Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

The effects of Sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiac outcomes, cardiovascular mortality (CVM), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients have been reported heterogeneously in different studies.

PubMed, Scopus, Embase, Cochrane Library, and Scholar databases were searched with relevant MeSH terms from January 1, 2010, to November 14, 2023. The study used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcomes in all trials included the risk of ACM, CVM, hospitalization for heart failure (HHF), myocardial infarction (MI), and cerebrovascular accidents (CVA) in T2DM patients who were treated with one of the SGLT-2 inhibitors. Heterogeneity between studies was evaluated using Cochran's Q and I2 tests. The Egger's test was used to check for publication bias.

Eighteen studies, including 70,830 participants, were included. A pooled estimate showed that SGLT-2 inhibitor treatment was significantly associated with reduced ACM (OR: 0.82, 95% CI: 0.75-0.90, p-value: 0.001, I2: 35.1%), CVM (OR: 0.88, 95% CI: 0.80-0.96, p-value: 0.001, I2: 0%), MI (OR: 0.88, 95% CI: 0.79-0.98, p-value: 0.001, I2: 0%), and HHF (OR: 0.67, 95% CI: 0.58-0.77, p-value: 0.001). SGL-2 inhibitor treatment had no significant relationship with CVA (stroke) (OR: 0.95, 95% CI: 0.8-1.10, p-value: 0.896). Subgroup analysis showed that the effect of SGLT-2 inhibitor treatment on outcomes varied based on the type of SGLT-2 inhibitor.

SGLT-2 inhibitor treatment significantly reduced CVM, ACM, MI, and HHF. Empagliflozin, Canagliflozin, and Dapagliflozin significantly reduced ACM. Canagliflozin was significantly associated with a reduction in CVM. All SGLT-2 inhibitor treatments were associated with a reduction in HHF.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase ketoacidosis risk, limiting their use in type 1 diabetes. To better understand the pathophysiology of SGLT2 inhibitor-mediated ketoacidosis, we measured blood glucose, capillary blood and plasma β-hydroxybutyrate (BOHB) and breath acetone (BrACE) during supervised insulin withdrawal in adults with type 1 diabetes with and without dapagliflozin treatment.

Twenty adults with type 1 diabetes underwent supervised insulin withdrawal twice in a randomized crossover design: during usual care and after treatment with dapagliflozin (10 mg daily for 2 weeks plus the test day). After insulin withdrawal, capillary blood glucose, BOHB and BrACE measurements were obtained at least hourly until stopping rules were met (>8 h elapsed, symptoms of ketosis, glucose >400 mg/dL, BOHB >4 mmol/L or participant request).

The peak BOHB and BrACE values achieved during supervised insulin withdrawal were both greater with dapagliflozin than with usual care. Throughout the insulin withdrawal study, dapagliflozin treatment was associated with significantly greater BOHB and BrACE concentrations. The proportions of participants reaching BOHB >1.5 mmol/L and >2.5 mmol/L during supervised insulin withdrawal were greater in the dapagliflozin arm. Blood glucose reached a lower peak in the dapagliflozin arm.

In adults with type 1 diabetes undergoing supervised insulin withdrawal, dapagliflozin treatment compared to usual care was associated with greater blood and breath ketone concentrations in the absence of significant hyperglycaemia.

This review examines the evolving role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in acute cardiac care. Originally developed as antidiabetic agents, SGLT2i have demonstrated significant and early benefits in chronic heart failure by reducing hospitalizations and cardiovascular mortality across all the ejection fraction spectrum. Recent evidence now suggests that these agents may also offer advantages in acute settings, including acute decompensated heart failure (ADHF) and post - acute myocardial infarction (AMI). Several clinical trials have explored early SGLT2i initiation during hospitalization, reporting improvements in diuretic efficiency, cardiac biomarkers, and favorable remodeling, without notable safety concerns. The present review discusses the multifaceted mechanisms underlying these benefits, which include osmotic diuresis, modulation of neurohormonal activation, anti-inflammatory effects, and direct myocardial protection. Together, these actions not only facilitate decongestion and renal preservation but also enhance cardiac energetics. Current data are promising and support a pivotal role of a SGLT2i as a therapeutic strategy in the whole acute cardiac care setting for their short and long-term benefit. Future research is essential to validate these findings and refine the best patients to be treated with early SGLT2i implementation in the acute cardiac care spectrum.

Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease.

This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases.

We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.

The aim of our study was to evaluate the effects of dapagliflozin on the ventricular arrhythmia burden (VAb) in patients with heart failure with reduced ejection fraction (HFrEF) and an implantable cardioverter defibrillator (ICD), correlating the possible reduction in arrhythmic events and ICD therapies with the basal functional capacity, as well as the remodeling parameters induced by treatment.

A total of 117 outpatient ICD patients with a known diagnosis of HFrEF who underwent treatment with dapagliflozin were evaluated according to a prospective observational protocol. VAb (including sustained ventricular tachycardia, non-sustained ventricular tachycardia, ventricular fibrillation, and total ventricular events) and specific ICD therapies (anti-tachycardia pacing (ATP) and ICD shocks) were extrapolated from the devices' memory (events per patient per month) by comparing events in the observation period before and after the introduction of dapagliflozin.

The VAb was significantly reduced after dapagliflozin introduction (2.9 ± 1.8 vs. 4.5 ± 2.0, P = 0.01). The burden of appropriate ATPs was significantly reduced (0.57 ± 0.80 vs. 0.65 ± 0.91, P = 0.03), but not for ICD shocks. In patients with a more advanced functional class, a greater reduction in VAb was observed than in patients with a better initial functional capacity (2.2 ± 0.8 vs. 5.5 ± 1.8, P = 0.001 in the New York Heart Association (NYHA) III/IV group; 3.5 ± 2.1 vs. 4.5 ± 2.2, P = 0.02 in the NYHA I/II group). Considering two independent groups according to reverse remodeling (Δleft ventricular ejection fraction (LVEF) > 15%), a significant reduction in VAb was observed only in those patients who presented significant reverse remodeling (2.5 ± 1.1 vs. 5.1 ± 1.6, P = 0.01). A statistically significant interaction between the variation of total ventricular arrhythmias (VTA) and the basal NYHA class (F(1,115) = 142.25, P < 0.0001, partial η2 = 0.553), as well as between the variation of VTA and the ΔLVEF (F(1,115) = 107.678, P < 0.0001, partial η2 = 0.484) has been demonstrated using a two-way analysis of variance (ANOVA) test.

In ICD outpatients with HFrEF, dapagliflozin treatment produces a reduction in arrhythmic ventricular events. This improvement is more evident in patients who have a worse functional class and thus a more precarious hemodynamic state, and in patients who present with significant ventricular reverse remodeling. Therefore, we can hypothesize that the hemodynamic and structural improvements induced by treatment represent, at least in the short-medium term, some of the principal elements justifying the significant reduction in VAb.

Metabolic syndrome-related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid-induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.

Heart failure with preserved ejection fraction (HFpEF) is a major subtype of heart failure, primarily characterized by a normal or mildly reduced left ventricular ejection fraction along with left ventricular diastolic dysfunction. Recent studies have shown that the prevalence of HFpEF is higher in women than that in men, particularly in postmenopausal women. Concurrently, it has been observed that the incidence of risk factors contributing to HFpEF (such as obesity, hypertension, diabetes, and atrial fibrillation) also notably increases post-menopause, affecting the incidence of HFpEF. This review aimed to examine the relationship between estrogen and risk factors associated with HFpEF, clarifying the underlying mechanisms through which estrogen affects these risk factors from epidemiological and pathophysiological perspectives. This review also provides a comprehensive understanding of the association between estrogen and the risk factors for HFpEF, thus helping explore potential targets for HFpEF treatment.

In recent years, new drugs for the treatment of type 2 diabetes (T2D) have been proposed, including glucagon-like peptide 1 (GLP-1) agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. Over time, some of these agents (in particular, GLP-1 agonists and SGLT2 inhibitors), which were initially developed for their glucose-lowering actions, have demonstrated significant beneficial pleiotropic effects, thus expanding their potential therapeutic applications. This review aims to discuss the mechanisms, pleiotropic effects, and therapeutic potential of GLP-1, DPP-4, and SGLT2, with a particular focus on their cardiorenal benefits beyond glycemic control.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).

Diabetes mellitus is a common metabolic disease in humans and cats. Cats share several features of human type-2 diabetes and can be considered an animal model for this disease. In the last decade, sodium-glucose transporter 2 inhibitors (SGLT2i) have been used successfully as a class of hypoglycemic drug that inhibits the reabsorption of glucose from the renal proximal tubules, consequently managing hyperglycemia through glycosuria. Furthermore, SGLT2i have been shown to have cardiac, renal, and other protective effects in diabetic humans acting as a pleiotropic drug. Currently, at least six SGLT2i are approved by the Food and Drug Administration (FDA) for use in humans with type-2 diabetes, and recently, two drugs were approved for use in diabetic cats. This narrative review focuses on the use of SGLT2i to treat diabetes mellitus in humans and cats. We summarize the human data that support the use of SGLT2i in controlling type-2 diabetes and protecting against cardiovascular and renal damage. We also review the available literature regarding other benefits of these drugs in humans as well as the effects of SGLT2i in cats. Adverse effects related to the use of these hypoglycemic drugs are also discussed.

Diabetic cardiomyopathy (DbCM) is one of the common complications in diabetic patients, but there is no effective treatment for it up to now. Ketone bodies such as β-OHB have been widely reported to be beneficial for metabolic diseases including various diabetic complications. However, the role of ketone metabolism, especially the relevant enzymes, in the pathogenesis of DbCM is poorly understood.

In this study, we firstly observed BDH1, the rate-limiting enzyme of ketone metabolism, was markedly diminished in cardiac tissues from db/db mice and diabetic patients, as well as in H9C2 cells treated with palmitic acid. Genetic deletion of BDH1 aggravated, whereas AAV-mediated BDH1 overexpression attenuated, the diastolic dysfunction and pathogenic progression including apoptosis, fibrosis and inflammation of hearts from db/db mice. Likewise, BDH1 knockdown promoted, whereas BDH1 overexpression reversed, the palmitic acid-induced lipotoxicity in H9C2 cells. Transcriptome analysis revealed that BDH1 negatively regulated LCN2 expression and LCN2 overexpression largely abrogated BDH1 overexpression-mediated myocardial protection in vitro and in vivo. Mechanistically, BDH1 overexpression reprogrammed ketone metabolism with increased AcAc and decreased β-OHB, thereby resulting in decreased β-hydroxybutyrylation of H3K9 on promoter region of LCN2, which repressed transcription of LCN2 and ultimately inhibited NF-κB activity through weakening interaction between NF-κB and RPS3. Furthermore, oral administration of β-hydroxybutyrylation inhibitor A485 to diabetic mice mitigated the cardiac injury concurrently with decreased expression of LCN2.

Our results uncovered a novel mechanism whereby myocardial BDH1 ameliorates DbCM via epigenetic regulation of LCN2, which highlights the potential of BDH1/LCN2-based therapeutics in DbCM.

In recent years, the introduction of sodium-glucose transporter-2 inhibitors (SGLT2is) marked a significant advancement in the treatment of cardiovascular disease (CVD). Beyond their known effects on glycemic control and lipid profile, SGLT2is demonstrate notable benefits for cardiovascular morbidity and mortality, regardless of diabetic status. These agents are currently recommended as first-line therapies in patients with heart failure, both with reduced and preserved ejection fraction, as they improve symptoms and reduce the risk of hospitalization. While several studies have demonstrated that SGLT2is can reduce the incidence of major adverse cardiovascular events (MACEs), the true impact of these agents on atherosclerosis progression and myocardial ischemia remains to be fully understood. A global beneficial effect related to improved glycemic and lipid control could be hypothesized, even though substantial evidence shows a direct impact on molecular pathways that enhance endothelial function, exhibit anti-inflammatory properties, and provide myocardial protection. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs in preventing and treating myocardial ischemia, aiming to define an additional area of application beyond glycemic control and heart failure.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD patients exhibit varying degrees of abnormal glucose metabolism throughout disease stages. Abnormal glucose metabolism is closely linked to the PD pathogenesis and progression. Key glucose metabolism processes involved in PD include glucose transport, glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, the pentose phosphate pathway, and gluconeogenesis. Recent studies suggest that glucose metabolism is a potential therapeutic target for PD. In this review, we explore the connection between PD and abnormal glucose metabolism, focusing on the underlying pathophysiological mechanisms. We also summarize potential therapeutic drugs related to glucose metabolism based on results from current cellular and animal model studies.

The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.

Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) lower blood sugar and reduce cardiovascular events and kidney failure. However, there have been increasing reports of euglycaemic diabetic ketoacidosis (eDKA) linked to SGLT2-i medicines.

Investigating the association between SGLT2-i use and the incidence of metabolic acidosis in patients with type 2 diabetes undergoing cardiac surgery.

A retrospective observational cohort study comprising 121 patients, with 38 in the SGLT2-i group and 83 in the control group.

A 2-year period at Haukeland University Hospital, a tertiary regional hospital in Western Norway.

Patients with type 2 diabetes undergoing cardiac surgery.

Collection of clinical and laboratory data, including acid/base balance parameters, surgery details and SGLT2-i use.

Base excess and anion gap measurements as indicators of ketosis development. A subgroup analysis in patients without renal failure (glomerular filtration rate > 60 ml min -1  m -2 ) .

Lower base excess levels and increased anion gaps were observed in the SGLT2-i group compared with controls at various time points postoperatively, with no significant differences in serum lactate levels.Twelve hours postoperatively, 41% of SGLT2-i patients without renal failure had a base excess -3 mmol l -1 or less after correction for serum lactate (indicating ketosis) compared with only 8% in the control group ( P  < 0.001). The anion gap was elevated in the SGLT2-i group compared to the control group at 12 h postoperatively ( P  = 0.018).Multivariable regression analysis identified SGLT2-i use as an independent factor associated with a lower base excess after correction for lactate levels ( P  < 0.001). Cessation of SGLT2-i medication did not correlate with the degree of acidosis.

While taking SGLT2 inhibitors, diabetic patients undergoing heart surgery are at an increased risk of ketosis and possibly metabolic acidosis. This emphasises the importance of careful observation and effective treatment strategies within this group.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Erythropoietin (EPO) is pivotal in regulating red blood cell (erythrocyte) concentrations and is primarily synthesized in the kidney. Recent research has unveiled a possible link between elevated circulating concentrations of ketone bodies (KB) and circulating EPO concentrations; however, it is not known whether nutritionally induced endogenous ketogenesis can be a stimulus to induce EPO in humans. Therefore, this study aimed to assess whether acute and chronic intake of medium-chain fatty acid-containing triacylglycerol (MCT), which rapidly enhances endogenous circulating KB, would elevate circulating EPO concentrations in humans, as indicated by prior work with exogenous KB administration. The study followed a crossover design involving 16 young men undergoing two 8-day MCT or energy-matched long-chain fatty acid-containing triacylglycerol (LCT) interventions in a randomized order. Five-hour test days were performed before and after each intervention, in which circulating KB and EPO concentrations as well as hematological parameters were assessed. Acute intake of MCT yielded a 222% sustained 5-h elevation in KB concentrations compared with LCT-with notable peak values of 0.7 ± 0.1 mmol·L-1 (312% above basal values). Remarkably, within just 8 days of daily MCT intake an impressive 38% increase in basal, fasting plasma EPO concentrations (7.19 ± 1.14 to 9.91 ± 1.25 mIU·mL-1) was demonstrated. In conclusion, this study unveils a novel physiological stimulus of circulating EPO concentrations in humans, potentially offering a new dietary approach to counter anemia in cardiovascular diseases.NEW & NOTEWORTHY This study is the first to assess the effects of nutritionally induced ketogenesis by acute and subchronic intake of medium-chain fatty acids on plasma erythropoietin concentrations. Medium-chain fatty acid intake increases postprandial ketone body concentrations and within only 8 days of daily intake substantially enhances basal plasma erythropoietin concentrations in young men. We therefore reveal a dietary stimulus of endogenous circulating erythropoietin concentrations in humans, with the potential to counter anemia in cardiovascular diseases.

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D).

FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin.

Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models.

Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment.

The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and now comprises more than half of all heart failure cases. There are many risk factors for HFpEF, including older age, hypertension, diabetes, dyslipidemia, sedentary behaviour, and obesity. The rising prevalence of obesity in society is a particularly important contributor to HFpEF development and severity. Obesity can adversely affect the heart, including inducing marked alterations in cardiac energy metabolism. This includes obesity-induced impairments in mitochondrial function, and an increase in fatty acid uptake and mitochondrial fatty acid β-oxidation. This increase in myocardial fatty acid metabolism is accompanied by an impaired myocardial insulin signaling and a marked decrease in glucose oxidation. This switch from glucose to fatty acid metabolism decreases cardiac efficiency and can contribute to severity of HFpEF. Increased myocardial fatty acid uptake in obesity is also associated with the accumulation of fatty acids, resulting in cardiac lipotoxicity. Obesity also results in dramatic changes in the release of adipokines, which can negatively impact cardiac function and energy metabolism. Obesity-induced increases in epicardial fat can also increase cardiac insulin resistance and negatively affect cardiac energy metabolism and HFpEF. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating HFpEF. This review discusses what is presently known about the effects of obesity on cardiac energy metabolism and insulin signaling in HFpEF. The clinical implications of obesity and energy metabolism on HFpEF are also discussed.

Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer.

The impacts of elevated ketone body levels on cardiac function and hemodynamics in patients with heart failure (HF) remain unclear.

The effects of ketone intervention on these parameters in patients with HF were evaluated quantitatively in this meta-analysis.

We searched the PubMed, Cochrane Library, and Embase databases for relevant studies published from inception to April 13, 2024. Ketone therapy included ketone ester and β-hydroxybutyrate intervention.

Seven human studies were included for the quantitative analysis.

Our results showed that ketone therapy significantly improved left ventricular ejection fraction (standardized mean difference, 0.52 [95% CI, 0.25-0.80]; I2 = 0%), cardiac output (0.84 [95% CI, 0.36-1.32]; I2 = 68%) and stroke volume (0.47 [95% CI, 0.10-0.84]; I2 = 39%), and significantly reduced systemic vascular resistance (-0.92 [95% CI, -1.52 to -0.33]; I2 = 74%) without influencing mean arterial pressure (-0.09 [95% CI: -0.40 to 0.22]; I2 = 0%) in patients with HF. Subgroup analysis revealed that the enhanced cardiac function and favorable hemodynamic effects of ketone therapy were also applicable to individuals without HF.

Ketone therapy may significantly improve cardiac systolic function and hemodynamics in patients with HF and in patients without HF, suggesting it may be a promising treatment for patients with HF and also a beneficial medical strategy for patients without HF or healthy individuals.

Diabetes is known to increase the risk of kidney stones, but the influence of antidiabetic drugs on this risk remains uncertain. Genetic instruments for antidiabetic drugs were identified as variants, which were associated with both the expression of genes encoding target proteins of drugs and glycated hemoglobin level (HbA1c). Here, we investigated the effect of antidiabetic drugs on kidney stones in a mendelian randomization (MR) framework, and further explore the potential effect on CaOx stone rat models induced by glyoxylic acid. Genetically proxied thiazolidinediones (PPARG agonists) significantly reduced the risk of kidney stones (OR = 0.42; P=0.004) per 1-SD decrement in HbA1c, while no significant association was noted in sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs. Other antidiabetic drugs were not analyzed due to unclear pharmacological targets or no identified instruments. Additionally, PPARG agonists pioglitazone ameliorated CaOx nephrocalcinosis in glyoxylic acid-induced rats. The summary-data-based MR (SMR) results showed that PPARG mRNA expression in blood or kidney was not associated with kidney stone risk, and thus we performed mediation MR of PPARG agonists, circulating metabolites, and kidney stones. Among 249 circulating metabolites, we identified an indirect effect of PPARG agonists on kidney stones through increasing phospholipids to total lipids ratio in very large VLDL, with a mediated proportion of 6.87% (P = 0.018). Our study provided evidence that PPARG agonists reduced the risk of kidney stones partially via regulating lipid metabolism, and PPARG agonists may be a promising study subject in clinical studies for the prevention of kidney stones.

BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated significant cardiovascular benefits in clinical trial. While their role in reducing heart failure hospitalizations and cardiovascular mortality is well established, the precise mechanisms underlying their direct cardiac effects remain unclear. This literature review aims to synthesize current knowledge on the molecular and physiological pathways by which SGLT2 inhibitors may exert effects on cardiac tissue, independent of glycemic control.MethodsA comprehensive review of peer-reviewed articles, randomized controlled trials, meta-analyses, and mechanistic studies published in PubMed and related databases was conducted. The search focused on studies examining the direct impact of SGLT2 inhibitors on cardiac function, remodeling, metabolism, and intracellular signaling pathways. Only studies evaluating the cardiac effects separate from their glucose-lowering action were included in the analysis.ResultsThis review identified several key mechanisms by which SGLT2 inhibitors may benefit the heart directly, including reductions in oxidative stress, inflammation, and myocardial fibrosis. Emerging evidence suggests that these drugs modulate key pathways such as sodium-hydrogen exchange (NHE) inhibition, improvement of mitochondrial function, and promotion of ketone body utilization in cardiomyocytes.ConclusionsSGLT2 inhibitors appear to confer direct cardioprotective effects. These include anti-inflammatory, anti-fibrotic, and energy efficiency improvements in the myocardium. The findings highlight new potential therapeutic mechanisms and provide a foundation for further research into the non-diabetic use of SGLT2 inhibitors in heart failure and other cardiac conditions. Understanding these direct effects could lead to optimized treatment strategies for patients with and without diabetes.

The metabolic and lipid profiles of horses treated with sodium-glucose cotransporter 2 inhibitors are not well understood. This retrospective study evaluated blood parameters in hyperinsulinemic horses treated with either ertugliflozin (0.05 mg/kg) or dapagliflozin (0.02 mg/kg) orally once daily. Blood samples were collected at baseline (day 0) and after 7 and/or 30 days of treatment. Statistical analyses were conducted using Wilcoxon signed-rank, Mann-Whitney and Spearman's rank correlation tests. Thirty-four horses received dapagliflozin and 24 received ertugliflozin. Significant (p<0.05) within-horse changes between day 0 and day 30 included [median, inter-quartile range (IQR)]: basal serum [Insulin] (uU/ml) reduced 170 (92-280) to 28.7 (14.5-90); [triglycerides] (mmol/l) increased 0.5 (0.3-0.6) to 1.0 (0.6-1.56), [β-hydroxybutyrate] (umol/l) increased 0.22 (0.17-2.7) to 0.30 (0.24-0.35); [total cholesterol] (mmol/l) increased 2.36 (2-2.6) to 2.84 (2.4-3.7); and GGT (IU/ml) increased 21 (16-32) to 25 (18-38). As a percentage of total serum lipids, high-density lipoprotein (HDL) reduced 52.4 % (47.9 %-61.0 %) to 50 % (41 %-54.8 %) and very-low density lipoprotein (VLDL) increased 10.4 % (6.4 %-14.4 %) to 12.3 % (9.9 %-16.8 %) (all p<0.05). Differences between ertugliflozin and dapagliflozin groups were not significant in any of these parameters at days 0, 7 or 30. At day 30, 10/48 (21 %) cases had [triglycerides] > 2.0 mmol/l (maximum = 10.8mmol/l). Day 30 [triglyceride] correlated with day 0: basal insulin (rho=0.47); [triglyceride] (rho=0.42); %VLDL (rho=0.34) day 30: [total cholesterol] (rho=0.67), %HDL (rho=-0.432) and %VLDL (rho=0.708). Our findings suggest that SGLT2 inhibitors induce minor changes in lipid profiles, with occasional cases of marked hypertriglyceridemia, and that dapagliflozin and ertugliflozin exhibit similar biochemical effects.

The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.

Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.

BACKGROUNDSodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODSWe measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTSHigher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54-0.98] and HR = 0.67 [95% CI: 0.48-0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50-0.99] and HR = 0.63 [95% CI: 0.42-0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSIONIn T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent disease with limited treatment options. The aim of this study was to evaluate the preventive effects of a sodium-glucose co-transporter (SGLT)-2 inhibitor, empagliflozin, on a dietary mouse model of MASLD.

In total, 24 C57BL/6 J mice of both sexes were randomly allocated to three groups, as follows: the fast food diet (FFD) group (eight mice, receiving a high-fat, high-cholesterol, high-fructose diet, FFD), the EMPA group (eight mice, fed a FFD with 10 mg/kg/d empagliflozin), and the chow diet (eight mice, CD) group. The mice were weighed and blood samples were drawn every 4 weeks; after 25 weeks the mice were euthanized, at which point liver tissues were histologically evaluated.

After 25 weeks, there was no significant difference in body weight between the three groups, whereas liver-to-body weight ratio was greater in the EMPA compared to the CD group (p = 0.002). Hepatic fibrosis was marginally different between the three groups (p = 0.045). Fibrosis stage 1 was present in five mice on FFD (62.5%), in one mouse on EMPA (12.5%), and in one mouse on CD (12.5%). Lipogenic, inflammatory, and fibrogenic genes did not differ between the EMPA and FFD groups. Interestingly, mRNA encoding for SGLT-1 and SGLT-2 was detected in the mouse livers.

Empagliflozin treatment in mice on a FFD did not result in any significant effects on morphological, biochemical, or histological features or on expression of hepatic genes associated with MASLD compared to those fed a FFD without empagliflozin. The observed effects on mild hepatic fibrosis warrant validation, possibly via studies of longer duration.

The very high energy demand of the heart is primarily met by adenosine triphosphate (ATP) production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure [including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), and diabetic cardiomyopathies] is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signalling and post-translational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.

A retrospective study reported that empagliflozin reduced the risk of urinary stone events in patients with diabetes mellitus. To further investigate empagliflozin's potential, we conducted an animal experiment to determine whether empagliflozin can prevent renal stone formation in hyperoxaluria rats. Hyperoxaluria rat models were constructed by administrating 0.75 % ethylene glycol and 1 % ammonium chloride in water. The empagliflozin-treated rats were gauged with empagliflozin at different concentrations, and their body weight and blood sugar data were recorded. After 30 days of treatment, we obtained 24-h urine, kidney, and blood samples. The urine samples were subjected to component detection. Blood samples were prepared for component detection and cytokines detection. Renal samples were subjected to von Kossa staining, transmission electron microscopy, immunohistochemistry, and transcriptome sequencing analysis. Results showed that in empagliflozin-treated hyperoxaluria rats, renal crystal deposition and mitochondria injury, urinary concentration, and excretion of oxalate were significantly decreased. Additionally, plasma levels of VEGF, IL-2, IL-1β, and MCP-1 were decreased. Immunohistochemistry showed that renal expression of KIM-1, MCP-1 was significantly decreased in empagliflozin-treated hyperoxaluria rats. Transcriptome sequencing of renal tissue represented that 25 genes were down-regulated while 12 were up-regulated in empagliflozin-treated hyperoxaluria rats. These regulated genes were mainly enriched in fatty acid metabolism, insulin resistance, muscle contraction, bile secretion, and parathyroid metabolism. Our animal experiments found that empagliflozin could reduce urinary concentration and excretion of oxalate and inhibit renal inflammation, then abating renal calcium oxalate deposition in hyperoxaluria rats in a non-diabetic state.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors afford significant cardiovascular benefits to patients with diabetes mellitus and heart failure. Three large randomized clinical trials (EMPAREG-Outcomes, DECLARE-TIMI58, and DAPA-HF) have shown that SGLT2 inhibitors prevent cardiovascular events and reduce the risk of death and hospital admission resulting from heart failure. Patients without type 2 diabetes mellitus (T2DM) also experience a similar degree of cardiovascular benefit as those with T2DM do. SGLT2 inhibitors could improve cardiac function through potential non-hypoglycemic mechanisms, including the reduction of the circulatory volume load, regulation of energy metabolism, maintenance of ion homeostasis, alleviation of inflammation and oxidative stress, and direct inhibition of cardiac SGLT1 receptors and antimyocardial fibrosis. This article reviews the mechanism through which SGLT2 inhibitors prevent/alleviate heart failure through non-hypoglycemic pathways, to support their use for the treatment of heart failure in non-T2DM patients.

Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium-glucose cotransporter 2 inhibitor therapy as one of the four 'pillars' of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear.

The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF.

This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF).

Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 ± 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01). SUA was reduced early (after 4 weeks vs placebo -0.99 ± 0.03 mg/dL; P < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07).

Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia.

Background: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, initially designed for type 2 diabetes, promote glucose excretion and lower blood glucose. Newer analogs like empagliflozin and dapagliflozin improve cardiovascular outcomes through mechanisms other than glycemic control, including blood pressure reduction and anti-inflammatory effects. Given the high cardiovascular risk present in diabetes, our study aims to emphasize the cardioprotective benefits of SGLT-2 inhibitors as a preventive therapy for heart failure (HF) in high-risk T2DM patients. Methods: Using data from 2542 patients identified by the ICD-10 E11 code from 2016 to 2020, this longitudinal study excluded those with E10 codes or those undergoing insulin treatment to focus on non-insulin-dependent T2DM. a multiple logistic regression model assessed HF incidence while adjusting for demographics and HbA1c. Results: SGLT-2 inhibitor use significantly lowered the odds of heart failure events (OR = 0.55, 95% CI: 0.31-0.99, p = 0.046), with a significant difference by gender (OR = 0.45, 95% CI: 0.28-0.71, p = 0.001) and eGFR (OR = 0.98, 95% CI: 0.97-0.99, p = 0.004). Conclusions: The real-world data highlight SGLT-2 inhibitors as promising for HF prevention and broader cardiometabolic health in T2DM, with potential value in managing complex comorbid profiles.

Type 2 diabetes mellitus (T2DM) is associated with a heightened risk of cardiovascular and renal complications. While glycemic control remains essential, newer therapeutic options, such as SGLT2 inhibitors, offer additional benefits beyond glucose reduction. This review delves into the mechanisms underlying the cardio-renal protective effects of SGLT2 inhibitors. By inducing relative hypoglycemia, these agents promote ketogenesis, optimize myocardial energy metabolism, and reduce lipotoxicity. Additionally, SGLT2 inhibitors exert renoprotective actions by enhancing renal perfusion, attenuating inflammation, and improving iron metabolism. These pleiotropic effects, including modulation of blood pressure, reduction of uric acid, and improved endothelial function, collectively contribute to the cardiovascular and renal benefits observed with SGLT2 inhibitor therapy. This review will provide clinicians with essential knowledge, understanding, and a clear recollection of this pharmacological group's mechanism of action.