In clinical practice, sodium-glucose transporter 2 inhibitor (SGLT2i) reduces the composite renal outcomes in patients with diabetic kidney disease (DKD). However, its effect on regulating renal mitochondria remains unclear. Mitochondrial quality control (MQC) has been identified as a key factor in DKD. Peroxiredoxin3 (Prdx3) serves as a primary antioxidant protein in mitochondria. In this study, we investigated the expression of Prdx3 in patients with DKD, diabetic mice and HK-2 cells exposed to high glucose and explored SGLT2i potential mechanism of action. The results also showed that empagliflozin (Empa) treatment improved proteinuria and ameliorated renal pathological damage. We observed that Empa has an impact on the expression of Prdx3 in diabetic mice and HK-2 cells exposed to high glucose, so does the mitochondrial dynamic proteins and mitophagy-related proteins Mfn2, Drp1, PINK1, Parkin, LC3II, and P62. In vitro experiments after transfected with pcDNA3.1(+)-Prdx3 and siPrdx3 the expression of Mfn2, Drp1, PINK1, Parkin, LC3II, and P62 changed. The expression of PINK1 decreased after the knockdown of Prdx3. Furthermore, the knockdown of PINK1 accelerated the MQC damage and weakened the protective effect of Empa. Because Empa has impacts on Prdx3, which plays a protective role by influencing MQC, we investigated the latent impact of Prdx3 deficiency on renal injury and its molecular mechanism in vivo and in vitro in DKD. Herein, we demonstrate that Empa treatment modulates MQC potentially via Prdx3 through interacting with PINK1.

Type 2 diabetes mellitus (T2DM) is a condition marked by insulin resistance and hyperglycemia. Static training, as a form of exercise intervention, is increasingly demonstrating benefits for improving T2DM. However, the underlying mechanisms remain inadequately elucidated. Research suggests that insulin-like growth factor 2 (IGF-2) could be a significant contributor to this phenomenon. In this study, static training significantly reduced fasting and random blood glucose, total cholesterol, triglycerides, and LDL, while increasing HDL and improving insulin sensitivity. Transcriptomics suggested that static training might regulate the IGF-2 pathway and related genes. WB and PCR results showed that IGF-2 expression was upregulated in the static training group, and IGF-2 inhibitors attenuated these effects, whereas IGF-2 overexpression enhanced them. In conclusion, static training improves insulin resistance in T2DM mice via the IGF-2/IGF-1R pathway, suggesting its potential as a therapeutic intervention.

This study aimed to evaluate the cardiorenal effect of combining sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) when compared with monotherapy of either agent in patients with type 2 diabetes (T2D).

PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were systematically searched from inception to June 2024. Eligible studies included randomised controlled trials and observational studies assessing that compared with SGLT2i or GLP-1RA monotherapy, the risk of cardiorenal outcomes in patients with T2D who treated with combination therapy. Pooled relative risk (RR) and 95% confidence intervals (CIs) were computed in random-effects model.

In all, five RCTs, 10 post hoc analyses and one observational study were included. The reduced risk of the composite cardiovascular outcome was observed in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.57, 95% CI 0.38-0.86, p = 0.008) or GLP-1RA monotherapy (RR = 0.77, 95% CI 0.65-0.91, p = 0.002). Likewise, the composite renal adverse events were less frequent in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.69, 95% CI 0.59-0.82, p < 0.001) or GLP-1RA monotherapy (RR = 0.66, 95% CI 0.53-0.83, p < 0.001). Compared with GLP-1RA monotherapy, the combination therapy of SGLT2i and GLP-1RA was associated with lower risks of heart failure-related outcomes (RR = 0.63, 95% CI 0.51-0.77, p < 0.001) and all-cause mortality (RR = 0.66, 95% CI 0.50-0.88, p = 0.004) in patients with T2D.

The cardiorenal benefits might be magnified with the combination therapy of SGLT2i and GLP-1RA when compared with monotherapy of either agent. Further investigations are needed to validate the findings.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed.

A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses.

A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74-0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64-0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65-0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65-0.99; P = 0.04).

SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD.

PROSPERO (CRD42024601914).

This article discusses the study by Grubić Rotkvić et al on the mechanisms of action of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). T2DM and HF are highly comorbid, with a significantly increased prevalence of HF in patients with T2DM. SGLT2i exhibit potential in reducing hospitalization rates for HF and cardiovascular mortality through multiple mechanisms, including improving blood glucose control, promoting urinary sodium excretion, reducing sympathetic nervous system activity, lowering both preload and afterload on the heart, alleviating inflammation and oxidative stress, enhancing endothelial function, improving myocardial energy metabolism, and stabilizing cardiac ion homeostasis. Further research and clinical practice will help optimize the use of SGLT2i in HF patients.

The objective is to assess the effectiveness and safety of tirzepatide, liraglutide, and SGLT2i in individuals diagnosed with type 2 diabetes.

An inquiry was undertaken within the electronic database spanning from its inception to February 11th, 2024, aimed at identifying randomized controlled trials that assess the efficacy and safety of tirzepatide, liraglutide, canagliflozin, ertugliflozin, empagliflozin, dapagliflozin, and henagliflozin. Perform a network meta-analysis to examine the distinctions among them (PROSPERO registration number: CRD42024537006).

Twenty-eight RCTs were included, involving 8499 participants. Compared with placebo, all treatments improved HbA1c levels: tirzepatide 15 mg reduced HbA1c the most (MD [95% CI], -2.24% [-2.52, -1.96]%), followed by tirzepatide 10 mg (MD [95% CI], -1.99% [-2.29, -1.69]%), tirzepatide 5 mg (MD [95% CI], -1.82% [-2.11, -1.53]%), and liraglutide 1.2 mg (MD [95% CI], -1.23% [-1.41, -1.05]%). Canagliflozin 300 mg also showed a significant reduction in HbA1c (MD [95% CI], -1.00% [-1.18, -0.82]). Tirzepatide was also the most effective in promoting weight loss, with the following results compared with placebo: tirzepatide 15 mg (MD [95% CI], -8.74 kg [-9.83, -7.66] kg), tirzepatide 10 mg (MD [95% CI], -7.13 kg [-8.40, -5.88] kg), tirzepatide 5 mg (MD [95% CI], -5.38 kg [-6.65, -4.11] kg), canagliflozin 300 mg (MD [95% CI], -2.31 kg [-2.79, -1.83] kg), and empagliflozin 10 mg (MD [95% CI], -2.00 kg [-2.44, -1.55] kg). In reducing systolic blood pressure (SBP), canagliflozin 300 mg showed the greatest effect (MD [95% CI], -5.96% [-7.96, -3.96] %). For diastolic blood pressure (DBP), henagliflozin 5 mg demonstrated the most significant reduction compared to placebo (MD [95% CI], -2.46% [-3.82, -1.10] %). Liraglutide 1.8 mg was most likely to cause adverse events (AE) (OR [95% CI], 2.57 [1.78, 3.70]), but there was no significant difference in serious adverse events (SAEs) between the interventions (including placebo).

Out of the seven medications examined in this study, tirzepatide demonstrates the most effective antidiabetic and weight-reducing effects. Furthermore, the dosage of Liraglutide at 1.2 mg and above demonstrates a more pronounced hypoglycemic effect in comparison to SGLT2 inhibitors. SGLT2 inhibitors exhibit a distinct hypotensive effect and are suitable for diabetic individuals experiencing hypertension.

To assess glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and sodium-glucose cotransporter protein-2 inhibitors (SGLT-2 inhibitors) in patients with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH]), we performed a systematic review and network meta-analysis of randomized controlled trials.

The study searched Pubmed, Embase, the Cochrane Library, and Web of Science databases up to November 26, 2023. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias.

Thirty-seven studies were included in the analysis. GLP-1 receptor agonists were found to be more effective than placebo in resolving NASH (relative risk: 2.48, 95% CI:1.86 to 3.30). Both drugs were superior to placebo in reducing liver fat content, as well as decreasing levels of liver enzyme. Network meta-analysis indicated that SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels. According to the surface under the cumulative probability ranking curve values, GLP-1 receptor agonists and SGLT-2 inhibitors consistently ranked among the top 2 in terms of reducing anthropometric data compared to other included drugs.

GLP-1 receptor agonists and SGLT-2 inhibitors have significant effects on reducing liver fat content and liver enzymes in NAFLD or NASH patients compared to placebo. GLP-1 receptor agonists were found to be superior to placebo in resolving NASH. SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels.

Sodium-glucose cotransporter two inhibitors can reduce cardiovascular events by modulating lipid profiles in patients with heart failure, irrespective of diabetes status. In this study, we aimed to assess the effects of SGLT-2 inhibitors on the lipid profiles of patients with heart failure via a meta-analysis.

The PubMed, Scopus, Web of Science, and Google Scholar databases were searched up to 2023 to retrieve relevant article titles, abstracts, and full texts. STATA software was used to conduct the meta-analysis.

The Forest plot of fasting blood sugar levels in patients receiving SGLT-2 inhibitors differed significantly from those the in control group (mean difference = -0.08, 95% CI [-0.13, -0.02], P < 0.05). Analysis of lipid profile parameters, including total cholesterol, triglyceride, HDL, and LDL in patients with HF receiving SGLT-2 inhibitors, did not show a notable difference from the control group (P > 0.005). However, the mean difference was towards the reduction of LDL, cholesterol, and triglycerides and showed an increase in HDL levels. Egger's test for publication bias revealed some publication bias (P < 0.05).

Our topic analysis did not reveal any notable alterations in the lipid profile. To arrive at a more definite agreement, further research on subjects with heart failure is necessary because there is currently insufficient evidence.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in patients with diabetes remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts, highlights advanced methodologies, and presents the latest therapeutic strategies for mitigating the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Heart failure (HF) represents a growing global burden of morbidity and mortality. Identifying individuals at risk for HF development is increasingly important, particularly given the advent of disease-modifying therapies for HF as well as its major risk factors such as obesity actalnd diabetes. We aim to review the key circulating biomarkers associated with future HF which may contribute to HF risk prediction.

While current guidelines recommend the use of natriuretic peptides and cardiac troponins in HF risk stratification, there are a diverse array of other emerging protein, metabolic, transcriptomic, and genomic biomarkers of future HF development. These biomarkers not only lend insight into the underlying pathophysiology of HF, which spans inflammation to cardiac fibrosis, but also offer an opportunity to further refine HF risk in addition to established biomarkers. As evolving techniques in molecular biology enable an increased understanding of the complex biologic contributions to HF pathophysiology, there is an important opportunity to construct integrated clinical and multi-omic models to best capture HF risk. Moving forward, future studies should seek to understand the contributions of sex differences, underlying comorbidity burden, and HF subtypes to an individual's HF risk. Further studies are necessary to fully define the clinical utility of biomarker screening approaches to refine HF risk assessment, as well as to link risk assessment directly to preventive strategies for HF.

To investigate the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with acute coronary syndrome (ACS) and type 2 diabetes (T2D).

The clinical data of 88 patients with ACS and T2D who were treated with SGLT2i between January 2020 and December 2021 were collected as the case group through convenience sampling. Patients taking other hypoglycaemic drugs were included as the control group in a 1:1 ratio matched with the case group using retrospective propensity score matching. Relevant data were subsequently collected from both groups for comparison.

Statistically significant differences were observed in glycated haemoglobin (HbA1c) between the two groups (8.11[6.93, 9.41] vs 7.51[6.52, 9.14]%; Z=2.109; P=0.035). The SGLT2i group showed a decrease in major adverse cardiovascular events (MACEs) (P<0.001), secondary composite endpoint events (P=0.024), heart failure readmission (P=0.042) and unplanned revascularisation (P=0.014) compared with the control group. Moreover, the multivariate analysis showed that SGLT2i significantly reduced the risk of MACEs (hazard ratio [HR], 0.472; 95% CI, 0.321-0.694; P<0.001) and unplanned revascularisation (HR, 0.422; 95% CI, 0.212-0.842; P=0.014). In patients with reduced ejection fraction, SGLT2i significantly reduced the risk of MACEs (HR, 0.258; 95% CI, 0.106-0.626; P=0.003) compared with the control group. By contrast, in patients without reduced ejection fraction, SGLT2i significantly reduced the risk of MACEs (HR, 0.640; 95% CI, 0.412-0.996; P=0.048) and unplanned revascularisation (HR, 0.464; 95% CI, 0.222-0.969; P=0.041) compared with the control group.

In addition to significantly reducing the risk of adverse cardiovascular events and unplanned revascularisation in patients with ACS and T2D, the use of SGLT2i can reduce the risk of adverse cardiovascular events regardless of the presence of reduced ejection fraction.

Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) represent a deep revolution of the therapeutic approach to heart failure (HF), preventing its insurgence but also improving the management of the disease and slowing its natural progression. To date, few studies have explored the effectiveness of SGLT2i and, in particular, Dapagliflozin in a real-world population. Therefore, in this observational prospective study, we evaluated Dapagliflozin's effectiveness in a real-world HF population categorized in the different hemodynamic profiles.

From January 2022 to June 2023, we enrolled 240 patients with chronic HF and reduced ejection fraction (HFrEF) on optimal medical therapy, according to 2021 ESC guidelines, that added treatment with Dapagliflozin from the HF Clinics of 6 Italian University Hospitals. Clinical, biochemical, and echocardiographic parameters were collected before and after 6 months of Dapagliflozin introduction. Moreover, the HFrEF population was classified according to hemodynamic profiles (A: SV ≥ 35 ml/m2; E/e' < 15; B: SV ≥ 35 ml/m2; E/e' ≥ 15; C: SV < 35 ml/m2; E/e' < 15; D: SV < 35 ml/m2; E/e' ≥ 15). Then, we compared the Dapagliflozin population with two retrospective HF cohorts, hereinafter referred to as Guide Line 2012 (GL 2012) group and Guide Line 2016 (GL 2016) group, in accordance with the HF ESC guidelines in force at the time of patients enrolment. Precisely, we evaluated the changes to baseline in clinical, functional, biochemical, and echocardiographic parameters and compared them to the GL 2012 and GL 2016 groups.

Dapagliflozin population (67.18 ± 11.11 years) showed a significant improvement in the echocardiographic and functional parameters (left ventricular ejection fraction [LVEF], LV end-diastolic volume [LVEDV], LVEDV index, stroke volume index [SVi], left atrium volume index [LAVi], filling pressure [E/e' ratio], tricuspid annular plane systolic excursion [TAPSE], tricuspid annular S' velocity [RVs'], fractional area change [FAC], inferior vena cava [IVC diameter], pulmonary artery systolic pressure [sPAP], NYHA class, and quality of life) compared to baseline. In particular, TAPSE and right ventricle diameter (RVD1) ameliorate in congestive profiles (B and D); accordingly, the furosemide dose significantly decreased in these profiles. Comparing the three populations, the analysis of echocardiographic parameters (baseline vs follow-up) highlighted a significant decrease of sPAP in the Dapagliflozin population (p < 0.05), while no changes were recorded in the GL 2012 and GL 2016 population. Moreover, at the baseline evaluation, the GL 2012 and 2016 groups needed a higher significant dose of furosemide compared to Dapagliflozin group. Finally, Dapagliflozin patients had significantly fewer rehospitalizations (1.25%) compared with the other two groups (GL 2012 18.89%, p 0.0097; GL 2016 15.32%, p 0.0497).

We demonstrate that Dapagliflozin is rapidly effective in an HFrEF real-world population; furthermore, the more significant effect is recorded in HFrEF patients with a congestive profile (B and D), supporting the introduction of Dapagliflozin in patients with a congestive profile and a worse prognosis. In conclusion, our data suggest evaluating the patient's hemodynamic state beyond LVEF in HFrEF.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D.

Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.

The loss of peroxisome proliferator-activated receptor gamma (PPARγ) exacerbates pulmonary arterial hypertension (PAH), while its upregulation reduces cell proliferation and vascular remodeling, thereby decreasing PAH severity. SGLT2 inhibitors, developed for type 2 diabetes, might also affect signal transduction in addition to modulating sodium-glucose cotransporters. Pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with idiopathic pulmonary arterial hypertension (IPAH) were treated with three SGLT2 inhibitors, canagliflozin (Cana), dapagliflozin (Dapa), and empagliflozin (Empa), to investigate their antiproliferative effects. To assess the impact of Empa on PPARγ, luciferase reporter assays and siRNA-mediated PPARγ knockdown were employed to examine regulation of the γ-secretase complex and its downstream target Notch3. Therapy involving daily administration of Empa was initiated 21 days after inducing hypoxia-induced PAH in mice. Empa exhibited significant antiproliferative effects on fast-growing IPAH PASMCs. Empa activated PPARγ to prevent formation of the γ-secretase complex, with specific impacts on presenilin enhancer 2 (PEN2), which plays a crucial role in maintaining γ-secretase complex stability, thereby inhibiting Notch3. Similar results were obtained in lung tissue of chronically hypoxic mice. Empa attenuated pulmonary arterial remodeling and right ventricle hypertrophy in a hypoxic PAH mouse model. Moreover, PPARγ expression was significantly decreased and PEN2, and Notch3 levels were increased in lung tissue from PAH patients compared with non-PAH lung tissue. Empa reverses vascular remodeling by activating PPARγ to suppress the γ-secretase-Notch3 axis. We propose Empa as a PPARγ activator and potential therapeutic for PAH.

To evaluate the efficacy and safety of non-steroid mineralocorticoid receptor antagonists (ns-MRAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) in patients with diabetic kidney disease (DKD).

Systematic literature searches were performed using PubMed, Embase and Web of Science encompassing inception until January 20, 2024. Randomized control trials (RCTs) comparing ns-MRAs and SGLT2is in DKD were selected. The efficacy outcomes of interest included kidney-specific composite outcome, cardiovascular (CV)-specific composite outcome, end-stage kidney disease (ESKD), and overall mortality. We also investigated safety outcomes, including acute kidney injury (AKI) and hyperkalemia.

A total of 10 randomized clinical trials with 35,786 patients applying various treatments were included. SGLT2is (SUCRA 99.84%) have potential superiority in kidney protection. SGLT2is (RR 1.41, 95%CI 1.26 to 1.57) and ns-MRAs (RR 1.17, 95% CI 1.08 to 1.27) were associated with significantly lower kidney-specific composite outcome than the placebo. Regarding the reduction in CV-specific composite outcome and ESKD, SGLT2is (SUCRA 91.61%; 91.38%) have potential superiority in playing cardiorenal protection. Concerning the CV-specific composite outcome (RR 1.27, 95%CI 1.09 to 1.43) and ESKD (RR 1.43, 95%CI 1.20 to 1.72), SGLT2is significantly reduced the risks compared to placebo. Regarding the reduction in overall mortality, SGLT2is (SUCRA 83.03%) have potential superiority in postponing mortality. Concerning the overall mortality, SGLT2is have comparable effects (RR 1.27, 95%CI 1.09 to 1.43) with placebo to reduce the risk of overall mortality compared to placebo. For AKI reduction, ns-MRAs (SUCRA 63.58%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. For hyperkalemia reduction, SGLT2is (SUCRA 93.12%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. Concerning hyperkalemia reduction, nsMRAs (RR 1.24 95%CI 0.39 to 3.72) and SGLT2is (RR 1.01 95%CI 0.40 to 3.02) did not show significant benefit compared to placebo.

Concerning the efficacy and safety outcomes, SGLT2is may be recommended as a treatment regimen for maximizing kidney and cardiovascular protection, with a minimal risk of hyperkalemia in DKD.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023458613.

Recent studies have revealed the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure patients. However, their effects on acute myocardial infarction (AMI) remain uncertain. Therefore, we conducted this meta-analysis to assess the effectiveness of SGLT2i in patients with AMI with or without diabetes. We conducted a comprehensive search of PubMed, Embase, and Cochrane Library encompassing data from inception until November 30, 2023. Relevant studies comparing SGLT2i with placebo or non-SGLT2i in patients with AMI were included. The mean difference and/or odds ratio (OR) with 95% confidence intervals were pooled using a fixed-effects model when the heterogeneity statistic (I2) was less than 50%; otherwise, a random-effects model was employed. Four randomized controlled trials and 4 observational studies involving 9397 patients with AMI were included in this meta-analysis. Patients treated with SGLT2i exhibited a significantly lower rate of hospitalization for heart failure (OR = 0.50, 95% CI: 0.32-0.80) and all-cause death (OR = 0.65, 95% CI: 0.44-0.95) compared with those treated with placebo or non-SGLT2i. Furthermore, the use of SGLT2i was associated with a significant increase in left ventricular ejection fraction (mean difference = 1.90, 95% CI: 1.62-2.17) and a greater reduction of N-terminal prohormone of brain natriuretic peptide (OR = 0.88, 95% CI 0.82-0.94). Subgroup analysis revealed that in patients with diabetes, SGLT2i exhibited similar effects. The present meta-analysis provided evidence indicating the effectiveness of SGLT2i in patients with AMI; SGLT2i may serve as an additional therapeutic option for patients with AMI, regardless of the presence or absence of diabetes.

Acute coronary syndrome (ACS) remains a risk factor for heart failure (HF). Therefore, we aimed to assess the cardioprotective role of sodium-glucose cotransporter-2 (SGLT2) inhibitors post-ACS in patients with acute HF (AHF) and diabetes.

We conducted a retrospective observational cohort study employing propensity score matching. This study involved patients with diabetes admitted with ACS complicated by AHF, defined as either new clinical HF requiring diuretics during the index admission or having an ejection fraction (EF) of <40%. The study population was divided into two groups; (1) SGLT2 inhibitor users and (2) SGLT2 inhibitor non-users. The Cox proportional hazard regression analysis was used to evaluate the outcomes.

A total of 465 patients (93% male; mean age, 55 ± 10 years) were included in this study. Using a 1 : 1 propensity score matching, 78 patients were included per arm with an absolute standardized difference of <0.1 for all baseline characteristics. The use of SGLT2 inhibitors resulted in lower composite outcomes of ACS, HF hospitalization, and all-cause mortality at 1 month and 12 months [1 month: 2.6% vs. 11.5%, HR = 0.20 (0.04-0.94), p = 0.041; 12 months: 14.1% vs. 23.1%, HR = 0.46 (0.22-0.99), p = 0.046].

The findings suggest that SGLT2 inhibitors may confer cardioprotective effects in ACS-induced AHF, thereby widening the spectrum for indications of SGLT2 inhibitors.

To review the pharmacology of bexagliflozin in addition to its safety and efficacy from available clinical trials used for its approval, as well as available clinical evidence to date.

A search of the National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) and PubMed database was performed from inception through June 1, 2023.

The following study designs were included: meta-analyses, systematic review, clinical trial, or observational study design. Abstracts and drug monographs were also reviewed. Narrative or scoping reviews were excluded. Only articles in the English language and those evaluating the pharmacology, pharmacokinetics, safety, or efficacy of bexaglifozin in humans were included.

Bexagliflozin reduces hemoglobin A1c ~0.5% with similar reductions in systolic blood pressure and body weight to other SGLT2 inhibitors. No cardiovascular outcomes trial is published, nor ongoing at this time. Adverse effects are similar to other SGLT2 inhibitors (genital mycotic and urinary tract infections, increased urination) including a warning for lower extremity amputation similar to canagliflozin.

Although no cost-effectiveness data are available, statements from the manufacturer suggest a competitive price point. Given limited trial data, lower cost, if chosen, may create a temporary niche for bexagliflozin pending generic availability of other SGLT2 inhibitors. However, given lack of cardiovascular and renal outcome data, empagliflozin, dapagliflozin, or canagliflozin may be preferred.

Bexagliflozin appears safe and effective as monotherapy and add-on pharmacological therapy for the treatment of T2D.

The purpose of this systematic review and meta-analysis was to evaluate the common clinical adverse events associated with sodium/glucose cotransporter-2 inhibitor (SGLT2i) use compared to placebo in patients with chronic kidney disease (CKD) with or without type 2 diabetes.

Twelve articles were chosen via a systematic search of the PubMed, Embase, and Cochrane Library databases. We screened for randomised placebo-controlled trials. The main clinical adverse events included diabetes ketoacidosis (DKA), amputation, and volume depletion. We performed heterogeneity testing and assessment of publication bias.

In all, 65 600 patients were included in the analysis. Compared to placebo, SGLT2i may increase the risk of DKA and volume depletion in patients with CKD with or without type 2 diabetes. For DKA, compared with placebo, the combined effect of SGLT2i was OR 2.03 (95% CI: 1.28 to 3.23 I2: 2.3%, P: 0.420). For volume depletion, compared with placebo, the combined effect of SGLT2i was OR 1.24 (95% CI: 1.13 to 1.37 I2: 0.0%, P: 0.484). For the risk of amputation, despite low heterogeneity for amputation, the forest plot indicated no statistical significance, and thus it cannot be concluded that SGLT2i increases the risk of amputation. Compared with placebo, the combined effect of SGLT2i was OR 1.10 (95% CI: 0.94 to 1.29 I2: 0.0%, P: 0.642).

The use of SGLT2i may increase the risk of DKA and volume depletion in patients with chronic renal insufficiency with or without type 2 diabetes.

Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population.

Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are hypoglycemic agents, have been shown to be cardioprotective through a variety of mechanisms, and the effect of lowering uric acid (UA) levels may be one of the mechanisms. In the present retrospective study, we investigated the changes in serum UA levels in patients with chronic kidney disease (CKD) treated with SGLT2 inhibitors. Methods We included 31 patients with CKD who were newly started on dapagliflozin for renal protection and evaluated trends in various parameters, including serum UA levels and UA excretion from urine. Results The patients' median age was 71 years old, 20 patients were men, 7 patients had diabetes, and the median estimated glomerular filtration rate was 33.9 mL/min/1.73 m2 (CKD stage 3: 21 cases, stage 4: 10 cases). The differences in UA and fractional excretion of UA after three weeks and three months of prescription showed significantly decreased UA values and an increased fractional excretion of UA. Conclusion Our findings suggest that dapagliflozin can lower serum UA levels via increased UA excretion, even in patients with advanced CKD.

Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period.

We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks).

The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52.

Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.

Canagliflozin has been reported to increase the risk of bone fracture-possibly mediated by decreasing 1,25-dihydroxyvitamin D (1,25(OH)2D) and increasing parathyroid hormone (PTH).

This work investigated whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective.

This community-based, outpatient study had a paired design comparing individual participants before and after VitD3 supplementation. Eleven VitD-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals were recruited from the Amish population in Lancaster, Pennsylvania. Participants underwent 2 canagliflozin challenge protocols (300 mg daily for 5 days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50 000 IU once or twice a week depending on body mass index for 4-6 weeks) to achieve 25(OH)D of 30 ng/mL or greater. Two coprimary end points were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)2D and PTH. Secondary end points included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH.

VitD3 supplementation increased mean 25(OH)D from 16.5 ± 1.6 to 44.3 ± 5.5 ng/mL (P = .0006) and 24,25-dihydroxyvitamin D (24,25(OH)2D) from 1.0 ± 0.1 to 4.3 ± 0.6 ng/mL (P = .0002). Mean 1,25(OH)2D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; P = .04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P = .005).

VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin's short-term adverse effects on 1,25(OH)2D and PTH.

Epicardial adipose tissue (EAT) is located between the myocardium and visceral pericardium. The unique anatomy and physiology of the EAT determines its great potential in locally influencing adjacent tissues such as the myocardium and coronary arteries. Classified by research methodologies, this study reviews the latest research progress on the role of EAT in cardiovascular diseases (CVDs), particularly in patients with metabolic disorders. Studies based on imaging techniques demonstrated that increased EAT amount in patients with metabolic disorders is associated with higher risk of CVDs and increased mortality. Then, in-depth profiling studies indicate that remodeled EAT may serve as a local mediator of the deleterious effects of cardiometabolic conditions and plays a crucial role in CVDs. Further, in vitro coculture studies provided preliminary evidence that the paracrine effect of remodeled EAT on adjacent cardiomyocytes can promote the occurrence and progression of CVDs. Considering the important role of EAT in CVDs, targeting EAT might be a potential strategy to reduce cardiovascular risks. Several interventions have been proved effective in reducing EAT amount. Our review provides valuable insights of the relationship between EAT, metabolic disorders, and CVDs, as well as an overview of the methodological constructs of EAT-related studies.

Recently established heart failure therapies, including sodium glucose co-transporter 2 inhibitors, angiotensin-neprilysin inhibitors, and cardiac resynchronization therapy, have led to both clinical and structural improvements. Reverse remodelling describes the structural and functional responses to therapy and has been shown to correlate with patients' clinical response, acting as a biomarker for treatment success. The introduction of these new therapeutic agents in addition to advances in non-invasive cardiac imaging has led to an expansion in the evaluation and the validation of cardiac reverse remodelling. Methods including volumetric changes as well as strain and myocardial work have all been shown to be non-invasive end-points of reverse remodelling, correlating with clinical outcomes. Our review summarizes the current available evidence on reverse remodelling in heart failure by the non-invasive cardiac imaging techniques, in particular transthoracic echocardiography.

Acute coronary syndrome (ACS) remains the leading cause of death and disability worldwide, especially when combined with type 2 diabetes mellitus (T2DM). Many multicenter randomized controlled trials have established the cardiovascular benefits of Sodium-Glucose cotransporter 2 inhibitors (SGLT-2i) in patients with T2DM at high cardiovascular risk. However, these studies did not include patients in the early stages of acute coronary events. This study investigated the cardiovascular protective effects of SGLT-2i in patients with ACS and T2DM.

A total of 232 hospitalized patients with ACS and T2DM were enrolled and divided into two groups based on their hypoglycemic drug treatment: the SGLT-2i and the non-SGLT-2i groups. Kaplan-Meier analysis and Cox regression were used to compare adverse cardiovascular outcomes in both groups.

There were no significant differences in the hospital clinical outcomes between the SGLT-2i and non-SGLT-2i groups. The adverse cardiovascular outcomes did not significantly differ between both groups (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.35-1.25, P = 0.195). Moreover, the rehospitalization rates for ACS or heart failure (HF) were not significantly different between both groups (adjusted HR 0.56, 95%CI 0.28-1.10, P = 0.093). When analyzed separately, there was no significant difference in rehospitalizations for ACS (HR 0.87, 95% CI 0.40-1.87, P = 0.713). However, the SGLT-2i group showed lower rates of rehospitalizations for HF (adjusted HR 0.20, 95% CI 0.04-0.96, P = 0.045). Additionally, there was no significant difference in cardiovascular mortality between both groups (HR 1.75, 95% CI 0.28-10.97, P = 0.543). Notably, the SGLT-2i group exhibited a higher angina symptom control rate than the non-SGLT-2i group (adjusted odd ration (OR) 0.45, 95%CI 0.21-0.93, P = 0.031).

In recently diagnosed patients with ACS, who have T2DM, early initiation of SGLT-2i was associated with a lower risk of rehospitalization for HF and a higher rate of angina symptom control.

Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-κB/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.

Hypertensive nephropathy (HTN) is a common complication of hypertension. Although various agents for treatment of hypertension exert significant effects, there is currently no effective treatment for hypertensive nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin (DAPA), are a new class of hypoglycemic agents shown to improve the prognosis of patients with chronic kidney disease and diabetes mellitus. However, the mechanisms underlying the protective effects of DAPA remain unclear. RNA-sequencing (RNA-Seq)-based computational analysis was conducted to explore the transcriptomic changes to spontaneously hypertensive rats (SHRs) treated with DAPA for 8 weeks. Differentially expressed genes in SHRs were related to dysregulation of lipid metabolism, oxidation-reduction reaction, immunity and inflammation in HTN. Transcriptome analysis showed that 8 weeks of DAPA therapy exerted protective effects on the renal tissues of SHRs through the lysosomal, phagosomal, and autophagic pathways. VENN diagram analysis identified Zinc finger and BTB domain-containing 20 (Zbtb20) as the potential target of DAPA therapy. Consistent with the RNA-Seq findings, real-time quantitative PCR and immunohistochemical analyses revealed increased expression of Zbtb20 in the renal tissues of SHRs, whereas expression was decreased following 8 weeks of DAPA administration. The results of this study clarified the transcriptome signature of HTN and the beneficial effects of DAPA on renal tissues by alleviating dysregulation of metabolic processes and reducing inflammation.

Postmenopausal individuals with type 2 diabetes are susceptible to fractures due to the interaction of elevated blood glucose levels and a deficiency of the hormone estrogen. Despite continued concerns of fracture risks associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), existing evidence in this high-risk population is lacking.

To assess the risk of fractures associated with SGLT2i vs incretin-based drugs of dipeptidyl-peptidase 4 inhibitors (DPP4i) and glucagon-like peptide 1 receptor agonists (GLP1RA), separately, in postmenopausal individuals with type 2 diabetes.

This active-comparator, new-user cohort study used nationwide claims data of Korea and took place from January 1, 2013, to December 31, 2020. Postmenopausal individuals (aged ≥45 years) with type 2 diabetes were included.

New users of SGLT2i or comparator drugs.

The primary outcome was overall fractures, comprising vertebral, hip, humerus, and distal radius fractures. Patients were followed up from the day after drug initiation until the earliest of outcome occurrence, drug discontinuation (90-day grace period) or switch, death, or end of the study period. After propensity score fine stratification, hazard ratios (HRs) with 95% CIs were estimated using weighted Cox models.

Among 37 530 (mean [SD] age, 60.6 [9.7] years) and 332 004 (mean [SD] age, 60.6 [9.9] years) new users of SGLT2i and DPP4i, respectively, a lower rate of incident overall fractures was presented with SGLT2i vs DPP4i (weighted HR, 0.78; 95% CI, 0.72-0.84). Among 111 835 (mean [SD] age, 61.4 [9.8] years) and 8177 (mean [SD] age, 61.1 [10.3] years) new users of SGLT2i and GLP1RA, respectively, no association with an increased risk of overall fractures was presented with SGLT2i vs GLP1RA (weighted HR, 0.92; 95% CI, 0.68-1.24). Results from several subgroup and sensitivity analyses presented consistent results from main analysis.

This population-based cohort study suggests that SGLT2i was not associated with an increased rate of incident fractures compared with DPP4i and GLP1RA, separately, among postmenopausal individuals with type 2 diabetes.

Context. Canagliflozin has been reported to increase the risk of bone fracture - possibly mediated by decreasing 1,25-dihydroxyvitamin D [1,25(OH) 2 D] and increasing PTH. Objective. To investigate whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective. Design. This study had a paired design comparing individual participants before and after VitD3 supplementation. Setting. Community-based outpatient. Patients. 11 VitD deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals recruited from the Amish population in Lancaster PA. Interventions. Participants underwent two canagliflozin challenge protocols (300 mg daily for five days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4-6 weeks) to achieve 25(OH)D ≥ 30 ng/mL. Main Outcome Measures. Two co-primary endpoints were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH) 2 D and PTH. Secondary endpoints included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH. Results. VitD3 supplementation increased mean 25(OH)D from 16.5±1.6 to 44.3±5.5 ng/mL (p=0.0006) and 24,25-dihydroxyvitamin D [24,25(OH) 2 D] from 1.0±0.1 to 4.3±0.6 ng/mL (p=0.0002). Mean 1,25(OH) 2 D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH) 2 D (from -31.3%±4.7% to -9.3%±8.3%; p=0.04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; p=0.005). Conclusions. VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin's short-term adverse effects on 1,25(OH) 2 D and PTH.

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce atherosclerotic cardiovascular disease (ASCVD) events in patients with prior ASCVD and type 2 diabetes; however, this benefit is uncertain in patients without established ASCVD. Methods and Results Large-scale cardiovascular outcome randomized controlled trials or their prespecified subgroup analyses were selected, evaluating SGLT2 inhibitors versus placebo for primary prevention of ASCVD (inception, March 2023). The primary outcome was atherosclerotic major adverse cardiovascular events (MACEs), which was a composite of cardiovascular mortality, myocardial infarction, and stroke. The secondary outcomes were individual components of MACEs and all-cause mortality. The outcomes were reported as random-effect relative risk (RR) with a 95% CI. This analysis, comprising 23 987 patients enrolled in 5 randomized controlled trials with a mean follow-up duration of ≈135 weeks, found no significant reduction in atherosclerotic MACEs with SGLT2 inhibitors in comparison to placebo (RR, 0.85 [95% CI, 0.71-1.01]; P=0.07; I2=44). There were no significant differences in cardiovascular mortality (RR, 0.93 [95% CI, 0.77-1.14]; P=0.50; I2=0), myocardial infarction (RR, 0.88 [95% CI, 0.69-1.11]; P=0.28; I2=23), and stroke (RR, 0.84 [95% CI, 0.62-1.16]; P=0.29; I2=46). SGLT2 inhibitors significantly improved all-cause mortality (RR, 0.85 [95% CI, 0.72-1.0]; P=0.04; I2=23). On subgroup analyses, the use of SGLT2 inhibitors led to significant reductions in MACEs (RR, 0.74 [95% CI, 0.61-0.89]; P=0.001), myocardial infarction (RR, 0.67 [95% CI, 0.47-0.97]; P=0.03), and stroke (RR, 0.61 [95% CI, 0.41-0.91]; P=0.01) primarily in patients with chronic kidney disease along with type 2 diabetes, whereas these benefits were not observed in patients with type 2 diabetes without chronic kidney disease. Conclusions SGLT2 inhibitors significantly reduced atherosclerotic MACEs in subjects having both chronic kidney disease and type 2 diabetes without established ASCVD.

Recently, there is a lack of studies comparing the renoprotective effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This study therefore aimed to investigate the renoprotective effects of SGLT-2 inhibitors and DPP-4 inhibitors on Thai patients with type 2 diabetes mellitus.

Patient medication records of all patients who used those two antidiabetic classes at Fort Wachirawut Hospital were reviewed. Renal function tests, blood glucose levels, and other baseline characteristics were collected. Continuous variables were compared within the group using the Wilcoxon signed-rank test and between groups using the Mann-Whitney U test.

There were 388 and 691 patients with SGLT-2 inhibitors and DPP-4 inhibitors, respectively. The mean estimated glomerular filtration rate (eGFR) of the SGLT-2 inhibitor group was significantly lower from baseline at 18 months of treatment, as well as the DPP-4 inhibitor group. However, the trend of eGFR reduction in patients with baseline eGFR <60 mL/min/1.73 m² was smaller than those with baseline eGFR ≥60 mL/min/1.73 m². In addition, the fasting blood sugar and haemoglobin A1c levels significantly decreased from baseline in both the groups.

Both SGLT-2 inhibitors and DPP-4 inhibitors showed the same trends of eGFR reductions from baseline in Thai patients with type 2 diabetes mellitus. However, SGLT-2 inhibitors should be considered in patients with impaired renal function rather than in all T2DM patients.

Obstructive sleep apnea (OSA) is characterized by hypoxic episodes due to collapse of the airway during sleep and is frequently associated with obesity, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). There is currently no pharmacological agent approved for the treatment of OSA. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have the potential to both increase life expectancy and quality of life of these patients making them promising agents for this role. There are relatively few studies investigating this possible beneficial relationship between these drugs and OSA.

We aimed to increase awareness on the potential benefits of SGLT2 inhibitors in OSA patients by describing the current evidence on the effectiveness of these inhibitors in both overall and cardiovascular morbidity and mortality. We performed a literature search for articles reporting on the use of SGLT2 inhibitors in patients with OSA and T2DM.

We identified 4 manuscripts studying the use of SGLT2 inhibitors in 475 OSA patients with T2DM. Among them, 332 patients were administered SGLT2 inhibitors, and 143 patients were in a control group. SGLT2 inhibitors have many potential positive impacts on OSA patients by targeting various mechanisms involved in OSA pathogenesis.

SGLT2 inhibitors are prime pharmacological candidates for the treatment of OSA, and additional studies are needed to better explore mechanisms and outcomes unique to this population. Additionally, patients with OSA often have multiple comorbidities that are clinical indications for SGLT2 inhibitor therapy. Physicians should recognize and encourage the use of these agents in such patients.

Small extracellular vesicles derived from mesenchymal stem cells (MSCs) play important roles in cardiac protection. Studies have shown that the cardiovascular protection of sodium-glucose cotransporter 2 inhibitor (SGLT2i) is independent of its hypoglycemic effect. This study is aimed at investigating whether small extracellular vesicles derived from MSCs pretreated with empagliflozin (EMPA) has a stronger cardioprotective function after myocardial infarction (MI) and to explore the underlying mechanisms.

We evaluated the effects of EMPA on MSCs and the effects of EMPA-pretreated MSCs-derived small extracellular vesicles (EMPA-sEV) on myocardial apoptosis, angiogenesis, and cardiac function after MI in vitro and in vivo. The small extracellular vesicles of control MSCs (MSC-sEV) and EMPA-pretreated MSCs were extracted, respectively. Small extracellular vesicles were cocultured with apoptotic H9c2 cells induced by H₂O₂ or injected into the infarcted area of the Sprague-Dawley (SD) rat myocardial infarction model. EMPA increased the cell viability, migration ability, and inhibited apoptosis and senescence of MSCs. In vitro, EMPA-sEV inhibited apoptosis of H9c2 cells compared with the control group (MSC-sEV). In the SD rat model of MI, EMPA-sEV inhibited myocardial apoptosis and promoted angiogenesis in the infarct marginal areas compared with the MSC-sEV. Meanwhile, EMPA-sEV reduced infarct size and improved cardiac function. Through small extracellular vesicles (miRNA) sequencing, we found several differentially expressed miRNAs, among which miR-214-3p was significantly elevated in EMPA-sEV. Coculture of miR-214-3p high expression MSC-derived small extracellular vesicles with H9c2 cells produced similar protective effects. In addition, miR-214-3p was found to promote AKT phosphorylation in H9c2 cells.

Our data suggest that EMPA-sEV significantly improve cardiac repair after MI by inhibiting myocardial apoptosis. miR-214-3p at least partially mediated the myocardial protection of EMPA-sEV through the AKT signaling pathway.

SGLT2 inhibitors provide cardiovascular and renal protection in people with type 2 diabetes (T2DM). Real-world data on their effect on improving glucose and cardiovascular risk factors, and adverse effects in South Asians are limited.

We retrospectively analyzed clinical, demographic, anthropometric and biochemical data among adults with T2DM, commenced on empagliflozin and followed up for at least one month in a diabetes clinic in Colombo.

Among 1523 participants (men 49.6 %, age 54.9 (± 10.8) years, diabetes duration 11.5 (± 7.6) years, body mass index 28.2 (± 4.5 kg/m²), over a median follow up of 12 months (range: 1-24 months), reduction in HbA1c, weight, systolic blood pressure (SBP) and urine albumin-creatinine ratio were evident within the first month. Benefits sustained up to two-years (mean changes from baseline: HbA1c - 0.31 (± 1.49), weight - 1.14 (± 4.17), SBP - 3.44 (± 21.75), UACR - 19.84 (± 108.22) follow up. eGFR declined by the third month, returned to baseline by 12th and remained stable over 24 months. Higher baseline HbA1c, weight and SBP predicted greater decline in HbA1c, weight and SBP respectively. Weight reduction independently predicted the SBP reduction. Eighteen participants per 100 patient-years discontinued therapy due to adverse effects: genital mycotic infections and features of hypovolaemia were the commonest. We observed only two events of diabetic ketoacidosis.

Empagliflozin effectively improves glucose, weight and SBP and retards progression of renal impairment in South Asians with T2D. Genital mycotic infections and hypovolaemia were the commonest reasons for discontinuation. Careful patient selection and advice can avoid other sinister complications.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. The identification and management of fracture risk in these patients remains challenging. This manuscript explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated areal bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (FRAX) in these patients. It further reviews the impact of diabetes drugs on bone tissue as well as the efficacy of osteoporosis treatments in this population. An algorithm for the identification and management of diabetic patients at increased fracture risk is proposed.