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Introduction: This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium–glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). Methods: The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. Results: In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = − 23.13%; 95% CI = [− 33.69, − 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = − 1.03 mL/min/1.73 m2; 95% CI = [− 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = − 2.23 mL/min/1.73 m2; 95% CI = [− 3.62, − 0.84]; P = 0.002). Conclusion: Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D. [ABSTRACT FROM AUTHOR]

The prevalence and burden of diabetes are on the rise in India, making it 'the diabetes capital of the world'. Comorbidities such as obesity, cardiovascular (CV) complications, chronic kidney disease (CKD), non-alcoholic fatty liver disease (NAFLD), and neurodegenerative diseases are common in patients with diabetes. Recent breakthroughs in diabetes medications and continuous glucose monitoring have resulted in a paradigm shift in diabetes care. Hence, a review in the Indian context is warranted. This review focuses on the existing evidence (gathered by a systematic literature search utilising online databases such as PubMed) on the metabolic, cardio-renoprotective, and hepatoprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition, particularly in the Indian setting. The study revealed that the SGLT2 inhibitors (SGLT2i), with their numerous pleiotropic benefits, have received considerable attention recently as a novel class of antihyperglycaemic agents (AHAs) for the management of diabetes. SGLT2i play a crucial role in the transition from glycaemic control to metabolic care, particularly in the context of obesity, CV disease and renal disease. In addition to improving glycaemic control, SGLT2i have been shown to promote weight loss, reduce blood pressure and improve lipid profiles, which are key components of metabolic health. Moreover, SGLT2i have demonstrated renal protective effects, including a reduction in albuminuria and a slower decline in the estimated glomerular filtration rate (eGFR), suggesting a potential role in the management of renal dysfunction.

The prevalence and burden of diabetes are on the rise in India, making it 'the diabetes capital of the world'. Comorbidities such as obesity, cardiovascular (CV) complications, chronic kidney disease (CKD), non-alcoholic fatty liver disease (NAFLD), and neurodegenerative diseases are common in patients with diabetes. Recent breakthroughs in diabetes medications and continuous glucose monitoring have resulted in a paradigm shift in diabetes care. Hence, a review in the Indian context is warranted. This review focuses on the existing evidence (gathered by a systematic literature search utilising online databases such as PubMed) on the metabolic, cardio-renoprotective, and hepatoprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition, particularly in the Indian setting. The study revealed that the SGLT2 inhibitors (SGLT2i), with their numerous pleiotropic benefits, have received considerable attention recently as a novel class of antihyperglycaemic agents (AHAs) for the management of diabetes. SGLT2i play a crucial role in the transition from glycaemic control to metabolic care, particularly in the context of obesity, CV disease and renal disease. In addition to improving glycaemic control, SGLT2i have been shown to promote weight loss, reduce blood pressure and improve lipid profiles, which are key components of metabolic health. Moreover, SGLT2i have demonstrated renal protective effects, including a reduction in albuminuria and a slower decline in the estimated glomerular filtration rate (eGFR), suggesting a potential role in the management of renal dysfunction. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a chronic condition with considerable clinical burden for patients and economic burden for healthcare systems. Treatment for HF is typically based on ejection fraction (EF) phenotype. The cost-effectiveness of empagliflozin + standard of care (SoC) compared to SoC has been examined for HF phenotypes below or above 40% EF separately, but not across the full spectrum of EF in Spain. The results of two preexisting, validated, and published phenotype-specific Markov cohort models were combined using a population-weighted approach, reflecting the incidence of each phenotype in the total HF population in Spain. A probabilistic sensitivity analysis was performed by sampling each model's probabilistic results. Empagliflozin + SoC compared to SoC resulted in increased life-years (LYs) (6.48 vs. 6.35), quality-adjusted LYs (QALYs) (4.80 vs. 4.63), and healthcare costs (€19,090 vs. €18,246), over a lifetime time horizon for the combined HF population in Spain. The incremental cost-effectiveness ratio (ICER) was €5,089/QALY. All subgroup, scenario, and probabilistic ICERs were consistently below €10,000/QALY. Empagliflozin is the first treatment with established efficacy and cost-effectiveness for HF patients across EF from the perspective of healthcare payers in Spain. Empagliflozin also proved to be cost-effective for all subgroups of patients included in the analysis. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium‐glucose co‐transporters 1 and 2, in adults with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3). Materials and Methods: This phase 3, randomized, placebo‐controlled trial evaluated sotagliflozin 200 and 400 mg in 787 patients with T2D and an estimated glomerular filtration rate of 30‐59 ml/min/1.73m2. The primary objective was superiority of week 26 HbA1c reductions with sotagliflozin versus placebo. Secondary endpoints included changes in other glycaemic and renal endpoints overall and in CKD3 subgroups. Results: At 26 weeks, the placebo‐adjusted mean change in HbA1c (from a baseline of 8.3% ± 1.0%) was –0.1% (95% CI: –0.2% to 0.05%; P =.2095) and –0.2% (–0.4% to –0.09%; P =.0021) in the sotagliflozin 200 and 400 mg groups, respectively. Significant reductions in fasting plasma glucose and body weight, but not systolic blood pressure, were observed. Among patients with at least A2 albuminuria at week 26, the urine albumin‐creatinine ratio (UACR) was reduced with both sotagliflozin doses relative to placebo. At week 52, UACR was reduced with sotagliflozin 200 mg in the CKD3B group. Adverse events (AEs), including serious AEs, were similar between the treatment groups. Conclusions: After 26 weeks, HbA1c was significantly reduced with sotagliflozin 400 but not 200 mg compared with placebo in this CKD3 cohort. UACR in patients with at least A2 albuminuria was reduced with each of the two doses at 26 weeks, but changes were not sustained at week 52. The safety findings were consistent with previous reports (NCT03242252). [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium–glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need. [ABSTRACT FROM AUTHOR]

Background Sodium‐glucose co‐transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty‐one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66–0.86]; I2=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57–0.85]; I2=0%)—similar to the effect estimate for patients without AF, P value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.

Glucose is an important energy source for cells. Glucose transport is mediated by two types of glucose transporters: the active sodium-coupled glucose cotransporters (SGLTs), and the passive glucose transporters (GLUTs). Development of an easy way to detect glucose uptake by the cell can be valuable for research. 1-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-1-deoxy-D-glucose (1-NBDG) is a newly synthesized fluorescent glucose analogue. Unlike 2-NBDG, which is a good substrate of GLUTs but not SGLTs, 1-NBDG can be transported by both GLUTs and SGLTs. Thus, 1-NBDG is useful for the screening of SGLT1 and SGLT2 inhibitors. Here we further characterized 1-NBDG and compared it with 2- NBDG. The fluorescence of both 1-NBDG and 2-NBDG was quenched under alkaline conditions, but only 1-NBDG fluorescence could be restored upon neutralization. HPLC analysis revealed that 2-NBDG was decomposed leading to loss of fluorescence, whereas 1-NBDG remained intact in a NaOH solution. Thus, after cellular uptake, 1-NBDG fluorescence can be detected on a plate reader simply by cell lysis in a NaOH solution followed by neutralization with an HCl solution. The fluorescence stability of 1-NBDG was stable for up to 5 h once cells were lysed; however, similar to 2- NBDG, intracellular 1-NBDG was not stable and the fluorescence diminished substantially within one hour. 1-NBDG uptake could also be detected at the single cell level and inhibition of 1-NBDG uptake by SGLT inhibitors could be detected by flow cytometry. Furthermore, 1-NBDG was successfully used in a high-throughput cell-based method to screen for potential SGLT1 and SGLT2 inhibitors. The SGLT inhibitory activities of 67 flavonoids and flavonoid glycosides purified from plants were evaluated and several selective SGLT1, selective SGLT2, as well as dual SGLT1/2 inhibitors were identified. Structure-activity relationship analysis revealed that glycosyl residues were crucial since the aglycon showed no SGLT inhibitory activities. In addition, the sugar inter-linkage and their substitution positions to the aglycon affected not only the inhibitory activities but also the selectivity toward SGLT1 and SGLT2. [ABSTRACT FROM AUTHOR]

Dapagliflozin (SGLT‐2 inhibitor) and sotagliflozin (SGLT1/2 inhibitor) are two of the drugs of SGLT inhibitor class which have been recommended by the National Institute for Health and Care Excellence (NICE) in people with type 1 diabetes with BMI ≥27 kg/m2. Dapagliflozin is licensed in the UK for use in the NHS while sotagliflozin may be available in future. These and possibly other SGLT inhibitors may be increasingly used in people with type 1 diabetes as new licences are obtained. These drugs have the potential to improve glycaemic control in people with type 1 diabetes with the added benefit of weight loss, better control of blood pressure and more time in optimal glucose range. However, SGLT inhibitors are associated with a higher incidence of diabetic ketoacidosis without significant hyperglycaemia. The present ABCD/Diabetes UK joint updated position statement is to guide people with type 1 diabetes and clinicians using these drugs help mitigate this risk and other potential complications. Particularly, caution needs to be exercised in people who are at risk of diabetic ketoacidosis due to low calorie diets, illnesses, injuries, starvation, excessive exercise, excessive alcohol consumption and reduced insulin administration among other precipitating factors for diabetic ketoacidosis. [ABSTRACT FROM AUTHOR]

Objective: Despite improvements in glucose monitoring technologies, insulin formulations and insulin delivery systems, too many patients with type 1 diabetes (T1D) continue to struggle to meet their glycemic goals. As a result, they suffer from high rates of microvascular and macrovascular disease. Titration of insulin therapy, while essential to the care of these patients, is often limited by undesirable side effects of hypoglycemia and weight gain. Sodium-glucose cotransporter (SGLT) inhibitors have been proposed as a potential adjunctive therapy to insulin that may offset some of these effects, while simultaneously enabling patients with T1D to potentially reap the cardiovascular and renal benefits afforded by these agents in those with type 2 diabetes. This review summarizes and contextualizes the clinical trial data that has emerged with these agents in this specific population., Methods: A clinical review based on current literature was generated by the authors., Results: This review summarizes the data from several clinical trial programs investigating the use of SGLT inhibitors in T1D, describing the potential benefits and the ketosis-related adverse events of these agents (including euglycemic DKA), along with a discussion of possible mitigation strategies to reduce this risk., Conclusion: Although theoretically SGLT inhibitors have the potential to improve metabolic, cardiovascular, and renal outcomes in patients with T1D, the risks of diabetic ketoacidosis currently represent an important limitation to the widespread use of these agents. If treatment is undertaken, caution must be taken, with implementation of effective mitigation strategies being essential., Competing Interests: Disclosure Silvio Inzucchi received grant funding from NIDDK, consultation fees from clinical trial committees and/or advisory boards (AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Merck, Pfizer, and Bayer), lecture fees from AstraZeneca and Boehringer-Ingelheim. The other author has no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Young adults with type 1 diabetes (T1D) tend to have higher A1C than older adults and are at increased risk for diabetic ketoacidosis (DKA). Oral adjuncts to insulin have not been previously studied in this population. Methods: In this phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults aged 18-30 years with T1D and A1C ≥9.0% were randomly assigned to placebo (n = 42) or sotagliflozin 400 mg (n = 43), in addition to insulin for 12 weeks. Insulin doses were adjusted to meet glucose targets (preprandial 80-130 mg/dL, postprandial <180 mg/dL). The primary endpoint was change from baseline in A1C at week 12. Results: From a baseline of 9.8%, mean A1C decreased by 1.0% with placebo and 1.3% with sotagliflozin (-0.4% [95% confidence interval (CI): -0.8 to 0.1]; P = 0.10 vs. placebo). In the prespecified A1C ≤10.0% subgroup, the treatment difference was -0.8% (-1.3 to -0.2; P = 0.006), favoring sotagliflozin. Overall, relative to placebo, postprandial glucose (PPG) decreased by 56.6 mg/dL (-89.7 to -23.6; P < 0.001) and weight decreased by 2.37 kg (-3.5 to -1.2; P < 0.001). More patients achieved an A1C <7.0% with sotagliflozin (16.3%) than placebo (2.4%; P = 0.026). Rates of documented hypoglycemia and severe hypoglycemia were similar between groups. One DKA event occurred with placebo, and none occurred with sotagliflozin. Conclusions: In young adults with T1D and suboptimal glycemic control, sotagliflozin plus insulin for 12 weeks numerically improved A1C and significantly improved A1C goal attainment, PPG, and body weight. Sotagliflozin plus insulin was generally well tolerated without any episodes of DKA (NCT02383940). [ABSTRACT FROM AUTHOR]

In spite of developments with novel insulin preparations, novel modes of insulin delivery with insulin infusion pumps, and the facility of continuous glucose monitoring, only 20% of patients with type 1 diabetes are under adequate control. The need for innovation is clear, and, therefore, the use of adjunct therapies with other pharmacological agents currently in use for type 2 diabetes, has been tried. Currently, pramlintide is the only agent licensed for use in this condition in addition to insulin. Global trials have been conducted with liraglutide, a glucagon‐like peptide 1 receptor agonist (GLP‐1RA), dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, and sotagliflozin, an inhibitor of both SGLT1 and SGLT2 transporters. While dapagliflozin and sotagliflozin have now been licensed for clinical use in this condition in Europe and Japan, they have hitherto not been licensed in the United States due to a small increase in the risk of diabetic ketoacidosis. However, these agents reduce glycosylated hemoglobin (HbA1c) by 0.4%, reduce glycemic oscillations, and do not increase the risk of hypoglycemia. Liraglutide, on the other hand, induced a smaller reduction in HbA1c and thus was not considered for a license. However, further trials are currently being conducted with a combination of semaglutide, the most potent GLP‐1RA, and dapagliflozin to determine whether this approach would yield better outcomes. [ABSTRACT FROM AUTHOR]

Introduction Sodium-glucose co-transporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are novel antihyperglycemic agents that reduce cardiovascular mortality through insulin-independent mechanisms. In this cross-sectional study, we investigated prescription patterns of these drugs and identified inequities in antihyperglycemic utilization. Methods Unique encounters for diabetes care between January 1, 2020, and December 31, 2020, were identified through a systematic query of our healthcare system's database. All patients ≥18 years old with a hemoglobin A1C level of ≥8% were included in the sample. Demographic data, SGLT2I or GLP-1RA prescription status, diabetes-related complications, and mortality were abstracted. Results A total of 2,746 patients were included in the sample. Among these individuals, 670 (24.4%) were prescribed either an SGLT2I or a GLP-1RA (users) and 2,076 (75.6%) were not prescribed either agent (non-users). There were significantly more males than females in the cohort, but there was no significant difference in the sex distribution between users and non-users. Compared to non-users, users were younger (mean age of 65.1 ± 9.4 years versus 66.4 ± 9.9 years, p-value = 0.005), more likely to be non-Hispanic (86.3% versus 13.7%), more likely to live in a middle-income zip code, and have private insurance. The mortality rate was lower among users when compared to non-users, but the difference did not reach statistical significance (2.7% versus 5.5%, p-value = 0.62). SGLT2I use was associated with a 60% lower risk of mortality. Conclusion Ethnicity, median household income, and insurance type influence the likelihood of being prescribed an SGLT2I or a GLP-1RA. Individuals prescribed either agent appear to have better mortality outcomes than those prescribed other medications. Further investigation may reveal underlying causes and potential solutions for disparities in prescription patterns., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Antwi-Amoabeng et al.)

Recent phase 3 clinical trials have evaluated the impact of adding sodium‐glucose co‐transporter (SGLT) inhibitors to the type 1 diabetes armamentarium. These trials studied SGLT2 inhibitors (dapagliflozin and empagliflozin) and a dual SGLT1 and SGLT2 inhibitor (sotagliflozin), and demonstrated that these oral non‐insulin antihyperglycaemic medications are able not only to improve glycaemic control, but also to reduce body weight and extend time in range without increasing rates of hypoglycaemia in type 1 diabetes. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes and the risk is increased when SGLT inhibitors are used in type 1 diabetes. To minimize the risk of DKA and still gain the multiple benefits, we developed the "STOP DKA Protocol ", an easily accessible and practical tool, that provides a risk mitigation strategy for reducing DKA in patients with type 1 diabetes being treated with SGLT inhibitors. [ABSTRACT FROM AUTHOR]

Glucose, the key source of metabolic energy, is imported into cells by two categories of transporters: 1) facilitative glucose transporters (GLUTs) and 2) secondary active sodium-glucose cotransporters (SGLTs). Cancer cells have an increased demand for glucose uptake and utilisation compared to normal cells. Previous studies have demonstrated the overexpression of GLUTs, mainly GLUT1, in many cancer types. As the current standard positron emission tomography (PET) tracer 2-deoxy-2-(18F)fluoro-D-glucose (2-FDG) for imaging tumour cells via GLUT1 lacks in sensitivity and specificity, it may soon be replaced by the newly designed, highly sensitive and specific SGLT tracer α-methyl-4-(F-18)fluoro-4-deoxy-Dglucopyranoside (Me-4FDG) in clinical detection and tumour staging. This tracer has recently demonstrated the functional activity of SGLT in pancreatic, prostate, and brain cancers. The mRNA and protein expression of SGLTs have also been reported in colon/colorectal, lung, ovarian, head, neck, and oral squamous carcinomas. So far, SGLTs have been poorly investigated in cancer, and their protein expression and localisation are often controversial due to a lack of specific SGLT antibodies. In this review, we describe current knowledge concerning SGLT1 and SGLT2 (over)expression in various cancer types. The findings of SGLTs in malignant cells may help in developing novel cancer therapies with SGLT2 or SGLT1/SGLT2 inhibitors already used in diabetes mellitus treatment. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is the leading cause of cardiovascular morbidity and mortality. Phlorizin (PHLOR) and quercetin-3-O-glucoside (QUER-3-G) are two natural compounds reported to have antidiabetic properties by inhibiting sodium/glucose transporters. Their effects on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin (STZ)-induced diabetic rats were investigated. Video edge detection and fluorescence photometry were used to measure ventricular myocyte shortening and intracellular Ca2+, respectively. Blood glucose in STZ rats was 4-fold higher (469.64±22.23 mg/dl, n=14) than in Controls (104.06±3.36 mg/dl, n=16). The amplitude of shortening was reduced by PHLOR in STZ (84.76±2.91 %, n=20) and Control (83.72±2.65 %, n=23) myocytes, and by QUER-3-G in STZ (79.12±2.28 %, n=20) and Control (76.69±1.92 %, n=30) myocytes. The amplitude of intracellular Ca2+ was also reduced by PHLOR in STZ (82.37±3.16 %, n=16) and Control (73.94±5.22 %, n=21) myocytes, and by QUER-3-G in STZ (73.62±5.83 %, n=18) and Control (78.32±3.54 %, n=41) myocytes. Myofilament sensitivity to Ca2+ was not significantly altered by PHLOR; however, it was reduced by QUER-3-G modestly in STZ myocytes and significantly in Controls. PHLOR and QUER-3-G did not significantly alter sarcoplasmic reticulum Ca2+ in STZ or Control myocytes. Altered mechanisms of Ca2+ transport partly underlie PHLOR and QUER-3-G negative inotropic effects in ventricular myocytes from STZ and Control rats. [ABSTRACT FROM AUTHOR]