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The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation. [ABSTRACT FROM AUTHOR]

Abstract The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the most recent pharmaceutical group for type 2 diabetes (T2D) treatment. Evidence indicates contradictory relationships between sodium-glucose cotransporter-2 inhibitors and bladder cancer (BC). Hence, this study aims to investigate the relationship between SGLT2 inhibitors and BC in patients with T2D. Materials and Methods: This study is a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). International databases including Cochrane, Web of Science, Scopus, PubMed, and Google Scholar were conducted for searching with keywords and without time and language limitations. The reference searching stage continued upgrading until November, 2022. Data analysis was performed with STATA 14 software. The tests with P values lower than 0.05 were considered statistically significant. Results: The four reviewed studies with a sample size comprising 497 755 individuals indicated the impact of SGLT2 inhibitors on BC of patients with T2D (OR: 0.68; 95% CI: 0.37, 1.2). The effect of dapagliflozin, canagliflozin and empagliflozin administration on the incidence of BC among the T2D patients were (OR: 0.72; 95% CI: 0.39, 1.30), (OR: 0.53; 95% CI: 0.23, 1.20), and (OR: 0.51; 95% CI: 0.20, 1.28), respectively. Conclusion: The general conclusion of this study revealed that SGLT2 inhibitors did not increase the risk of BC in T2D patients. The analysis of subgroups also indicated that the administration of dapagliflozin, canagliflozin, and empagliflozin also did not increase the risk of BC in T2D patients. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO website (ID=CRD42023389014). [ABSTRACT FROM AUTHOR]

Highlights 1. Androgen excess in PCOS model is associated with decreased markers of mitochondrial content in both subcutaneous and visceral white adipose tissue. 2. Androgen excess in PCOS model is associated with increased frequency of small adipocytes in subcutaneous white adipose tissue while decreasing frequency of small adipocytes in visceral white adipose tissue. 3. SGLT2 inhibition did not modify markers of mitochondrial content or oxidative stress in either subcutaneous or visceral white adipose tissue in PCOS model. 4. SGLT2 inhibition increased frequency of small adipocytes in both subcutaneous and visceral white adipose tissue in control rats; however, SGLT2 inhibition only increased frequency of small adipocytes in visceral white adipose tissue in PCOS model.

Background: 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. Method: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with type 2 diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men. Methods We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1000 participants and report data about sex differences in their primary cardiovascular or renal outcomes. Results The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% CI, 0.73-0.85) and women (0.78, 95% CI, 0.72-0.84) for adverse cardiorenal outcomes. Conclusion In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex. [ABSTRACT FROM AUTHOR]

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the most recent pharmaceutical group for type 2 diabetes (T2D) treatment. Evidence indicates contradictory relationships between sodium-glucose cotransporter-2 inhibitors and bladder cancer (BC). Hence, this study aims to investigate the relationship between SGLT2 inhibitors and BC in patients with T2D. Materials and Methods: This study is a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). International databases including Cochrane, Web of Science, Scopus, PubMed, and Google Scholar were conducted for searching with keywords and without time and language limitations. The reference searching stage continued upgrading until November, 2022. Data analysis was performed with STATA 14 software. The tests with P values lower than 0.05 were considered statistically significant. Results: The four reviewed studies with a sample size comprising 497 755 individuals indicated the impact of SGLT2 inhibitors on BC of patients with T2D (OR: 0.68; 95% CI: 0.37, 1.2). The effect of dapagliflozin, canagliflozin and empagliflozin administration on the incidence of BC among the T2D patients were (OR: 0.72; 95% CI: 0.39, 1.30), (OR: 0.53; 95% CI: 0.23, 1.20), and (OR: 0.51; 95% CI: 0.20, 1.28), respectively. Conclusion: The general conclusion of this study revealed that SGLT2 inhibitors did not increase the risk of BC in T2D patients. The analysis of subgroups also indicated that the administration of dapagliflozin, canagliflozin, and empagliflozin also did not increase the risk of BC in T2D patients. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO website (ID=CRD42023389014).

Background: Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. Methods: Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. Results: PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. Conclusions: Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model. Highlights: Androgen excess in PCOS model is associated with decreased markers of mitochondrial content in both subcutaneous and visceral white adipose tissue. Androgen excess in PCOS model is associated with increased frequency of small adipocytes in subcutaneous white adipose tissue while decreasing frequency of small adipocytes in visceral white adipose tissue. SGLT2 inhibition did not modify markers of mitochondrial content or oxidative stress in either subcutaneous or visceral white adipose tissue in PCOS model. SGLT2 inhibition increased frequency of small adipocytes in both subcutaneous and visceral white adipose tissue in control rats; however, SGLT2 inhibition only increased frequency of small adipocytes in visceral white adipose tissue in PCOS model. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are a new class of heart failure medications that have previously been exclusively utilized in the management of type 2 diabetes mellitus (T2DM). The rationale for using SGLT-2 inhibitors in patients with heart failure has stemmed from recent landmark clinical trials in T2DM in which reductions in mortality and hospitalization for heart failure were first observed. On the basis of these robust outcomes, empagliflozin has further been evaluated in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction and dapagliflozin solely in the management of HFrEF. While cardiovascular outcomes among each agent vary depending on the patient population, updates among both the American and European guidelines have included SGLT-2 inhibitors as pillars of therapy. The exact mechanisms for how SGLT-2 inhibitors are beneficial in heart failure are unknown, but current hypotheses include multiple metabolic and hemodynamic mechanisms. The purpose of this review is to summarize available literature focusing on the use of the SGLT-2 inhibitors as adjunctive therapy in heart failure, as well as evaluate mechanisms for heart failure benefit, adverse effects, and practical considerations for using these agents in the clinical setting. [ABSTRACT FROM AUTHOR]

Chronic heart failure (CHF) occurs in 4.3-28% of patients with diabetes mellitus and is most often associated with the presence of coronary heart disease, arterial hypertension and the direct adverse effects of insulin-resistance, hyperinsulinemia and hyperglycemia on the myocardium. Diabetes mellitus occurs in 12-47% of patients with CHF and can develop within several years after a diagnosis of HF in 22% of patients due to insulin-resistance of failure tissues. The presence of diabetes mellitus leads to a greater severity of clinical symptoms and hospitalization rate, worsening of quality of life and prognosis in CHF. A decreased left ventricular ejection fraction is an independent predictor of the poor prognosis in the patients with diabetes mellitus. The algorithm of the treatment of CHF in the patients with and without diabetes mellitus is not fundamentally different, but it requires taking into account the metabolic effects of the prescribed drugs. Angiotensin receptor-neprilysin inhibitor are increasingly used in clinical practice and are gradually replacing angiotensin-converting enzyme inhibitors and sartans in CHF both without diabetes mellitus and in its presence. Recently, the effectiveness of type 2 sodium glucose cotransporter inhibitors has been proven in patients with CHF with and without diabetes mellitus. This review is devoted to the relationship of diabetes mellitus and CHF, as well as the approaches to the management of such comorbid patients.

Background : Randomized controlled trials demonstrated lowering risks of cardiovascular events with sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk. We analyzed the effects of cardiovascular function on SGLT2 inhibitors compared with dipeptidyl peptidase-4 (DPP4) inhibitors in T2DM with atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF). Methods : This is a retrospective, observational, single center study. Data from 89 patients with ASCVD or HF from January 2015 to February 2018 were analyzed regarding the effect of SGLT2 inhibitors and DPP4 inhibitors. Cardiovascular function was assessed by 2-D echocardiography and N-terminal prohormone of brain natriuretic peptide (NT-pro BNP). Results : A total of 89 patients with T2DM were considered in two groups of SGLT2 inhibitors (n=41) and DPP4 inhibitors (n=48). The mean follow-up period was 2 years, with a total of 89 patient-years. Despite no significant change in systolic function, SGLT2 inhibitors improved cardiovascular function, as demonstrated by a reduced left ventricular ejection fraction less than 40%, ratio of mitral peak velocity of early filling velocity to early diastolic mitral annular velocity, ratio of early to late ventricular filling velocities, and NT-pro BNP compared with the DPP4 inhibitor group. Conclusion : SGLT2 inhibitors improve cardiovascular function in T2DM with coronary artery disease compared to DPP4 inhibitors.

Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.

Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules. [ABSTRACT FROM AUTHOR]

Background and Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of drugs that lower glucose by inducing renal glycosuria. We aimed to explore whether SGLT2 inhibitor added to the usual care for patients with type 2 diabetes mellitus (T2DM) and biopsy-proven nonalcoholic steatohepatitis (NASH) will benefit NASH histology.Methods: In this investigator-initiated, single-arm, open-label, pilot study, nine biopsy-proven NASH patients with T2DM were given empagliflozin 25 mg daily for 24 weeks. Liver biopsy was repeated at the end of treatment. The histological outcomes were compared with the placebo group of a previous 48-week clinical trial.Results: There was a significant reduction in body mass index (median change, Δ = -0.7 kg per m2, p = 0.011), waist circumference (Δ = -3 cm, p = 0.033), systolic blood pressure (Δ = -9 mmHg, p = 0.024), diastolic blood pressure (Δ = -6 mmHg, p = 0.033), fasting blood glucose (Δ = -1.7 mmol/L, p = 0.008), total cholesterol (Δ = -0.5 mmol/L, p = 0.011), gamma glutamyl transpeptidase (Δ = -19 U/L, p = 0.013), volumetric liver fat fraction (Δ = -7.8%, p = 0.017), steatosis (Δ = -1, p = 0.014), ballooning (Δ = -1, p = 0.034), and fibrosis (Δ = 0, p = 0.046). All histological components either remained unchanged or improved, except in one patient who had worsening ballooning. Empagliflozin resulted in significantly greater improvements in steatosis (67% vs. 26%, p = 0.025), ballooning (78% vs. 34%, p = 0.024), and fibrosis (44% vs. 6%, p = 0.008) compared with historical placebo.Conclusion: This pilot study provides primary histological evidence that empagliflozin may be useful for the treatment of NASH. This preliminary finding should prompt larger clinical trials to assess the effectiveness of empagliflozin and other SGLT2 inhibitors for the treatment of NASH in T2DM patients. Trial registry number ClincialTrials.gov number, NCT02964715. [ABSTRACT FROM AUTHOR]

Recent large clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, with the aim of verifying cardiovascular safety, have revealed that these medications have a preventative advantage on adverse cardiovascular outcomes, including worsening of heart failure and deterioration of nephropathy, in patients with type 2 diabetes (T2D). These observed benefits do not seem to correlate with the glucose-lowering effect, and the underlying mechanism is being intensively investigated. Given the results from recent studies, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that patients with T2D and clinical cardiovascular disease (CVD) with inadequate glucose control despite treatment with metformin should receive an SGLT2 inhibitor or GLP-1 receptor agonist. In this review we summarize the results of recent cardiovascular outcome trials and discuss the potential clinical advantage of SGLT2 inhibitors and GLP-1 receptor agonists. We also present practical implications of these glucose-lowering agents for reducing the risk of adverse cardiovascular events and progressive renal comorbidity in patients with T2D and CVD. [ABSTRACT FROM AUTHOR]

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys.

Aims/hypothesis: Sodium–glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. Methods: We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Results: Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29–0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Conclusions/interpretation: Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects. [ABSTRACT FROM AUTHOR]

Besides lowering glucose, empagliflozin, a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor, have been known to provide cardiovascular and renal protection due to effects on diuresis and natriuresis. However, the natriuretic effect of SGLT2 inhibitors has been reported to be transient, and long-term data related to diuretic change are sparse. This study was performed to assess the renal effects of a 12-week treatment with empagliflozin (3 mg/kg) in diabetic OLETF rats by comparing it with other antihyperglycemic agents including lixisenatide (10 μg/kg), a glucagon-like peptide receptor-1 agonist, and voglibose (0.6 mg/kg), an α-glucosidase inhibitor. At 12 weeks of treatment, empagliflozin-treated diabetic rats produced still high urine volume and glycosuria, and showed significantly higher electrolyte-free water clearance than lixisenatide or voglibose-treated diabetic rats without significant change of serum sodium level and fractional excretion of sodium. In empagliflozin-treated rats, renal expression of Na+-Cl- cotransporter was unaltered, and expressions of Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, and epithelial Na+ channel were decreased compared with control diabetic rats. Empagliflozin increased an expression of aquaporin (AQP)7 but did not affect AQP3 and AQP1 protein expressions in diabetic kidneys. Despite the increased expression in vasopressin V2 receptor, protein and mRNA levels of AQP2 in empagliflozin-treated diabetic kidneys were significantly decreased compared to control diabetic kidneys. In addition, empagliflozin resulted in the increased phosphorylation of AQP2 at S261 through the increased cyclin-dependent kinases 1 and 5 and protein phosphatase 2B. These results suggest that empagliflozin may contribute in part to polyuria via its regulation of sodium channels and AQP2 in diabetic kidneys. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are commonly prescribed to manage patients with diabetes mellitus. These agents may rarely lead to the development of euglycemic diabetic ketoacidosis (EDKA), which may complicate the disease course of these patients., Aim: To analyze the demographic profile, predisposing factors, symptomology, clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series., Methods: We performed a systematic search of PubMed, Science Direct, Google Scholar and Reference Citation Analysis databases using the terms "canagliflozin" OR "empagliflozin" OR "dapagliflozin" OR "SGLT2 inhibitors" OR "Sodium-glucose cotransporter-2" AND "euglycemia" OR "euglycemic diabetic ketoacidosis" OR "metabolic acidosis". The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported EDKA secondary to SGLT2i. Furthermore, the data were filtered from the literature published in the English language and on adults (> 18 years). We excluded: (1) Conference abstracts; and (2) Case reports or series which did not have individual biochemical data. All the case reports and case series were evaluated. The data extracted included patient demographics, clinical symptomatology, clinical interventions, intensive care unit course, need for organ support and outcomes., Results: Overall, 108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included. The majority of patients were females (54.4%, n = 92), and the commonly reported symptoms were gastrointestinal (nausea/vomiting 65.1%, abdominal pain 37.3%) and respiratory (breathlessness 30.8%). One hundred and forty-nine (88.2%) patients had underlying type II diabetes, and the most commonly involved SGLT-2 inhibitor reported was empagliflozin (46.8%). A triggering factor was reported in most patients (78.7%), the commonest being acute severe infection (37.9%), which included patients with sepsis, coronavirus disease 2019, other viral illnesses, and acute pancreatitis. 61.5% were reported to require intensive unit care, but only a minority of patients required organ support in the form of invasive mechanical ventilation (13%), vasopressors (6.5%) or renal replacement therapy (5.9%). The overall mortality rate was only 2.4%., Conclusion: Patients on SGLT2i may rarely develop EDKA, especially in the presence of certain predisposing factors, including severe acute infections and following major surgery. The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels, which may make the diagnosis challenging. Outcomes of EDKA are good if recognized early and corrective actions are taken. Hence, physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The sodium-glucose cotransporter-2 inhibitor (SGLT2i) is a new anti-hyperglycemic agent that have function to concomitantly inhibit the reabsorption of glucose and sodium in the renal proximal convoluting tubule. Recent two cardiovascular outcome trials showed that a lower risk of cardiovascular events with SGLT2i in people with type 2 diabetes. In addition, prior real-world data demonstrated similar SGLT2i effects, but these studies were limited to the United States and Europe. Thus, the CVDREAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors) 2 Study was investigated cardiovascular outcomes in those initiated on SGLT2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions. In Korea, 336,644 episodes of initiation in SGLT2i or oGLD group between September 2014 and December 2016 were identified in Korea National Health Insurance database after propensity score matching. SGLT2i users was associated with a lower risk of all-cause death (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.67~0.77), hospitalization for heart failure (HHF) (HR, 0.87; 95% CI, 0.82~0.92), all-cause death or HHF (HR, 0.81; 95% CI, 0.78~0.85), myocardial infarction (HR, 0.81; 95% CI, 0.74~0.89), and stroke (HR, 0.82; 95% CI, 0.78~0.86) compared with oGLD users. In conclusion, initiation of SGLT2i had a lower risk of cardiovascular events in people with type 2 diabetes compared with oGLDs. [ABSTRACT FROM AUTHOR]

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is mainly used for the treatment of type 2 diabetes mellitus. The study's objective was to assess empagliflozin's effects and impacts on post-myocardial patients to highlight its worth in comparison to alternative therapies. Only studies evaluating the effects of empagliflozin on individuals who have undergone a myocardial infarction (MI) are included in this review of the literature, which employed PubMed, Google Scholar, and Embase. To compare the advantages of empagliflozin for individuals who have recently experienced a myocardial infarction, abstracts from pertinent articles were retrieved, and complete publications were reviewed. A total of four articles were reviewed, which showed that in patients who suffered from a recent MI, empagliflozin caused a significant decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP). Additionally, it was shown that these individuals had better echocardiographic results for both structural and functional metrics. With studies showing a significantly larger median NT-proBNP decrease with empagliflozin compared to placebo among patients hospitalised with an acute big MI when empagliflozin was started early and administered in addition to the post-MI care suggested by guidelines, it is safe to say that the benefits outweigh the risks. There are currently larger double-blind trials in progress to prove the hypothesis of the benefits of empagliflozin for post-MI patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ravendran et al.)

Objective: To evaluate data sources pertaining to the safety and efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitor use for diabetes management in patients following kidney transplantation. Data Sources: A literature search was conducted through PubMed (1966-January 2023), EMBASE (1973-January 2023), and clinicaltrials.gov databases using the search terms kidney transplantation, diabetes mellitus, and SGLT2 inhibitor or empagliflozin, dapagliflozin, and canagliflozin. Study Selection and Data Extraction: Studies evaluating human kidney transplant recipients (KTR) receiving SGLT2 inhibitors treatment and published in the English language were included. Eight case series or retrospective analyses, 4 prospective observational studies, and 1 randomized controlled trial were identified. Data Synthesis: Available literature provides evidence that the addition of SGLT2 inhibitors may provide modest benefits on glycemic control, body weight, and serum uric acid levels in certain KTR. Various studies and case reports found that incidence of urinary tract infections was low, but still present. Overall, there are limited data on mortality and graft survival; however, one study reported a benefit of SGLT2 inhibitor use in KTR relative to these outcomes. Conclusions: The current literature evaluated demonstrates that there may be benefit to the addition of SGLT2 inhibitors for diabetes management in select KTR. However, the limited evidence within a large diverse population and extended duration of treatment makes it difficult to definitively identify the true efficacy and safety of SGLT2 inhibitor use in this population., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Introduction: The rising burden of diabetes mellitus led to the development of novel drugs like dapagliflozin and vildagliptin. Their efficacies in chronic diabetic patients have been thoroughly studied. However, there is a paucity of comparative studies on these drugs in newly diagnosed diabetic patients. The endpoints of our study were changes in glycated hemoglobin (HbA 1c ), fasting blood glucose (FBG), and postprandial blood glucose (PPBG) at 24 weeks from baseline., Methods: This randomized, open-label, 24-week study was conducted at Kalinga Institute of Medical Sciences, Bhubaneswar, India, from January 2021 to November 2022. The participants were randomized in a 1:1 ratio to receive tablets of either dapagliflozin 10mg once daily or vildagliptin 50mg once daily as an add-on to metformin 500-2000 mg. The analyses were performed in the per-protocol population. We used R software v. 4.1.1 (R Foundation, Indianapolis, IN) for data analysis., Results: 114 (83.8%) of 136 enrolled participants completed this study. The mean age of the study population was 41.08±5.17 years. Additionally, 52 (45.6%) of them were females. The mean changes in HbA 1c from baseline were -1.19 (95% CI: -1.36 to -1.03) and -1.28 (95% CI: -1.37 to -1.18) in dapagliflozin and vildagliptin groups, respectively (p=0.21). The median changes in FBG and PPBG in both groups were -38.76, -46.13 (p=0.07), and -51.84, -53.56 (p=0.14), respectively., Conclusions: Reductions in HbA 1c , FBG, and PPBG with add-on treatment of vildagliptin were more pronounced than dapagliflozin after a 24-week intervention. However, the differences were not statistically significant., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gautam et al.)

The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5′ AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNF α ) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNF α in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies. [ABSTRACT FROM AUTHOR]

Introduction: In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with type 2 diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men., Methods: We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1000 participants and report data about sex differences in their primary cardiovascular or renal outcomes., Results: The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% CI, 0.73-0.85) and women (0.78, 95% CI, 0.72-0.84) for adverse cardiorenal outcomes., Conclusion: In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Various diabetic drugs have been developed as the number of patients with type 2 diabetes has increased. Sodium-glucose cotransporter (SGLT)-2 inhibitors have been developed as novel therapeutic agents. However, SGLT-2 inhibitors cause skin dryness. The mechanism through which SGLT-2 inhibitors cause skin dryness is unknown. The purpose of this study was to investigate the mechanism through which dapagliflozin, a SGLT-2 inhibitor, induces skin dryness. Specific pathogen-free KK-Ay/TaJcl (type 2 diabetes model) mice were orally administered with SGLT-2 inhibitor (dapagliflozin) daily for 4 weeks at a dose of 1 mg/kg/d. Skin dryness induced in KK-Ay/TaJcl mice became severe after dapagliflozin administration. Dapagliflozin treatment decreased collagen type I and hyaluronic acid levels in mice; additionally, it affected the transforming growth factor (TGF)-β/hyaluronan synthase pathway, further reducing hyaluronic acid levels. The results indicate that the reduction in hyaluronic acid levels plays an important role in the occurrence of dry skin in diabetes.

Abstract: Sodium–glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of the kidneys and plays a key role in renal glucose reabsorption. A novel class of antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM). In this review, we summarize recent animal and human studies on ipragliflozin and other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and luseogliflozin. These agents all show potent and selective SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several advantages over other classes of hypoglycemic agents. Due to their insulin-independent mode of action, SGLT2 inhibitors provide steady glucose control without major risk for hypoglycemia and may also reverse β-cell dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors include a reduction in both body weight and blood pressure. SGLT2 inhibitors are safe and well tolerated and can easily be combined with other classes of antidiabetic medications to achieve tighter glycemic control. The long-term safety and efficacy of these agents are under evaluation. [Copyright &y& Elsevier]

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI. [ABSTRACT FROM AUTHOR]

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel glucose-lowering drugs (GLDs) which additionally promote weight loss and blood pressure reduction among other beneficial effects. Areas covered: This review reflects on the extra-glycemic effects of SGLT2 inhibitors and their impact on important clinical endpoints, and provides an overview of data relating to a newer member of the SGLT2 inhibitor class, bexagliflozin. Expert opinion: SGLT2 inhibitors, while consolidating glycemic control as adjunctive therapy, indisputably affect cardio-renal benefits in the T2D population which is prevalently afflicted by heightened cardiovascular risk and a disproportionately increased incidence of unfavorable cardiovascular and renal outcomes. The data from landmark trials demonstrate that beneficial effects of SGLT2 inhibitors extend to non-diabetic patients with chronic kidney disease (CKD) and/or heart failure with reduced ejection fraction (HFrEF). Preliminary findings from the BEST trial suggest that Bexagliflozin's effects reflect those of other licensed drugs in its class. Bexagliflozin has also been shown to be safe and effective in patients with diabetes and CKD stage 3b. If and when approved, it presents physicians with the prospect of an additional therapeutic option in managing patients with type 2 diabetes mellitus (T2D), and conceivably also, nondiabetic patients with established CKD and/or HFrEF.

Optimal blood glucose control helps reduce the development of the complications of type II diabetes mellitus (T2DM). T2DM patients usually are at increased risk of cardiovascular (CV) events and mortality. Therapies and strategies to treat diabetes and its related CV outcomes still need more investigation to find the best management options for this population. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have several benefits over multiple organ systems of the human body. However, the comparative effectiveness of this drug class is still not well-established. Our review aims to assess SGLT-2 inhibitors' effects on the CV complications that occur because of uncontrolled diabetes. A comprehensive literature search was conducted on PubMed and PubMed Central to find the relevant studies that were done from 2016 through 2020 to gather data for this review article. Those studies include reviews, randomized clinical trials, systematic reviews, and meta-analyses. Studies used in this article found an associated decrease in CV complications and mortality in patients with T2DM who received treatment with SGLT-2 inhibitors compared to the placebo group. These drugs have shown significant efficacy and safety outcomes in diabetic patients with heart disease, as they are glycosuric and diuretics, both of which are characteristics that could provide benefits to this population. SGLT-2 inhibitors appear to reduce the risk of cardiovascular events and mortality, suggesting that the benefits of these drugs seen in people with diabetes may apply to a broad population in the real world. We recommend further studies should confirm the immense clinical benefits with SGLT-2 inhibitors in patients with T2DM., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Aftab et al.)

Background: Randomized controlled trials demonstrated lowering risks of cardiovascular events with sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk. We analyzed the effects of cardiovascular function on SGLT2 inhibitors compared with dipeptidyl peptidase-4 (DPP4) inhibitors in T2DM with atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF)., Methods: This is a retrospective, observational, single center study. Data from 89 patients with ASCVD or HF from January 2015 to February 2018 were analyzed regarding the effect of SGLT2 inhibitors and DPP4 inhibitors. Cardiovascular function was assessed by 2-D echocardiography and N-terminal prohormone of brain natriuretic peptide (NT-pro BNP)., Results: A total of 89 patients with T2DM were considered in two groups of SGLT2 inhibitors (n=41) and DPP4 inhibitors (n=48). The mean follow-up period was 2 years, with a total of 89 patient-years. Despite no significant change in systolic function, SGLT2 inhibitors improved cardiovascular function, as demonstrated by a reduced left ventricular ejection fraction less than 40%, ratio of mitral peak velocity of early filling velocity to early diastolic mitral annular velocity, ratio of early to late ventricular filling velocities, and NT-pro BNP compared with the DPP4 inhibitor group., Conclusion: SGLT2 inhibitors improve cardiovascular function in T2DM with coronary artery disease compared to DPP4 inhibitors., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest., (Copyright © 2019 Korean Society for the Study of Obesity.)

Purpose Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, may be beneficial in obese diabetic patients based on its potential to decrease blood glucose and body weight, but there is limited proof. This analysis aimed to investigate the efficacy and safety of luseogliflozin in patients with varying levels of obesity. Methods A pooled analysis of four 52-week Phase III trials of luseogliflozin 2.5 mg daily (or up to 5 mg daily) in Japanese patients with type 2 diabetes mellitus stratified according to baseline body mass index (BMI) was conducted. Efficacy end points included changes in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight. Findings In total, 1031 patients were included and stratified into 5 BMI (kg/m 2 ) groups: low-to-medium (<22.5, n = 222); medium (≥22.5 to <25, n = 270); high-level 1 (≥25 to <27.5, n = 262); high-level 2 (≥27.5 to <30, n = 142); and very-high (≥30, n = 135). HbA1c decreased significantly compared with baseline until week 52 in all groups, and a similar trend was observed with FPG and body weight. The reduction in glycemic parameters tended to be slightly smaller in patients with BMI <22.5 kg/m 2 , and the reduction in body weight tended to be greater in patients with higher BMI, especially those with BMI ≥30 kg/m 2 . Levels of fasting insulin, C-peptide immunoreactivity, triglyceride, blood pressure, aspartate aminotransferase, alanine aminotransferase, and uric acid decreased significantly at week 52 in all groups (except for aspartate aminotransferase in patients with BMI <22.5 kg/m 2 ). Levels of these parameters tended to be higher at baseline and these enhanced levels resulted in a greater decrease in patients with higher BMI. In safety, the incidence of adverse events was similar between groups, and most of them were mild in severity. Implications HbA1c and body weight decreased significantly in all groups. Decrease in glycemic parameters tended to be smaller in patients with BMI <22.5 kg/m 2 , while that of body weight was larger in patients with higher BMI. Furthermore, luseogliflozin was especially beneficial in patients with higher BMI in terms of metabolic abnormalities, including insulin secretion and hypertension. Luseogliflozin exhibited a favorable and similar safety profile over 52 weeks in all groups. This agent can be an effective and well-tolerated therapeutic option in patients with a wide range of BMI levels, and it may be more beneficial in patients with higher BMI. [ABSTRACT FROM AUTHOR]