Sodium-glucose Cotransporter Type 2 Inhibitors Research Articles

Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis.

Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits but their comparative effects on mortality in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD) are unknown. Hence, we evaluated and compared lifetime benefits arising from metformin or SGLT2 inhibitors in T2DM patients with CVD. Studies published in the PubMed, EMBASE and CENTRAL databases before 28 October 2023 were retrieved. Treatment effects of metformin against US FDA-approved SGLT2 inhibitors in T2DM patients with CVD were evaluated and lifetime gains in event-free survival were estimated from our primary endpoints of all-cause and cardiovascular mortality. Risk ratios were derived to assess their impact on secondary outcomes such as major adverse cardiovascular events and hospitalizations for heart failure. Overall, 14 studies were included. Five studies published Kaplan-Meier curves for the primary outcome of all-cause mortality. Individual participant data were reconstructed from these Kaplan-Meier curves, from which we conducted our two-stage meta-analysis. Participants receiving metformin and SGLT2 inhibitors experienced a reduction in the risk for all-cause mortality as compared with those not taking metformin and placebo. However, participants receiving SGLT2 inhibitors had a higher all-cause mortality (hazard ratio 1.308, 95% confidence interval 1.103-1.550) versus metformin. Treatment with metformin was estimated to offer an additional 23.26months of survival free from all-cause mortality versus 23.04months with SGLT2 inhibitors. In patients with T2DM and CVD, metformin and SGLT2 inhibitors were associated with substantially lower all-cause mortality rates and slightly longer life expectancies than in patients without. Metformin presented an advantage over SGLT2 inhibitors in reducing all-cause mortality.

Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

A Methodological Framework for Meta-analysis and Clinical Interpretation of Subgroup Data: The Case of Major Adverse Cardiovascular Events With GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes.

We present a methodological framework for conducting and interpreting subgroup meta-analyses. Methodological steps comprised evaluation of clinical heterogeneity regarding the definition of subpopulations, credibility assessment of subgroup meta-analysis, and translation of relative into absolute treatment effects. We used subgroup data from type 2 diabetes cardiovascular outcomes trials (CVOTs) with glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with established cardiovascular disease and those at high cardiovascular risk without manifest cardiovascular disease. First, we evaluated the variability in definitions of the subpopulations across CVOTs using major adverse cardiovascular events (MACE) incidence in the placebo arm as a proxy for baseline cardiovascular risk. As baseline risk did not differ considerably across CVOTs, we conducted subgroup meta-analyses of hazard ratios (HRs) for MACE and assessed the credibility of a potential effect modification. Results suggested using the same overall relative effect for each of the two subpopulations (HR 0.85, 95% CI 0.80-0.90, for GLP-1 receptor agonists and HR 0.91, 95% CI 0.85-0.97, for SGLT2 inhibitors). Finally, we calculated 5-year absolute treatment effects (number of fewer patients with event per 1,000 patients). Treatment with GLP-1 receptor agonists resulted in 30 fewer patients with event in the subpopulation with established cardiovascular disease and 14 fewer patients with event in patients without manifest cardiovascular disease. For SGLT2 inhibitors, the respective absolute effects were 18 and 8 fewer patients with event per 1,000 patients. This framework can be applied to subgroup meta-analyses regardless of outcomes or modification variables.

Long-Term Mortality and SGLT2 Inhibitors in Type 2 Diabetes with and without Renal Impairment: An Observational Cohort Study

Aim: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a vital part of management of type 2 diabetes, as they have been shown to have both cardiovascular and renal benefits along with an improved survival rate in several randomized clinical trials. We designed a retrospective cohort study to investigate the impact of SGLT2 inhibitors on mortality among type 2 diabetes patients. Methods: Patients with type 2 diabetes who presented to the Dasman Diabetes Institute in Kuwait were followed from January 1st, 2015, until January 20th, 2023. To control for non-random allocation of SGLT2 inhibitors and measured confounders, we performed one-to-one propensity score matching and evaluated outcomes in the matched cohorts using a Cox proportional hazards model. The primary treatment variable was SGLT2 inhibitor use; time to mortality from any cause was used as the outcome of interest. Results: 1,551 patients were taking SGLT2 inhibitors, and 1,687 patients were not. After propensity score matching, 845 patients were on SGLT2 inhibitors, and 845 patients were not. In post-matching analysis, all-cause mortality was higher among patients who did not take SGLT2 inhibitors compared to patients taking SGLT2 inhibitors (5.2 vs. 2.1%, p = 0.0012). The hazard ratio of all-cause mortality in patients taking SGLT2 inhibitors was 0.42 (95% confidence interval [95% CI], 0.24–0.72). Additional adjustment of matching factors did not change the results. Conclusion: This observational study demonstrated substantial long-term reduction in mortality risk among patients with type 2 diabetes treated with SGLT2 inhibitors. This is irrespective of the stage of their renal diseases or GLP1 agonist.

Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) reabsorbs 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. The aim of this work was to obtain new potential SGLT2 inhibitors. A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived from spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. These compounds are proposed as potential SGLT2 inhibitors.

Modern glucose-lowering drugs in liver transplant recipients: improvement in weight, glycemic control, and potentially allograft steatosis.

Recurrent allograft steatosis occurs in one-third of transplanted livers. Antidiabetic agents like glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type-2 (SGLT2) inhibitors are effective in the management of obesity and hepatic steatosis in the general population; however, there is limited evidence supporting their use in allograft steatosis. We aimed to evaluate their effects on steatosis, body weight, and glycemic control in liver transplant recipients at our institution. In this single-center retrospective cohort study of liver transplant recipients currently on a GLP1RA or SGLT2 inhibitor (transplanted 2015-2022), we compared clinical and radiological data before medication use and at follow-up. Differences were compared using Wilcoxon signed-rank test. Thirty-seven liver transplant recipients were taking the agents. Diabetes was the most common indication (n = 33) followed by obesity (n = 4). Median follow up was 427 days (301,798). Among those with documented steatosis (n = 21), steatosis improved in 5, worsened in 4, remained unchanged in 1, and change could not be evaluated in 11 due to lack of comparable pre and post imaging. Average weight loss was 3.2 kg (p < 0.001) and BMI decreased by 1.2 kg/m2 (p < 0.001). Hemoglobin A1c decreased by 0.6 mmol/mol (p = 0.0014), insulin requirement reduced by 7 units/day (p = 0.02), and there was no change in additional antidiabetic medications. GLP1RA and SGLT-2 inhibitors are tolerated in transplant patients and result in weight loss and better glycemic control. They are promising agents to treat recurrent or de-novo liver allograft steatosis, but further research is needed to evaluate long-term outcomes in liver transplant recipients.

Editorial for the IJMS Special Issue on Sglt2 Inhibitors (Volume 2)

The goal of the second volume of this Special Issue was to build upon the success of the first one and to continue to highlight the ever-expanding list of pharmacological properties of the sodium/glucose co-transporter (SGLT) type 2 (SGLT2) inhibitor (SGLT2i) drug class (also known as gliflozins) [...]

Lower risk of atrial fibrillation development associated with SGLT-2 inhibitors in type 2 diabetic patients compared to DPP-4 inhibitors: a nationwide cohort study

Abstract Background Accumulating evidence shows that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiovascular outcomes. However, this favorable effect is unclear for newly atrial fibrillation (AF) development compared to other anti-diabetic drugs. Purpose We investigated the association of SGLT-2 inhibitor for newly AF development compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes. Methods Using the Korean National Health Insurance Service database, among 2,160,911 type 2 diabetes patients (age ≥20 years) between 1 May 2016 and 31 December 2018, we studied 42,806 patients with SGLT-2 inhibitors and 448,715 patients with DPP-4 inhibitors who had not prior AF diagnosis. Propensity score-matching (1:1 ratio) was used to correct for differences between the groups. Results During a median follow-up of 1.3 years, after propensity score matching, compared with patients with DPP-4 inhibitors (n=42,786), patients with SGLT-2 inhibitors (n=42,786) have shown lower incidence and risk of AF (2.7 and 3.3 per 1000 person-years; hazard ratio 0.73, 95% confidence interval 0.55-0.97; p=0.028) aand an absolute rate difference of −0.7 [95% confidence interval (CI) −1.3 to −0.1, p=0.034] per 1000 person-years by on-treatment analysis. In intention-to-treat analysis, these results were consistent (2.6 and 3.2 per 1000 person-years; hazard ratio 0.83, 95% confidence interval 0.66-1.03; p=0.092) with an absolute rate difference of −0.5 [95% confidence interval (CI) −1.2 to −0.1, p=0.093] per 1000 person-years . In subgroup analysis, SGLT-2 inhibitors were associated with lower risks of AF in heart failure compared to their counterparts in intention-to-treat analysis (p for interaction=0.036). Conclusion Based on this nationwide cohort of type 2 diabetes patients treated with SGLT-2 inhibitors or DPP-4 inhibitors, SGLT-2 inhibitors were associated with protection against newly AF development after adjusting for clinical confounders.Incidence rates and adjusted HR

Sodium-Glucose Co-transporter Type-2 Inhibitors' Effect on Quality of Life in Older Adult Population.

Introduction The global elderly population is expanding, with chronic conditions like diabetes diminishing their quality of life. Sodium-glucose co-transporter type 2 (SGLT-2) inhibitors hold promise in improving quality of life by addressing hypervolemia, obesity, and lipid irregularities. However, these drugs can lead to adverse effects, such as polyuria, dehydration, and weight loss, which may detrimentally impact older patients. We aimed to investigate the association between SGLT-2 inhibitors and quality of life in older adults with diabetes. Methods The research included 100 type II diabetes mellitus patients over 65, without active infections, malignancies, immunodeficiencies, and hematological disorders. Fifty patients were using empagliflozin or dapagliflozin and 50 patients were using other oral antidiabetics for at least six months. Patient demographics, laboratory studies, drug usage and side effects, additional diseases, Geriatric Depression Scale scores, and World Health Organization Quality of Life OLD (WHOQoL-OLD) module scores were noted. Results No significant difference between gender distribution, SGLT usage, chronic disease existence, chronic disease count, depression scores, or incidents of chronic diseases other than hyperlipidemia was observed. Hyperlipidemia incidence was significantly higher in the SGLT group, while other laboratory parameters were not statistically significantly different between groups. There were no significant differences in autonomy, past-present-future activities, social skills, death, intimacy, and total WHOQoL-OLD scores between the two groups. However, there were statistically significantly worse outcomes in patients with at least one SGLT adverse effect in terms of sensory quality of life scores. Dehydration existence was negatively correlated with lower autonomy, PPF activities, and total quality of life scores. Multivariate linear regression analysis showed no significant differences in the total WHOQoL-OLD score after adjusting for confounding factors. Conclusion Age and depression remained the main factors affecting the quality of life in diabetic patients. SGLT-2 inhibitor side effects did not decrease the quality of life in older individuals, who are more prone to unfavorable consequences.

The effect of a medicinal plant preparation on the frequency of episodes of exacerbation of recurrent cystitis and metabolic parameters in patients with type 2 diabetes mellitus taking glyphlosins

The problem of recurrent urinary tract infections (UTI) in patients with type 2 diabetes mellitus (DM 2) is relevant, especially when there is a combination of predisposing factors, such as female gender, history of UTI episodes, and therapy with sodium glucose cotransporter type 2 (SGLT-2) inhibitors, and the choice of effective and safe means could cause some difficulties, including ina terms of the burden of antibiotic resistance. To evaluate the effectiveness and safety of the phytoproduct Canephron® N for the prevention of exacerbations of recurrent cystitis and the effect on metabolic parameters in patients with type 2 diabetes taking SGLT-2 inhibitors. Prospective, randomized, open, parallel group study in 60 women. The main group took the drug Canephron® N for 3 months. The main parameters for evaluating were the frequency of recurrence of cystitis, level of albuminuria and LDL-cholesterol peroxidation product - malondialdehyde. Within 3 months of taking Canephron® N, exacerbations of chronic cystitis were diagnosed 2 times less often, a decrease in albuminuria was found in the form of an increase in the proportion of patients with an optimal level of albuminuria by 20%, a 50% reduction in the frequency of the initial increase in albuminuria, and the absence of moderate albuminuria in all patients at the end of course of therapy. A decrease in the level of MDA by 1.4 times was noted (p=0.019). Thus, the herbal drug Canephron® N can be used for accompanying therapy and prophylactic treatment in patients with recurrent cystitis on the background of DM 2, taking SGLT-2 inhibitors. The course of therapy should last at least 3 months.

Relationship between sodium-glucose cotransporter-2 inhibitors and muscle atrophy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

This study aims to assess the association between sodium-glucose cotransporter type-2 inhibitor (SGLT-2i) treatment and muscle atrophy in patients with type 2 diabetes mellitus (T2DM). We searched six databases from 1 January 2012 to 1 May 2023, without language restrictions. The primary outcome was muscle. Secondary outcomes were weight loss, weakness, malaise, or fatigue. Subgroup analyses were performed according to different definitions of muscle, treatment duration, and measurement methods. The quality of the studies was assessed using the Cochrane tool. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) tool. Nineteen randomized controlled trials (RCTs) involving 1,482 participants were included. Compared with the control group, a meta-analysis showed that T2DM participants in the group treated with SGLT-2i demonstrated statistically significant reductions in lean body mass of 0.66 (95% confidence interval (CI), -1.05 to -0.27; p = 0.0009) and skeletal muscle mass of 0.35 (95% CI, -0.66 to -0.04; p = 0.03). No deaths or serious adverse events were reported. The quality of evidence in the included trials was low. SGLT-2i may lead to a reduction in muscle strength in the treatment of T2DM compared to the control group. However, there is still a lack of high-quality evidence to evaluate muscle atrophy caused by SGLT-2i. https://inplasy.com/inplasy-2022-12-0061/, identifier 2022120061.

Assessment of cardiac functions using two-dimensional transthoracic and speckle tracking echocardiography after treatment with SGLT2 inhibitors in Patients with HFrEF

Abstract Background &amp; objective Recently, the antidiabetic drug sodium-glucose cotransporter type 2 inhibitor (SGLT2i) has been approved among the drugs that reduce mortality in patients with HFrEF. The impact of SGLT2i inhibitors on the left ventricle longitudinal myocardial function in heart failure (HF) patients remained vague. The effect of SGLT2i on left ventricular remodeling and function in patients with HFrEF was studied using STE and traditional echocardiography. Objectives Studying the effects of SGLT2i on left ventricular remodeling and function in HFrEF patients using STE and traditional echocardiography. Methods 300 patients with HFrEF were included.Study design: This prospective observational study involves 300 patients with HFrEF-administered SGLT2i (Empagliflozin &amp; Dapagliflozin) in addition to the classical treatment of heart failure. Then the patients were followed up 2, 4 &amp; 6 months after treatment with laboratory investigations of HbA1C and eGFR, in addition to 2D echo &amp; STE studies. Results Regarding Demographic data, the mean age was 50 ± 9.2 for males and females. The mean weight, height, and body mass index (BMI) were 85.6 ± 8.8 kg, 178.6 ± 7.2 cm, and 26.6 ± 2.9, respectively. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 115.3 ± 5.1 and 75.4 ± 4.5, respectively. The mean heart rate was 79.9 ± 10.2. The mean respiratory rate was15 ± 2.2. Regarding functional NYHA class, 1 (0.2%), 54(12%), 392 (87.1%), and 3 (0.7%) patients were class I, II, III, and IV, respectively. The lab investigations at first presentation were: mean HbA1C was 4.2 ± 0.6, and the mean of eGFR was 66.4 ± 9.3. Concerning Echocardiography data of patients LVEF by 2D echo show significant improvement from 34.73 ± 2.9 at baseline to 34.91 ± 1.2, 35.42 ± 3.5 &amp; 36.54 ± 3.6 at 2, 4 &amp; 6 months (P = 0.001) also GLS A4 showed significant improvement from −15.67 ± 2.74 to −16.5 ± 3.19, −17.32 ± 3.21, −18.03 ± 3.05at 2, 4 &amp; 6 months (P = 0.001), and from −15.66 ± 2.65 to −16.50 ± 3.31, −17.41 ± 3.23 &amp; −17.93 ± 3.32 (P = 0.001) by GLS A2 Regarding dapagliflozin LVEF by 2D echo show significant improvement from 34.87 ± 2.86 at baseline to 34.87 ± 2.86, 35.05 ± 3.01&amp; 37.53 ± 4.1 at 2, 4 &amp; 6 months (P = 0.001) also GLS A2 showed significant improvement from −15.67 ± 2.74 to −16.50 ± 3.31 −17.41 ± 3.23 −17.93 ± 3.32 at 2, 4 &amp; 6 months (P = 0.001), and from −15.54 ± 2.77 to −16.84 ± 3.49, −18.48 ± 2.23 &amp; −19.61 ± 2.98 (P = 0.001) by GLS A4, also E/e′ significantly reduced from 11.2 ± 2.7 to 9.1 ± 2.3 cm/s after administration of empagliflozin and dapagliflozin within 6 months (P = 0.01) also LAVI (ml/m2) improved from 45.6 ± 15.3 to 37.5 ± 6.5 (P = 0.001) after 6 month The results revealed a significant increase of ejection fraction at 4 and 6 months follow-up and a significant improvement of global longitudinal strain at 2, 4 &amp; 6 months follow-up in patients given SGLT2i. Conclusion SGLT2i was associated with improving LV longitudinal myocardial function, further improving LV diastolic function. SGLT2i is associated with increased EF and LV longitudinal myocardial function. Additional Content An author video to accompany this abstract is available on https://academic.oup.com/eurheartjsupp. Please click on the arrow next to ‘More Content’ and then click on ‘Author videos’.

Targeting Collagen Pathways as an HFpEF Therapeutic Strategy.

Heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous clinical syndrome. The prevalence is expected to increase in the coming years, resulting in heart failure with reduced ejection fraction (HFrEF). This condition poses a burden to the global health care system as the number of patients affected by this condition is constantly increasing due to a rising average lifespan. The absence of validated drugs effective in reducing hospitalization rates and mortality may reflect the impossibility of applying a one size fits all approach as in HFrEF, heading for a personalized approach. Available evidence demonstrated the link between collagen quantity and quality alterations, and cardiac remodeling. In the context of fibrosis, collagen cross-linking is strictly involved, displaying two types of mechanisms: enzymatic and non-enzymatic. In the murine model, enzymatic inhibition of fibrosis-inducing protease-activated receptor-1 (PAR1) and transforming growth factor (TGF)-β signaling appeared to reduce cardiac fibrosis. On the other hand, in the case of non-enzymatic cross-linking, sodium glucose co-transporter type 2 inhibitors (SGLT2is), appeared to counteract the deposition of advanced glycation end-products (AGEs), which in turn contributed to ventricular remodeling. In this review, we address the mechanisms associated with collagen alterations to identify potential targets of cardiac fibrosis in HFpEF patients.

SGLT-2 Inhibitors for Non-Alcoholic Fatty Liver Disease: A Review.

Non-alcoholic fatty liver disease (NAFLD) is a group of metabolic liver illnesses that lead to accumulation of liver fat mainly due to excessive nutrition. It is closely related to insulin resistance, obesity, type 2 diabetes, and cardiovascular disease, and has become one of the main causes of chronic liver disease worldwide. At present, there is no specific drug for the treatment of NAFLD; lifestyle interventions including dietary control and exercise are recommended as routine treatments. As a drug for the treatment of type 2 diabetes, sodium-glucose co-transporter type 2 (SGLT-2) inhibitors may also play a beneficial role in the treatment of NAFLD. This article reviews the mechanism of SGLT-2 inhibitors in the treatment of NAFLD.

Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis

BackgroundIn recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD.MethodsArticles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared.ResultsA total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m2, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m2, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function.ConclusionThe results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.

Short-term anti-remodeling effects of gliflozins in diabetic patients with heart failure and reduced ejection fraction: an explainable artificial intelligence approach.

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), gliflozins, play an emerging role for the treatment of heart failure with reduced left ventricular ejection fraction (HFrEF). Nevertheless, the effects of SGLT2i on ventricular remodeling and function have not been completely understood yet. Explainable artificial intelligence represents an unprecedented explorative option to clinical research in this field. Based on echocardiographic evaluations, we identified some key clinical responses to gliflozins by employing a machine learning approach. Methods: Seventy-eight consecutive diabetic outpatients followed for HFrEF were enrolled in the study. Using a random forests classification, a single subject analysis was performed to define the profile of patients treated with gliflozins. An explainability analysis using Shapley values was used to outline clinical parameters that mostly improved after gliflozin therapy and machine learning runs highlighted specific variables predictive of gliflozin response. Results: The five-fold cross-validation analyses showed that gliflozins patients can be identified with a 0.70 ± 0.03% accuracy. The most relevant parameters distinguishing gliflozins patients were Right Ventricular S'-Velocity, Left Ventricular End Systolic Diameter and E/e' ratio. In addition, low Tricuspid Annular Plane Systolic Excursion values along with high Left Ventricular End Systolic Diameter and End Diastolic Volume values were associated to lower gliflozin efficacy in terms of anti-remodeling effects. Discussion: In conclusion, a machine learning analysis on a population of diabetic patients with HFrEF showed that SGLT2i treatment improved left ventricular remodeling, left ventricular diastolic and biventricular systolic function. This cardiovascular response may be predicted by routine echocardiographic parameters, with an explainable artificial intelligence approach, suggesting a lower efficacy in case of advanced stages of cardiac remodeling.

Novel Drugs for the Management of Diabetes Kidney Transplant Patients: A Literature Review.

The management of diabetes and renal failure is changing thanks to the appearance of new drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) that have benefits in terms of survival and cardiorenal protection. Based on the potential mechanisms of GLP1-RA, kidney transplant recipients (KTRs) could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, in the transplant population, especially those related to cardiovascular benefits and renal protection. Studies with SGLT2i performed in KTRs are much less potent than in the general population and therefore no benefits in terms of patient or graft survival have been clearly demonstrated in this population to date. Additionally, the most frequently observed side effects could be potentially harmful to this population profile, including severe or recurrent urinary tract infections and impaired kidney function. However, benefits demonstrated in KTRs are in line with a known potential effects in cardiovascular and renal protection, which may be essential for the outcome of transplant recipients. Better studies are still needed to confirm the benefits of these new oral antidiabetics in the renal transplant population. Understanding the characteristics of these drugs may be critical for KTRs to be able to benefit from their effects without being damaged. This review discusses the results of the most important published studies on KTRs with GLP1-RA and SGLT2i as well as the potential beneficial effects of these drugs. Based on these results, approximate suggestions for the management of diabetes in KTRs were developed.

P71 SGLT2I IN THE REAL WORLD: DATA FROM THE PONTE (BRIDGE) HF PROJECT (PDTA FOR INTEGRATED TERRITORY HOSPITAL FOLLOW–UP OF PATIENTS WITH HEART FAILURE)

Abstract Background The DAPA–HF and the EMPEROR reduced trials showed that sodium–glucose cotransporter type 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin, on best medical therapy, resulted in a reduced incidence of the combined primary outcome cardiovascular death and worsening heart failure (–26%) and a preventive effect on renal function decline. Based on this evidence, the 2021 ESC guidelines have included SGLT2i in class I recommendations in combination with angiotensin and neprilysin receptor inhibitors (ARNI) or ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB), beta–blockers (BB), and mineral corticoid receptor antagonists (MRA). However, the effect of adding SGLT2i in real–life patients is just partly known. The aim of the study was therefore to evaluate the impact of SGLT2i in a real world population of patients with heart failure and reduced left ventricular ejection fraction (HFrEF). Methods 220 consecutive patients with HFrEF, treated with SGLT2i and with 6 months of follow–up already enrolled in the PONTE (BRIDGE) HF project (PDTA FOR THE INTEGRATED FOLLOW–UP IN THE HOSPITAL TERRITORY OF THE PATIENT WITH HEART FAILURE), a care model implemented in Puglia region (Italy) based on hospital–territory integration aimed at the optimized management of patient with HF after hospitalization, were considered for the study. Demographic, clinical, laboratory and instrumental characteristics and changes in NYHA class, creatinine, NT proBNP, loop diuretic dose, LVEF after initiation of therapy with SGLT2i were evaluated. Results The 220 enrolled patients (mean age of 62 years, 72% hypertensive, 38% diabetic, 67% with ischemic heart disease, 50% with ICD/CRT, 44% with atrial fibrillation, 5.6% in NYHA class I, 61% class II, 33% class III, mean LVEF 30±11%) were in treatment with BB in 93% of cases, with MRA in 94%, with ACE/ARB in 24% and with ARNI in 80%. At 6–month follow–up of, a reduction of patients in NYHA class III from 33 to 20%, an increase in patients in NYHA class II from 61 to 70%, and in NYHA class I from 5.6 to 10% were observed; the LVEF (30 vs 37.2%) and creatinine values (1.3 vs 1.5) increased significantly, while loop diuretic doses decreased (35 vs 97.5). Conclusions Data from patients treated with SGLT2i from real world seem to confirm the efficacy of this class of drugs already in a short term follow–up, with a positive effect on NYHA class, LVEF, and renal function.

Canagliflozin alleviates high glucose-induced peritoneal fibrosis via HIF-1α inhibition.

The cardioprotective effects of sodium-glucose cotransporter type 2 (SGLT2) inhibitors have been demonstrated in many studies. However, their benefits for end-stage kidney disease patients, particularly those on peritoneal dialysis, remain unclear. SGLT2 inhibition has shown peritoneal protective effects in some studies, but the mechanisms are still unknown. Herein, we investigated the peritoneal protective mechanisms of Canagliflozin in vitro by simulating hypoxia with CoCl2 in human peritoneal mesothelial cells (HPMCs) and rats by intraperitoneal injection of 4.25% peritoneal dialysate simulating chronic high glucose exposure. CoCl2 hypoxic intervention significantly increased HIF-1α abundance in HPMCs, activated TGF-β/p-Smad3 signaling, and promoted the production of fibrotic proteins (Fibronectin, COL1A2, and α-SMA). Meanwhile, Canagliflozin significantly improved the hypoxia of HPMCs, decreased HIF-1α abundance, inhibited TGF-β/p-Smad3 signaling, and decreased the expression of fibrotic proteins. Five-week intraperitoneal injection of 4.25% peritoneal dialysate remarkably increased peritoneal HIF-1α/TGF-β/p-Smad3 signaling and promoted peritoneal fibrosis and peritoneal thickening. At the same time, Canagliflozin significantly inhibited the HIF-1α/TGF-β/p-Smad3 signaling, prevented peritoneal fibrosis and peritoneal thickening, and improved peritoneal transportation and ultrafiltration. High glucose peritoneal dialysate increased the expression of peritoneal GLUT1, GLUT3 and SGLT2, all of which were inhibited by Canagliflozin. In conclusion, we showed that Canagliflozin could improve peritoneal fibrosis and function by ameliorating peritoneal hypoxia and inhibiting the HIF-1α/TGF-β/p-Smad3 signaling pathway, providing theoretical support for the clinical use of SGLT2 inhibitors in patients on peritoneal dialysis.

Impact of gliflozins on cardiac remodeling in patients with type 2 diabetes mellitus & reduced ejection fraction heart failure: A pilot prospective study. GLISCAR study

AimsType 2 diabetes mellitus (T2DM) and heart failure are closely related entities and together determine an increased risk of mortality compared to patients suffering from only one of these diseases. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have shown favorable effects on cardiovascular system, particularly on heart failure. Aim of this study is to verify whether in individuals with T2DM and heart failure with reduced ejection fraction (HFrEF) treated with SGLT-2i, echocardiographic signs of favorable reverse remodeling follow longitudinal observation. Methods31 subjects with T2DM and HFrEF were finally included. All individuals performed clinical visit, medical history, blood sampling and echocardiography at time 0′ and at the end of 6 months of follow-up on SGLT-2i treatment. ResultsAfter 6 months follow-up, left ventricular ejection fraction (LVEF), global work index (GWI), global work efficiency (GWE), global longitudinal strain (GLS), left atrial expansion index (LAEI) and total left atrial emptying fraction (TLAEF), tricuspid annular plane systolic excursion (TAPSE), septal thickness (St), pulmonary artery systolic pressures (PASP) and TAPSE/PASP ratio significantly improved. ConclusionsDespite the lack of a favorable effect on cardiac remodeling, SGLT-2i treatment significantly improved LV systolic and diastolic function, left atrial (LA) reservoir and total emptying function, RV systolic function and pulmonary artery pressure.