure-volume catheter, microsphere analysis, immunofluorescence, and immunoblotting, respectively. Compared with SIT, CANA was associated with improved stroke volume and cardiac output, with a trend towards reduced left ventricular stiffness. Both CANA and SIT trended towards improved perfusion compared to CON, but there were no differences between the two treatment groups. SIT was associated with improved capillary density with a trend towards improved arteriolar density compared to CANA. Both CANA and SIT were associated with increased expression of vascular endothelial cadherin compared to CON, without differences in treatment groups. SIT pigs had decreased 5' adenosine monophosphate-activated protein kinase activation compared to CON and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across groups. In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac function compared to sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization.

The Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Atrial Electromechanical Conduction Time.

This study aims to explore the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, a newer class of oral antidiabetic drugs, on atrial electromechanical delay (EMD) in patients with type 2 diabetes mellitus (DM). This is particularly relevant given the significantly higher incidence of atrial fibrillation (AF) in diabetic patients compared to the general population. Atrial electromechanical delay is recognized as an important factor influencing the development of atrial fibrillation. This study included 30 type 2 DM patients (53.3% female, mean age 60.07 ± 10.03 years), initiating treatment with SGLT-2 inhibitors. The patients were assessed using echocardiography at baseline and again at 6 months, focusing on basic echocardiographic parameters and atrial electromechanical delay times (EMD) measured via tissue Doppler imaging. No significant changes were observed in intra-atrial EMD times. However, significant reductions were noted in interatrial EMD times, decreasing from 15.13 ± 5.87 ms to 13.20 ± 6.12 ms (P = 0.029). Statistically significant shortening occurred in lateral pulmonary acceleration (PA) times (from 58.73 ± 6.41 ms to 54.37 ± 6.97 ms, P < 0.001), septal PA times (from 50.90 ± 6.02 ms to 48.23 ± 5), and tricuspid PA times (from 43.60 ± 6.28 ms to 41.30 ± 5.60 ms, P = 0.003). Additionally, there was a significant reduction in the E/e' ratio from 8.13 ± 4.0 to 6.50 ± 2.37 (P = 0.003). SGLT-2 inhibitors might positively influence atrial electromechanical conduction, reducing DM-related functional impairments and the risk of arrhythmias, particularly AF.

New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment.

Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.

MitoNEET Provides Cardioprotection via Reducing Oxidative Damage and Conserving Mitochondrial Function.

Cardiometabolic diseases exert a significant health impact, leading to a considerable economic burden globally. The metabolic syndrome, characterized by a well-defined cluster of clinical parameters, is closely linked to an elevated risk of cardiovascular disease. Current treatment strategies often focus on addressing individual aspects of metabolic syndrome. We propose that exploring novel therapeutic approaches that simultaneously target multiple facets may prove more effective in alleviating the burden of cardiometabolic disease. There is a growing body of evidence suggesting that mitochondria can serve as a pivotal target for the development of therapeutics aimed at resolving both metabolic and vascular dysfunction. MitoNEET was identified as a binding target for the thiazolidinedione (TZD) class of antidiabetic drugs and is now recognized for its role in regulating various crucial cellular processes. Indeed, mitoNEET has demonstrated promising potential as a therapeutic target in various chronic diseases, encompassing cardiovascular and metabolic diseases. In this review, we present a thorough overview of the molecular mechanisms of mitoNEET, with an emphasis on their implications for cardiometabolic diseases in more recent years. Furthermore, we explore the potential impact of these findings on the development of novel therapeutic strategies and discuss potential directions for future research.

Sodium glucose co-transporter-2 (SGLT) inhibitors in patients with compensated cirrhosis and diabetes: A prospective study

Aims and objective: Diabetes in patients with cirrhosis is common. SGLT-2 inhibitors are newer class of antidiabetic drugs with pleiotropic effects. Its safety and efficacy has not been evaluated in patients with advanced cirrhosis and diabetes. We evaluated safety and efficacy of SGLT-2 inhibitors in patients with compensated cirrhosis and diabetes. Material and method: Consecutive patients with compensated cirrhosis and diabetes who were started on SGLT-2 inhibitors were enrolled and followed every month for six months. Their clinical and biochemical parameters which include liver and kidney function tests, urine test, glycosylated haemoglobin (HbA1c), transient elastography (fibroscan), Mean Arterial Pressure (MAP) and change in weight since treatment initiation were noted. Any relevant side effects (urinary and genital infection, hypotension) were noted. Results: Twenty patients [(M:F: 13:7), age (55±11 yr), CTP score (6±1.3), etiology of cirrhosis (NASH related 17, HBV, n=1 and HCV, n=2), baseline MAP (91±5 mmHg)] were enrolled. Five patients had hypertension and taking angiotensin converting enzyme (ACE) inhibitors and 15 patients were also on carvidelol. Mean Fibroscan was (37±11kPa), large varices (n=3), small varices (n=16) and no varices were seen in one patient. All patients were followed up for 6 months. Patient were on dapagliflogin (n=11, 55%), empagliflogin (n=6, 30%) and remogliflogin (n=3, 15%). Twelve (60%) patients were also on metformin and 7 (35%) on Dipeptidyl peptidase 4(DPP4) inhibitors. Significant improvement was seen in total bilirubin Baseline (B), 1.19±0.5, Month 3 (Mo 3), 1.02±0.4 and Month 6 (Mo 6), 1.01±0.3 mg/dl], AST (B, 50.8±20.8, Mo 3, 49.4±20.5, Mo 6, 42.8±13.0 IU/L) and GGT (B, 63.8±24.5, Mo 3, 66.5±31.0 and Mo 6, 58.3±21.4 IU/dl) level at month 3 and 6. Glycemic index improved at month 3 and 6 and significant weight loss was seen at month 3 and 6. Serum creatinine, serum sodium level and mean arterial pressure remained unchanged at month 6. Urinary tract infection occurred in n=3 (15%), genital infection in (n=2, 10%) and compliant of frothy urine was seen in (n=4, 20%) without discontinuation of medicines.

Natural Inhibitors of Mammalian α-Amylases as Promising Drugs for the Treatment of Metabolic Diseases.

α-Amylase is a generally acknowledged molecular target of a distinct class of antidiabetic drugs named α-glucosidase inhibitors. This class of medications is scarce and rather underutilized, and treatment with current commercial drugs is accompanied by unpleasant adverse effects. However, mammalian α-amylase inhibitors are abundant in nature and form an extensive pool of high-affinity ligands that are available for drug discovery. Individual compounds and natural extracts and preparations are promising therapeutic agents for conditions associated with impaired starch metabolism, e.g., diabetes mellitus, obesity, and other metabolic disorders. This review focuses on the structural diversity and action mechanisms of active natural products with inhibitory activity toward mammalian α-amylases, and emphasizes proteinaceous inhibitors as more effective compounds with significant potential for clinical use.

The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful?

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.

Canagliflozin enhances endogenous eliminatiton of senescent cells through downregulation of PD-L1

Abstract Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed as a new class of anti-diabetic drug, and shown cardio- and renal-protective effects in patients with diabetes, heart failure, and chronic kidney diseases. Also, there's evidence that canagliflozin, one of the SGLT2 inhibitors has expanded lifespan in aged mice, but their detailed protective machinery is still to be clarified. Here we demonstrate that canagliflozin has a effect to eliminate senescent cells from pathological tissues, so-called "senolysis" in some murine disease models and alleviates their pathology. We treated canagliflozin mixed in food at 0.03% (w/w) to high-fat-diet(HFD)-fed obese mice and found that canagliflozin reduced senescent cells in visceral adipose tissue within 1 week. Also, we found that senolytic effect of canagliflozin was provided through enhancing endogenous senolytic function by NK or T cells. This machinery was mediated by enhanced AMPK signaling, which leads to the downregulation of PD-L1 expression on senescent cells. Furthermore, we treated canagliflozin to ApoE-knockout atherosclerotic mice with western diet feeding, progeroid mice and chronological aged mice. Canagliflozin reduced their senescent cell burden, resulting in alleviation of atherosclerosis, extended lifespan of progeroid, and altered physical function due to chronological aging. Our results would be promising evidence that SGLT2 inhibitors can be used as not only cardio- or renal-protective drugs but also anti-aging drugs.

Association between dapagliflozin, cardiac biomarkers, and cardiac remodeling in patients with diabetes mellitus and heart failure: a post-hoc analysis of a randomized study

Abstract Introduction Sodium-glucose Cotransporter-2 (SGLT-2) inhibitors are a relatively new class of antidiabetic drugs, which showed favorable effects in heart failure (HF) patients, irrespective of their left ventricular ejection fraction (LVEF). Recent studies have demonstrated the beneficial effects of empagliflozin on cardiac function and structure, however, less is known about dapagliflozin. Purpose To investigate the association between the use of dapagliflozin and cardiac biomarkers as well as cardiac structure in a cohort of patients with HF and diabetes mellitus (DM). Methods The present was a post-hoc analysis of a recently published randomized study, which included 110 patients (Dapagliflozin group n = 56, Control group n = 54) with HF and DM. Inclusion criteria included: age&amp;gt;18 years, history of DM and HF, regardless of LVEF, and hospitalization for HF exacerbation within 6 months. Exclusion criteria were previous treatment with SGLT2i or Glucagon-like Peptide-1 Receptor agonists, a GFR&amp;lt; 30 and life expectancy&amp;lt; 1 year. The evaluation of patients (at baseline, 6 and 12 months) included clinical assessment, laboratory blood tests, and echocardiography. In order to investigate the changes in biomarkers and ultrasound indexes throughout the follow-up period in the two groups, linear mixed regression analyses were conducted. The regression equation included terms for time, group, time-group interaction, age and heart rate (HR) at baseline. Adjusted regression coefficients (β) with standard errors (SE) were computed from the results of the mixed models. Statistical significance was set at p&amp;lt; 0.05 and analyses were conducted using STATA statistical software (version 13.0). Results After adjusting for age and baseline HR, troponin decreased significantly throughout the follow-up period in a similar degree in both groups. Brain Natriuretic peptide (BNP) decreased significantly across all follow-up time points in both groups. However, the degree of decrease was significantly greater in the SGLT2-inhibitor group (Figure 1A, Table 1). LVEF did not change significantly over the follow-up period in the Control group, while it increased significantly in the SGLT2-inhibitor group. Left atrium (LA) increased significantly throughout the follow-up period only in the Control group, while in the SGLT2-inhibitor group there was no significant change. LA Volume index (Figure 1B), LV end diastolic volume (LVEDV), LVEDV index (Figure 1C), LV end systolic volume (LVESV), LVESV index and Global longitudinal strain (GLS) (Figure 1D) increased significantly throughout the follow-up period in the Control group, while in the SGLT2-inhibitor group they decreased significantly. LV mass index increased significantly throughout the follow-up period in a similar degree in both groups. Conclusion(s) Dapagliflozin, an SGLT2i, was associated with a reduction in cardiac biomarkers and with reverse cardiac remodeling in patients with HF and DM.Figure1.Longitudinal changesTable1.Results of the mixed LR analysis

Abstract 14285: Sodium Glucose Co-Transporter 2 Inhibition Eliminates Senescent Cells Through Downregulation of PD-L1 and Improves Pathological Aging

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed as a new class of anti-diabetic drug, and shown cardio- and renal-protective effects in patients with diabetes, heart failure, and chronic kidney diseases. SGLT2 inhibitor also has effect to expand lifespan in aged mice, suggesting anti-aging effect. But the detailed machinery of these protective effects is still to be clarified. Here we demonstrate that canagliflozin has a effect to eliminate senescent cells from pathological tissues, so-called "senolysis" in murine aging or age-related disease models. Methods: Canagliflozin mixed in food at 0.03% (w/w) was administered for up to 4 weeks to high-fat-fed diabetic mice, for 2 weeks to ApoE-knockout atherosclerotic mice model, for 20 weeks for chronological aged mice, and for lifetime to Zmpste-knockout progeroid mice. Burden of senescent cell accumilation as well as pathological or aged phenotype were measured in each mice model. Results: Canagliflozin reduced senescent cells in visceral adipose tissue within 1 week. Also, we found that senolytic effect of canagliflozin was provided through enhancing endogenous senolytic function by immune cells such as CD8+T cells. This machinery was mediated by enhanced AMPK signaling through incrase of endogenous AICAR production, which leads to the downregulation of PD-L1 expression on senescent cells. Oppositely, inhibition of AMPK signaling with Compound C administration (10mg/kg ip daily) resulted in abolishing senolytic effect of canagliflozin. Furthermore, canagliflozin reduced their senescent cell burden and alleviated atherosclerosis in ApoE-knockout mice, extended lifespan in progeroid mice, and altered physical function in aged mice. Conclusions: Our results showed new aspect of protective efficacy of SGLT2 inhibitors and would be promising evidence that SGLT2 inhibitors can be used as not only cardio- or renal-protective drugs but also anti-aging drugs.

A pilot study: Drug utilization pattern and prevalence of micro and macrovascular complication in type 2 diabetes patient

Background: Diabetes mellitus is a chronic metabolic disorder resulting from the deficiency of insulin secretion and insulin resistance. Currently, there is a death of nationwide data regarding the prevalence of micro and macro complications and drug utilization patterns. This study will help health-care professionals approach management more aggressively to prevent complications. Objectives: To assess the risk factors associated with complications in diabetes patients, and to determine the pattern of drug prescription among type-2 DM patients patterns at Virudhunagar Medical College &amp; Hospital. Methods: This is a Prospective, prescription-based, and observational study. A sample size of 50 was selected systematically. Data were collected from patient case records and Prescriptions. The obtained data were entered in the structured patient profile form, and the filled forms were analyzed. Results: Out of the total 50 cases evaluated, 60 (60%) were males and 20(40%) were females. The 28 patients (56%) had a family history of diabetes. The prevalence of the associated diabetic complications was as follows viz. Hypertension (17.65%), IHD (1.47%), retinopathy (17.65%), nephropathy (7.35%), Neuropathy (47.06%), Stroke (5.88%) and CHF (2.94%). The overall utilization pattern of drugs were as follows viz. anti-diabetics (28%), anti-hypertensive (9%), antiplatelets (4%), lipid lowering agents (7%), vitamins and minerals (17%),GI drugs (14%), antimicrobials(6%). Among anti-diabetic drugs 48(96%) biguanides and 44(88%) of sulfonylureas classes of antidiabetic drugs were utilized. Likewise, preferred drugs for the management of hypertension, IHD, dyslipidemia, and neuropathy were Diuretics (25.93%), Clopidogrel (66.66%), Atorvastatin (100%), and Acetominophine (67.74%) respectively. Conclusion: The prevalence of micro and macro complications among type 2 diabetic patients was found to be high. Although polypharmacy was observed, drug utilization patterns can be rational owing to the higher prevalence of complications. Patient are not aware of the severity of the disease so complication makes the therapeutic more challenging. Patient education on disease severity and healthcare professionals need more focus on disease complications and severity to treat the disease earlier to improve patient health outcomes.

In vitro and in silico analysis proving DPP4 inhibition and diabetes-associated gene network modulation by a polyherbal formulation: Nisakathakadi Kashaya

Dipeptidyl-peptidase IV (DPP4) inhibitors are an important class of anti-diabetic drugs recognised for their systemic biological actions. Polyherbal preparations like Ayurveda formulations are considered to be ideal sources for discovering novel DPP4 inhibitors owing to their rich phytochemical composition. The current study reports the DPP4 inhibitory potential of a clinically established Ayurvedic anti-diabetic formulation Nisakathakadi Kashaya (NK) using in vitro assay and substantiates it by identifying potential bioactives responsible for DPP4 inhibition using computational biology tools. NK showed a dose-dependent DPP4 inhibition with an IC50 of 2.06 μg GAE/mL, and the molecular docking and simulation studies showed three compounds, namely Terchebin, Locaracemoside B and 1,2,4,6 Tetra o Galloyl Beta D Glucose having stable interactions with DPP4 similar to the standard drug Vildagliptin. Further, for the reason that polyherbal formulations exert a network pharmacology mode of action, in silico analysis was carried out to identify the other putative phytochemical-protein networks modulated by NK. The complex pharmacological network of the formulation was explored further using a subnetwork of diabetes proteins and their relationship with diabetes-associated comorbidities. A number of key targets like TNFα, TGFβ1, SOD1, SOD2, AKT1, DPP4 and GLP1R were identified in the protein-protein interaction network that is vital to diabetic progression and complications. A combination of in vitro and in silico methods allowed us to prove the DPP4 inhibition potential of NK as well as provided insights into the possible pharmacological networking through which NK potentially exerts its systemic effect in diabetes management. Communicated by Ramaswamy H. Sarma