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Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (P trend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934) [ABSTRACT FROM AUTHOR]

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1–3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03–0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment. [ABSTRACT FROM AUTHOR]

Objective: To describe the pharmacology, clinical efficacy, and safety evidence of sotagliflozin, the first approved dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in heart failure (HF) management. Data sources: A literature search of studies published between January 2012 and September 2023 were identified using PubMed, MEDLINE, and clinicaltrials.gov with search terms of "sotagliflozin," "Inpefa," or "LX4211." Study selection and data extraction: All available studies in English were considered. Studies were included if they investigated drug pharmacology, efficacy, or safety information. Data synthesis: Two phase 3 trials of sotagliflozin, SOLOIST-WHF and SCORED, evaluated sotagliflozin compared with placebo in patients with type 2 diabetes mellitus (T2DM). SOLOIST-WHF reported a statistically decreased rate of cardiovascular and HF events with sotagliflozin (hazard ratio [HR] = 0.67, 95% CI = 0.52-0.85), while SCORED found a statistically significant decrease in incidence of cardiovascular events in patients with T2DM, chronic kidney disease (CKD), and risk factors for cardiovascular disease in patients in the sotagliflozin group (HR = 0.74, 95% CI = 0.63-0.88). Relevance to patient care and clinical practice in comparison to existing agents: While approval of sotagliflozin expands treatment options for patients with HF, the SGLT2 inhibitors, dapagliflozin and empagliflozin, have more data supporting their use in HF, additional risk reduction benefits in patients with CKD, and approval for use in T2DM. Landmark trials of sotagliflozin required a previous diagnosis of T2DM, despite the broader approved indication. Where sotagliflozin will be adopted into the treatment of HF is unclear due to the evidence and benefits of already established SGLT2 inhibitors and the need for comparison with SGLT2 inhibitors. Conclusion: Given the limitations of currently available evidence, including difficulty in fully interpreting the trial results due to changes in primary endpoints, not adjudicating the events, and not reaching the original power calculations, more investigation is warranted to determine the benefit of sotagliflozin compared with SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001 were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.

Sotagliflozin is the first dual SGLT1/2 inhibitor antidiabetic drug approved by the US Food and Drug Administration for the management of heart failure. SGLT1/2 inhibition is observed to potentiate the secretion of the incretin hormone, glucagon‐like peptide‐1 (GLP‐1). The current preclinical research sought to investigate the effect of sotagliflozin on the secretion of fat‐regulating peptides such as GLP‐1, glucagon and fibroblast growth factor 21 (FGF21) and their prospective association with sotagliflozin's potential beneficial effects on dyslipidaemia. During an oral fat tolerance test in mice, sotagliflozin substantially increased GLP‐1 and insulin concentrations. Although sotagliflozin alone did not ameliorate postprandial lipemia, its combination with linagliptin (DPP‐IV inhibitor) significantly improved lipid tolerance comparable to orlistat (lipase inhibitor). In a triton‐induced hypertriglyceridemia model, sotagliflozin, along with other medications (fenofibrate, exenatide and linagliptin) reduced fat excursion; however, co‐administration with linagliptin provided no extra advantage. Furthermore, sotagliflozin stimulated glucagon secretion in the alpha TC1.6 cells and healthy mice, which resulted in an increased circulating FGF21 and β‐hydroxybutyrate concentration. Finally, chronic treatment of sotagliflozin in high‐fat diet (HFD)‐fed obese mice resulted in reduced body weight gain, liver triglyceride, cholesterol, interleukin‐6 (IL‐6) and tumour necrosis factor alpha (TNF‐α) levels compared with the placebo group. However, the addition of linagliptin did not provide any additional benefit. In conclusion, sotagliflozin was found to have an effect on GLP‐1 and also stimulate the release of glucagon and FGF21, which are important for regulating fat metabolism. Therefore, sotagliflozin might represent a potential therapeutic approach for the treatment of diabetic dyslipidemia and steatohepatitis. [ABSTRACT FROM AUTHOR]

Background and aim: Dapagliflozin inhibits the sodium-glucose cotransporter protein 2 (SGLT-2), while sotagliflozin, belonging to a new class of dual-acting SGLT-1/SGLT-2 inhibitors, has garnered considerable attention due to its efficacy and safety. Both Dapagliflozin and sotagliflozin play a significant role in treating worsening heart failure in diabetes/nondiabetes patients with heart failure. Therefore, this article was to analyze and compare the cost per outcome of both drugs in preventing one event in patients diagnosed with diabetes-related heart failure. Method: The Cost Needed to Treat (CNT) was employed to calculate the cost of preventing one event, and the Number Needed to Treat (NNT) represents the anticipated number of patients requiring the intervention treatment to prevent a single adverse event, or the anticipated number of patients needing multiple treatments to achieve a beneficial outcome. The efficacy and safety data were obtained from the results of two published clinical trials, DAPA-HF and SOLOISTWHF. Due to the temporal difference in the drugs' releases, we temporarily analyzed the price of dapagliflozin to calculate the price of sotagliflozin within the same timeframe. The secondary analyses aimed to assess the stability of the CNT study and minimize differences between the results of the RCT control and trial groups, employing one-way sensitivity analyses. Result: The final results revealed an annualized Number Needed to Treat (aNNT) of 4 (95% CI 3-7) for preventing one event with sotagliflozin, as opposed to 23 (95% CI 16-55) for dapagliflozin. We calculated dapagliflozin's cost per prevented event (CNT) to be $109,043 (95% CI $75,856-$260,755). The price of sotagliflozin was set below $27,260, providing a favorable advantage. Sensitivity analysis suggests that sotagliflozin may hold a cost advantage. Conclusion: In this study, sotagliflozin was observed to exhibit a price advantage over dapagliflozin in preventing one events, cardiovascular mortality, or all-cause mortality in patients with diabetes. [ABSTRACT FROM AUTHOR]

Evidence for reducing cardiovascular and renal events with sotagliflozin is uncertain among type 2 diabetes mellitus (T2DM) patients. To gather more evidence, this meta-analysis assesses the beneficial effects of sotagliflozin, a dual sodium--glucose cotransporter 1 and 2 inhibitor, in reducing the cardiovascular and renal events in diabetic patients with or without chronic kidney disease (CKD). Scopus, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were the databases used to search. The studies published from January 1, 2018, to January 30, 2022, were considered. The eligibility of studies was assessed independently. The data were collected in a modified Cochrane data extraction form. The included studies' quality was assessed with the Cochrane risk-of-bias tool. The quality of evidence for renal and cardiovascular outcomes was evaluated using GRADEpro software. The number of events of urgent visits to the hospital and requiring hospitalization was reduced (RR: 0.73; 95% CI: 0.69, 0.78; P value <0.00001). The mortality rate because of cardiovascular events was decreased with sotagliflozin (RR: 0.73; 95% CI: 0.67, 0.80; P value <0.00001). Patients taking sotagliflozin had a drastic decline in the number of deaths due to stroke and non-fatal myocardial infarction. Yet, there is no difference between the groups in terms of changes in mortality due to other causes or the glomerular filtration rate (GFR). Sotagliflozin demonstrated effectiveness in reducing the mortality rate related to heart failure and cardiovascular events when the dose was increased from 200 mg to 400 mg. Despite this, evidence is still needed to prove the renal protective action. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients.

Aim: To assesses the cost–effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes. Materials & methods: A de novo cost–effectiveness model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin’s efficacy was estimated from SOLOIST-WHF. Health benefits were calculated quality-adjusted life years (QALYs). Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost–effectiveness ratio (ICER). Results: Sotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs 0.153, difference: -0.061) and annualized mortality by 18.0% (0.298 vs 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in QAYs of 0.425 for sotagliflozin versus standard of care. Incremental costs using sotagliflozin increased by $19,374 over a 30-year time horizon of the patient, driven largely by increased pharmaceutical cost. Estimated ICER for sotagliflozin relative to standard of care was $45,596 per QALY. Conclusion: Sotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.

Aim: To investigate the renal safety profile of sotagliflozin, a novel sodium‐glucose co‐transporter‐1 and ‐2 inhibitor, in patients with type 1 diabetes and type 2 diabetes, with or without renal impairment, as well as its efficacy in decreasing the risk of further renal events, with an emphasis on those with previous renal impairment. Methods: Embase, Medline, CENTRAL and Scopus were searched from their inception until 24 April 2023 for randomized controlled trials that reported estimated glomerular filtration rate (eGFR), urinary albumin excretion or composite renal events (CRE). The Cochrane risk of bias 2 tool was used. Mean difference, relative risk (RR) and 95% confidence intervals were estimated (PROSPERO: CRD42023425583). Results: Fourteen studies were included in this review (n = 17 574 participants; intervention n = 9312, control n = 8262). The median follow‐up was 24.5 (Q1 = 15.25, Q3 = 28) months. Four studies recruited participants with renal impairment; baseline eGFR ranged from 23.8 to 50.5 mL/min/1.73m2. The change in eGFR for studies (n = 6) with a follow‐up of 52 weeks or longer was −1.23 (−1.45, −1.01) mL/min/1.73m2. Sotagliflozin did not significantly alter urinary albumin excretion. No change was observed in the risk of CRE (n = 6 studies; RR = 0.82 [0.61, 1.12]), including in participants with renal impairment. High risk of bias was a limitation of this review. Conclusions: Sotagliflozin did not adversely affect renal function or change the risk of key renal outcomes, including for participants with pre‐existing renal impairment. Therefore, sotagliflozin was safe; however, further research is needed to determine its efficacy in reducing the risk of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a highly prevalent disease, among the primary factors contributing to morbidity and death. One of its types is heart failure with preserved ejection fraction (HFpEF) comprising 40%–50% of newly diagnosed HF cases. Despite the high prevalence of HFpEF, there is still a lack of knowledge regarding the best drugs and treatment approaches to be used. However, the sodium-glucose co-transporter 2 (SGLT2) inhibitors could be a promising treatment. Objectives: To examine SGLT2 inhibitors' effect on hospitalization, cardiovascular death, and estimated glomerular filtration rate (eGFR) in HFpEF patients. Search methods: We conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, Scopus, and Web of Science up to July 2024. Selection criteria: We chose RCTs that examined the effects of SGLT2 inhibitors and placebo in individuals with higher than 40% ejection fraction (HFpEF). Data collection and analysis: The methodology for the systematic review and meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Main results: We included 8 studies with 16,509 participants. Drugs examined in our paper included empagliflozin, dapagliflozin, sotogliflozin, and ertugliflozin. Various outcomes were analyzed in different papers. However, different SGLT2 inhibitors lead to a decreased risk of cardiovascular hospitalization and kidney injury. Our meta-analysis showed a decreased risk of cardiovascular hospitalization but not death due to cardiovascular causes or other causes. These results were regardless of baseline status of eGFR, systolic blood pressure, atrial fibrillation or flutter, diabetes mellitus, sex, body mass index, and nt-proBNP. The included studies were of moderate to high quality. Conclusion: For individuals with HFpEF, SGLT2 inhibitors have been proven to be a safe and effective medication. However, more studies are needed for longer durations, reporting adverse events, effects on exercise tolerance, and other secondary outcomes. [ABSTRACT FROM AUTHOR]

Background: As an antidiabetic agent, sotagliflozin was recently approved for heart failure (HF). However, its cardiovascular benefits in type 2 diabetic mellitus (T2DM) patients with HF or cardiovascular (CV) risk factors have not been systematically evaluated. The aim of this study is to evaluate the cardiovascular benefits and safety of sotagliflozin in T2DM patients with HF or CV risk factors using Bayesian network meta-analysis. Methods: Data were retrieved from PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library from their inception to 16 August 2023. Randomized controlled trials (RCTs) comparing sotagliflozin with a placebo, dapagliflozin, and empagliflozin in adult T2DM patients with HF or CV risks for at least 12 weeks were included in the study. Data analysis was conducted using R 4.2.3 and Stata 17.0. Cardiovascular efficacy outcomes included HF events (hospitalization or urgent visits for HF), MACE (deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and strokes), cardiovascular death, the decrease in SBP, and weight loss. Safety outcomes are urinary tract infection, diarrhea, and diabetic ketoacidosis. Results: Eleven studies with 30,952 patients were included. Compared to dapagliflozin and empagliflozin, 200 mg of sotagliflozin showed the best effect in reducing HF events [OR (95% CI), 0.79 (0.66, 0.94) and 0.90 (0.63, 1.27)]. Compared to dapagliflozin, 200 mg of sotagliflozin [OR (95% CI), 0.76 (0.66, 0.87)] was superior in preventing MACE. Compared to empagliflozin, 200 mg of sotagliflozin [OR (95% CI), 1.46 (1.04, 2.05)] was inferior in preventing CV death. Sotagliflozin showed a poorer SBP decreasing effect than empagliflozin and dapagliflozin [MD (95% CI), 1.30 (0.03, 2.56) and 2.25 (0.35, 4.14), respectively]. There was no significant difference between sotagliflozin and other interventions in weight loss. Sotagliflozin exhibited no increased risk for diabetic ketoacidosis or urinary tract infection among all interventions, however, it showed a mild risk for diarrhea than placebo [OR (95% CI), 1.47 (1.28, 1.69)]. Conclusion: Sotagliflozin displayed moderate CV benefits and acceptable safety. Sotagliflozin can be one of the recommended options for T2DM patients with HF or CV risk factors, which will be important for evidence-based use of sotagliflozin as well as decision-making of T2DM medication. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a chronic disorder that decreases heart function and causes a person to be less tolerant to exercise, have a lower quality of life, and prone to death. Novel therapeutic strategies are still needed despite improvements in HF management. Sotagliflozin is a promising medication for the treatment of HF, which is a dual sodium-glucose cotransporter 1 as well as 2 (SGLT1 and SGLT2) inhibitor. The purpose of this in-depth study is to assess sotagliflozin's effectiveness and safety in the treatment of HF. The effects of sotagliflozin on different facets of HF pathophysiology, such as blood flow, myocardial remodeling, and neurohormonal stimulation, are discussed in preclinical and clinical investigations. Sotagliflozin has been shown to be effective in lowering the risk of HF hospitalization and heart attack in patients with HF with either type 2 diabetic mellitus (T2DM) and chronic kidney disease (CKD), according to numerous randomized trials, including the most recent SOLOIST-WHF or SCORED trials. Sotagliflozin's simultaneous inhibition of SGLT1 along with SGLT2 creates a special pharmacological profile that addresses both the metabolic as well as non-metabolic problems seen in HF. This review provides a comprehensive summary of various aspects related to sotagliflozin and heart failure, including the pathophysiology in heart failure, US-FDA approved treatment for HF, mechanism of action, pharmacokinetic, pharmacodynamics data of sotagliflozin, reported adverse drug reactions (ADRs), and ongoing clinical trials.

The SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trials demonstrated that sotagliflozin, an SGLT1 and SGLT2 inhibitor, improves outcomes in individuals with type 2 diabetes who have heart failure (HF) or kidney disease. We assessed the efficacy of sotagliflozin on HF clinical outcomes in individuals with differing baseline glycosylated hemoglobin (HbA1c) levels. We included all adults from SCORED and SOLOIST-WHF. The primary outcome was a composite of cardiovascular death, hospitalizations for HF, and urgent visits for HF. The efficacy of sotagliflozin compared with placebo was evaluated by baseline HbA1c using competing-risk marginal proportional hazards models. We identified 11,744 adults. Individuals with HbA1c ≤7.5% experienced the primary outcome at a lower rate in the sotagliflozin group (11.2 per 100 person-years) than the placebo group (15.5 per 100 person-years) (HR: 0.73; 95% CI: 0.57-0.93). Similarly, individuals with HbA1c of 7.6% to 9.0% experienced the primary outcome at a lower rate in the sotagliflozin group (7.3 per 100 person-years) than the placebo group (9.4 per 100 person-years) (HR: 0.77; 95% CI: 0.63-0.96). These findings were also consistent among individuals with HbA1c >9.0%, with a primary outcome rate in the sotagliflozin group (7.8 per 100 person-years) that was lower than the placebo group (11.6 per 100 person-years) (HR: 0.65; 95% CI: 0.50-0.84). The efficacy of sotagliflozin was consistent by baseline HbA1c level (P for interaction = 0.58). In individuals with type 2 diabetes and either HF or kidney disease, sotagliflozin reduced HF outcomes irrespective of baseline HbA1c. [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug–drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. Literature-search-terms in PubMed were 'adverse event/drug–drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.' AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months. DDI were mainly studied in healthy volunteers for 3–8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable. [ABSTRACT FROM AUTHOR]

Aim: To compare the relative effects of different dosages of sodium-glucose cotransport inhibitors (SGLT2i) for renoprotection in Type 2 diabetes mellitus. Methods: The study searched different databases (PubMed, Embase, Scopus, and Web of Science) for studies comparing dose-dependent renoprotective efficacy defined as a decline in eGFR with the different "-flozins namely Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin and Sotagliflozin. The studies were compared with the Bayesian approach of network meta-analysis coupled with the random-effect model using the Cochrane risk of bias tool (RoB 2.0), and the surface under the cumulative ranking curve (SUCRA) score was allotted to each dosage of different SGLT-2i. Results: A total of 43,434 citations were identified, out of which forty-five randomized trials with 48,067 patients, mentioning the flozin dose and eGFR as an endpoint, were found to be eligible for further analysis. The median duration of the follow-up in the trials was 12 months (IQR 5.5–16 months). Canagliflozin 100 mg demonstrated distinct eGFR benefit with an odds ratio of 2.3 (CI 0.72–3.9) compared to placebo. A statistically non-significant eGFR benefit was observed with all other "-flozins." Canagliflozin 100 mg drug dose category showed the highest sucra rank probability score of 93%, followed by the Canagliflozin 300 mg and Dapagliflozin 5 mg with sucra rank probability scores of 69% and 65%, respectively. The Flozin-dose assessment against eGFR was similar to the albumin-creatinine ratios as the secondary endpoint in the SUCRA ranking. Conclusion: The renoprotective efficacy of SGLT2i is independent of the incremental doses suggesting lower doses may suffice for renal outcomes. [ABSTRACT FROM AUTHOR]

Aim: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41–49%) regardless of baseline diabetes. Methods: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model. Results: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p

Objective: Sotagliflozin is a dual sodium-glucose co-transporter-1 and 2 (SGLT1/2) inhibitor with selectivity towards SGLT2. Previous studies showed that SGLT2 inhibitors can improve cardiac function and reduce myocardial infarction size in animal models of myocardial infarction (MI). However, it remains unknown whether the dual inhibition of SGLT1/2 by sotagliflozin has beneficial effects in this context. In this study, we investigated the potential cardioprotective effects of sotagliflozin in an animal model of MI. Methods: Sprague Dawley (SD) rats underwent left anterior descending coronary artery ligation or sham ligation then were randomly assigned to receive either sotagliflozin (10 mg/kg) or vehicle via intraperitoneal injection. Fourteen days post-MI, we assessed cardiac function using echocardiography and evaluated histological and molecular markers of cardiac remodeling and inflammation in the left ventricle. Results: Our findings indicate that sotagliflozin treatment resulted in improved cardiac function and reduced infarct size compared with the vehicle-treated group. Additionally, sotagliflozin improved cardiac remodeling as shown by the decreased cardiac hypertrophy and cardiac apoptosis in the post-MI heart. Mechanistically, an apparent reduction in the cardiac inflammatory response in sotagliflozin-treated hearts was observed in the post-MI rats. Conclusion: Overall, our results suggest that sotagliflozin may have cardioprotective effects against myocardial infarction.

Purpose This review describes the evidence from randomized controlled trials (RCTs) regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular (CV) clinical outcomes when therapy is initiated during acute heart failure (HF). Summary SGLT2 inhibitors have become a cornerstone of guideline-directed medical therapy (GDMT) for type 2 diabetes mellitus, chronic kidney disease, and HF. Because of their ability to promote natriuresis and diuresis as well as other potentially beneficial CV effects, use of SGLT2 inhibitors has been investigated when therapy is initiated during hospitalization for acute HF. We identified 5 placebo-controlled RCTs that reported CV clinical outcomes incorporating one or more components of all-cause mortality, CV mortality, CV hospitalization, HF worsening, and hospitalization for HF in patients treated with empagliflozin (n = 3 trials), dapagliflozin (n = 1 trial), and sotagliflozin (n = 1 trial). Nearly all CV outcomes in these trials showed benefit with SGLT2 inhibitor use during acute HF. Incidence of hypotension, hypokalemia, and acute renal failure was generally similar to that with placebo. These findings are limited by heterogeneous outcome definitions, variation in time to SGLT2 inhibitor initiation, and small sample sizes. Conclusion SGLT2 inhibitors may have a role in inpatient management of acute HF, provided there is close monitoring for fluctuations in hemodynamic, fluid, and electrolyte status. Initiation of SGLT2 inhibitors at the time of acute HF may promote optimized GDMT, continued medication adherence, and reduced risk of CV outcomes. [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]

Background: Hypoglycemia rates usually increase when insulin treatment is intensified to improve glycemic control. We evaluated (post hoc) hypoglycemic rates in adult patients with type 1 diabetes (T1D) on sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 1 and 2 inhibitor) in two phase 3, 52-week clinical trials (inTandem 1 and 2; NCT02384941 and NCT02421510). Materials and Methods: We analyzed rates of documented hypoglycemia (level 1, blood glucose ≥54 to

Abstract Heart failure with mildly reduced ejection fraction (HFmrEF) is associated with comparable poor outcomes as other subtypes of heart failure and remains a medical unmet need due to the paucity of effective therapies. According to large cardiovascular (CV) outcome trials in patients with heart failure, sodium–glucose co‐transporter‐2 inhibitors (SGLT2is) reduce CV mortality and hospitalizations for heart failure in patients with heart failure across the spectrum of left ventricular ejection fraction (LVEF). There has been a lack of dedicated trials in HFmrEF. However, several large outcome trials in heart failure that enrolled patients with HFmrEF could provide a hint on the role of SGLT2is in this subgroup. This review focuses on CV effects of three major SGLT2is—dapagliflozin, empagliflozin, and sotagliflozin—in patients with HFmrEF. A narrative review of trials investigating the efficacy of each medication in treating heart failure with LVEF > 40% is provided with a focus on their LVEF subgroup analyses. The purpose of this review is to discuss the current state of evidence regarding the potential of SGLT2is in HFmrEF management. Current limited evidence suggests that SGLT2is might be a favourable treatment modality for patients with HFmrEF to reduce hospitalization for heart failure and CV mortality. This conclusion needs to be further supported by clear HFmrEF subgroup analysis of the existing trials. Further outcome trials involving sufficient patients with different subtypes of HFmrEF are needed to confirm and assess CV benefits of SGLT2is in HFmrEF. Possible mechanisms by which SGLT2is exert their cardioprotective effect are also described briefly.

Cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the present work, we derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying disease-causing CFTR mutations. We evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner. Using this assay, we examined the effects of the sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and sotagliflozin on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts. Unexpectedly, both drugs promoted dF/dF HLO swelling. These results reveal SGLTs, especially SGLT1, as potential therapeutic targets for treating CF lung diseases and demonstrate the use of PSC-derived HLOs as a preclinical tool in CF drug development.

Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin–angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a class of oral antiglycemic agents that have emerged as a new therapeutic strategy for heart failure (HF) with reduced ejection fraction (HFrEF) and, potentially, for HF with preserved ejection fraction (HFpEF). Ongoing efforts to clarify the exact mechanisms of action of SGLT2 inhibitors (SGLT2i) reveal that glycosuria and osmotic diuresis, resulting from the blockade of renal receptors, is not the sole pathophysiological mechanism. Nevertheless, the underlying mechanisms, accounting for their cardiovascular beneficial effects which have been clearly demonstrated in clinical trials, remain unclear. The aim of this review is to summarize the primary outcomes of large-scale studies regarding the use of SGLT2i in HF and provide an overview of the potential pathways involved in the SGLT2i-mediated cardioprotection. SGLT2i exhibit favorable pleiotropic effects, which extend beyond their primary indication as pharmaceutical agents intended for glycemic control. Given their unique pathophysiological profile, these agents have revolutionized the management of HF, while in the near future, it is possible that evolving research in the field may unfold further perspectives on their potential use in the treatment of other chronic conditions. [ABSTRACT FROM AUTHOR]

Background: Heart failure is prevalent worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective in heart failure patients with reduced ejection fraction, whether SGLT2i are effective in heart failure with preserved ejection fraction (HFpEF) remains to be determined. Methods: All relevant citations in the PubMed, Embase and Cochrane databases were identified from inception to September, 2022. The primary outcome was a composite endpoint of cardiovascular death and hospitalization for heart failure (HHF). A subgroup analysis was performed according to diabetes mellitus status and the ejection fraction. Secondary endpoints were cardiovascular death, hospitalization for heart failure and all cause death. Results: Seven studies involving 11,604 patients were included in the metaanalysis. Compared with placebo, sodium-glucose cotransporter 2 inhibitors reduced the incidence of the primary outcome by 24%, with an odds ratio (OR) and 95% confidence interval (CI) 0.76 [0.69, 0.84]. For secondary outcomes, sodium-glucose cotransporter 2 inhibitors were associated with a lower incidence of hospitalization for heart failure, but not cardiovascular or all-cause death; the OR and 95% CI were 0.73 [0.66, 0.82], 0.92 [0.81, 1.04], 0.96 [0.88, 1.05], respectively. Conclusions: This study proves the clinical efficacy of SGLT2i for treatment of HFpEF patients with or without diabetes, which was mainly driven by prevention of HHF rather than cardiovascular or all-cause death. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter inhibitors (SGLT2i) are emerging as a new treatment for heart failure (HF) after demonstrating favorable clinical outcomes in several randomized controlled trials (RCTs). In this meta-analysis, we assessed the safety of SGLT2i in the trials that prespecified heart failure in their inclusion criteria. We searched the databases for RCTs comparing SGLT2i to placebo in heart failure patients. The primary outcome was the incidence of serious adverse events (SAEs). A sensitivity analysis according to the class of HF was also performed. The incidence of SAEs was significantly lower in the SGLT2i group (OR, 0.85; 95% CI, 0.77–0.92; P, 0.0002) and SAEs remained significantly lower after performing the sensitivity analysis (OR, 0.82; 95% CI, 0.75–0.89; P, <0.00001). Genital infections, urinary tract infections (UTIs), and hypotension were significantly higher in the SGLT2i group. SGLT2i remain a safe option for patients with HF with a lower incidence of SAEs. However, since they increase the risk of genital infection, UTIs and hypotension, the risks vs benefits in each patient should be weighed when making a prescribing decision. • SGLT2i are associated with lower SAEs and higher incidence of genital infections, UTIs, and hypotension. [ABSTRACT FROM AUTHOR]

Background: Diabetesmellitus (DM) is a global health problem, and it has become a shocking threat in the contemporary era. The objective of this study was to analyze the safety of sotagliflozin in patients with DM systematically and intuitively. Methods: On November 15, 2021, literature retrieval was performed on PubMed, Web of Science, EBSCO, and Cochrane libraries. The meta-analysis results included genital mycotic infection, related-to-acidosis events, and other related adverse events, including diarrhea, severe nocturnal hypoglycemia event, and volume depletion. In addition, a subgroup analysis was also conducted based on different doses of sotagliflozin. Moreover, the patient-treated years analyzed in the study were 12 weeks, 24 weeks, and 52 weeks, respectively, for type 1 diabetes, and were 12 weeks, 22 weeks, and 52 weeks, respectively, for type 2 diabetes. Results: The results of this meta-analysis illustrated that sotagliflozin could increase the risk of genital mycotic infection for patients with T1D and T2D (RR: 3.49, 95% Cl: 2.54-4.79, p < 0.001; RR: 2.83, 95% Cl: 2.04-3.93, p < 0.001; respectively). In addition, the subgroup analysis showed that the drug doses that could increase the risk of genital mycotic infection were 400 mg and 200 mg (RR: 3.63, 95% Cl: 2.46-5.36, p < 0.001; RR: 3.21, 95% Cl: 1.84-5.62, p < 0.001; respectively) in T1D. Moreover, sotagliflozin could increase the risk of events related to acidosis in the patients of T1D, including acidosis-related adverse events, positively adjudicated diabetic ketoacidosis, acidosis-related event, and diabetic ketoacidosis (RR: 7.49, 95% Cl: 3.20-17.52, p < 0.001; RR: 6.05, 95% Cl: 2.56-14.30, p < 0.001; RR: 4.83, 95% Cl: 3.13-7.45, p < 0.001; RR: 8.12, 95% Cl: 3.06-21.52, p < 0.001; respectively). In the patients of T2D, sotagliflozin could not increase the risk of DKA (RR: 1.30, 95% Cl: 0.34-4.99, p = 0.70). About serious of acidosis-related adverse events, positively adjudicated diabetic ketoacidosis (DKA) and acidosis-related event, the included studies were not reported for T2D patients. As for the other related adverse events, sotagliflozin was found to be a risk factor for diarrhea and volume depletion in T1D patients (RR: 1.44, 95% Cl: 1.09-1.90, p = 0.01; RR: 2.50, 95% Cl: 1.33-4.69, p < 0.01; respectively) and T2D patients (RR: 1.44, 95% Cl: 1.26-1.64, p < 0.001; RR: 1.25, 95% Cl: 1.07-1.45, p < 0.01; respectively). Conclusions: This meta-analysis showed that the adverse events of sotagliflozin were tolerable to patients with DM, in terms of the incidence of genital mycotic infection, related-to-acidosis events, diarrhea, volume depletion, and severe nocturnal hypoglycemia events. In addition, the subgroup analysis of sotagliflozin dosage is considered to have great clinical significance for future guidance of sotagliflozin application in patients with DM. [ABSTRACT FROM AUTHOR]

A new post hoc analysis of the SCORED phase 3 clinical trial reveals that sotagliflozin (Inpefa, Lexicon Pharmaceuticals) provides kidney protection for adults with diabetes and chronic kidney disease (CKD) across various baseline kidney function and glycemic control levels. The study, to be presented at Kidney Week 2024, included 10,584 adults with type 2 diabetes and CKD who were treated with sotagliflozin or a placebo. Sotagliflozin, a dual sodium glucose cotransporter (SGLT)-1 and SGLT-2 inhibitor, demonstrated a lower risk of cardiovascular events and improved kidney function compared to the placebo. [Extracted from the article]

Heart failure with mildly reduced ejection fraction (HFmrEF) is associated with comparable poor outcomes as other subtypes of heart failure and remains a medical unmet need due to the paucity of effective therapies. According to large cardiovascular (CV) outcome trials in patients with heart failure, sodium–glucose co‐transporter‐2 inhibitors (SGLT2is) reduce CV mortality and hospitalizations for heart failure in patients with heart failure across the spectrum of left ventricular ejection fraction (LVEF). There has been a lack of dedicated trials in HFmrEF. However, several large outcome trials in heart failure that enrolled patients with HFmrEF could provide a hint on the role of SGLT2is in this subgroup. This review focuses on CV effects of three major SGLT2is—dapagliflozin, empagliflozin, and sotagliflozin—in patients with HFmrEF. A narrative review of trials investigating the efficacy of each medication in treating heart failure with LVEF > 40% is provided with a focus on their LVEF subgroup analyses. The purpose of this review is to discuss the current state of evidence regarding the potential of SGLT2is in HFmrEF management. Current limited evidence suggests that SGLT2is might be a favourable treatment modality for patients with HFmrEF to reduce hospitalization for heart failure and CV mortality. This conclusion needs to be further supported by clear HFmrEF subgroup analysis of the existing trials. Further outcome trials involving sufficient patients with different subtypes of HFmrEF are needed to confirm and assess CV benefits of SGLT2is in HFmrEF. Possible mechanisms by which SGLT2is exert their cardioprotective effect are also described briefly. [ABSTRACT FROM AUTHOR]

Purpose of Review: Focused review highlighting select studies presented at the 2022 American College of Cardiology (ACC) Scientific Sessions. Recent Findings: Included studies assessed the impact of a low-sodium diet on heart failure outcomes (SODIUM-HF); outcomes of pregnant patients with chronic hypertension treated with antihypertensive therapies (CHAP); cardiovascular outcomes in patients with type 2 diabetes and renal impairment treated with sotagliflozin (SCORED); a safety and efficacy study investigating SLN360, a short interfering RNA targeting lipoprotein(a) (APOLLO); a supermarket and web-based intervention targeting nutrition for cardiovascular risk reduction (SuperWIN); a superiority trial comparing myocardial injury following very mild perioperative hypothermia versus aggressive warming after non-cardiac surgery (PROTECT); and 3-year efficacy outcomes of renal denervation on blood pressure reduction from the SPYRAL HTN-ON MED pilot study. Summary: Research presented at the 2022 ACC Scientific Sessions underscores the new potential and meaningful impact of cardiovascular disease prevention and management interventions. [ABSTRACT FROM AUTHOR]

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Sodium-glucose co-transporters (SGLTs) mediate sodium and glucose transport across cell membranes. SGLT2 inhibitors have a recognized place within heart failure (HF) guidelines. We evaluated the effect of sotagliflozin on HF and cardiovascular outcomes in participants with type 2 diabetes. Scopus, Medline, Embase and Central were searched from inception until 2 June 2023. Randomized controlled trials evaluating sotagliflozin in type 2 diabetes participants and reporting HF events were selected. Major adverse cardiovascular events (MACE) and systolic blood pressure were evaluated. The Cochrane risk of bias tool (RoB 2.0) was used. Pooled mean difference (MD), relative risk (RR), 95% confidence intervals and the number needed to treat (NNT) were estimated (PROSPERO: CRD42023432732). We selected nine studies (n = 15 320 participants: n = 8040 intervention and n = 7280 control). The median follow-up was 13.4 months (Q1 = 13, Q3 = 21). One study recruited participants with HF at baseline. After a follow-up of >52 weeks, sotagliflozin significantly reduced the risk of HF [n = 8 studies; RR = 0.66 (0.64, 0.69)], stroke [n = 6 studies; RR = 0.75 (0.58, 0.97)] and MACE [n = 8 studies; RR = 0.73 (0.66, 0.81)]. The NNT was 20 and 26 for HF and MACE, respectively. Sotagliflozin lowered systolic blood pressure [n = 7; MD = -2.38 mmHg (-2.79, -1.97)]. No dose-dependent effect was identified for HF [200 mg: RR = 0.38 (0.16, 0.89), 400 mg: RR = 0.57 (0.39, 0.85), P-value = 0.22]. The high risk of bias was a limitation of this review. Sotagliflozin reduced HF and cardiovascular events in type 2 diabetes participants. Research exploring its effects in HF and comparisons with SGLT2 inhibitors is warranted to determine if dual SGLT inhibition surpasses selective inhibition., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Despite the availability of established treatments, heart failure (HF) is associated with a poor prognosis and its management is suboptimal, highlighting the need for new options for treatment and prevention. Patients with type 2 diabetes (T2D) often experience cardiovascular (CV) complications, with HF being one of the most frequent. Consequently, several CV outcome trials have focused on glucose-lowering therapies and their impact on CV outcomes. An established treatment for T2D, sodium-glucose cotransporter-2 inhibitors (SGLT-2is; canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) have demonstrated beneficial effects on CV outcomes in long-term studies of patients with T2D with established CV disease and/or a broad range of CV risk factors. Recent studies have extended these findings to patients with HF, with and without T2D, finding that SGLT-2is (particularly dapagliflozin and empagliflozin) are effective therapeutic interventions for the treatment and prevention of HF. This narrative review article discusses the use of SGLT-2is in the treatment and prevention of HF in patients with and without T2D. Dapagliflozin was the first SGLT-2i to receive US Food and Drug Administration (FDA) approval for treatment of HF, to reduce the risk of CV death and hospitalization for HF in adults with HF with reduced ejection fraction (HFrEF) with and without T2D. Recently, the FDA also approved empagliflozin for this indication. Given the new HFrEF indications for dapagliflozin and empagliflozin, and the likelihood of similar approvals for other SGLT-2is, cardiology guidelines are beginning to integrate SGLT-2is into a standard-of-care treatment regimen for patients with HFrEF. The utility of SGLT-2is in HF with preserved EF (HFpEF) shows promise based on data from the EMPEROR-Preserved study of empagliflozin in patients with HFpEF. Further clinical trial evidence may lead to more widespread use and further integration of SGLT-2is into standard-of-care regimens for the treatment and management of HF in patients with and without T2D. Plain Language Summary: Heart failure is a medical condition in which the heart cannot pump enough blood. Several types of drugs have been used to treat heart failure, but these may not work for every patient, and heart failure can get worse over time even with treatment. That is why new drugs are needed to treat and prevent heart failure. People with diabetes (type 2 diabetes) often have other conditions related to the heart (cardiovascular system), heart failure being one of the most common. Because of this, there have been studies (clinical trials) in people with diabetes to see if diabetes drugs can also treat and/or reduce the risk of cardiovascular disease. In clinical trials, a type of diabetes drug, sodium-glucose cotransporter-2 inhibitors (SGLT-2is, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), has helped people with both diabetes and cardiovascular disease. Recent clinical trials of dapagliflozin and empagliflozin showed they were effective for treating and preventing heart failure in people without diabetes as well as in those with diabetes. Based on these studies, the US Food and Drug Administration approved dapagliflozin and empagliflozin for heart failure in patients with or without diabetes. These drugs can be prescribed for adults with or without diabetes to treat and prevent a type of heart failure, heart failure with reduced ejection fraction, in which the heart is too weak to pump enough blood to the body. Several clinical studies are ongoing that will provide more information about these drugs, SGLT-2is, which will help healthcare providers to treat people with heart failure. [ABSTRACT FROM AUTHOR]

The present meta-analysis included 8 cardiovascular outcome trials with 57,185 patients at high cardiometabolic risk. In comparison with placebo, treatment with sodium-glucose cotransporter inhibitors was associated with a significantly lower risk of pneumonia (RR 0.85, 95% CI 0.76–0.95, p = 0.004; I2 = 0, p = 0.48). [ABSTRACT FROM AUTHOR]

Aims: To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium‐glucose cotransporter‐1 and ‐2, in adults with type 2 diabetes (T2D) and stage 4 chronic kidney disease (CKD4). Materials and Methods: This 52‐week, phase 3, randomized (1:1:1), placebo‐controlled trial evaluated sotagliflozin 200 mg and sotagliflozin 400 mg once daily in 277 patients with T2D and estimated glomerular filtration rate (eGFR) 15 to 30 mL/min/1.73 m2. The primary endpoint was glycated haemoglobin (HbA1c) reduction with sotagliflozin 400 mg versus placebo at 26 weeks. A hierarchical statistical testing approach was used. Results: The baseline mean HbA1c was 65 ± 12 mmol/mol (8.1% ± 1.1%), systolic blood pressure (SBP) was 144 ± 15 mmHg, and eGFR was 24 ± 4 mL/min/1.73m2. Placebo‐adjusted changes with sotagliflozin 400 mg were –3 mmol/mol (−0.3%; 95% confidence interval –7 to 0.6 [−0.6 to 0.05]; P = 0.096) and –8 mmol/mol (−0.7%; –13 to –3 [−1.2 to −0.2]; P = 0.003) in HbA1c at Weeks 26 and 52, respectively, −1.5 kg (−3.0 to −0.1) in body weight at Week 26, −5.4 mmHg (−9.4 to −1.3) in SBP at Week 12, and −0.3 mL/min/1.73 m2 (−2.1 to 1.6; P = 0.776) in eGFR at Week 52. Over 52 weeks, 11.8%, 5.4% and 3.3% of patients receiving placebo and sotagliflozin 200 and 400 mg, respectively, required rescue therapy for hyperglycaemia. Adverse events (AEs) occurred in 82.8%, 86.2% and 81.1% of patients and serious cardiovascular AEs occurred in 12.9%, 3.2% and 4.4% of patients in the placebo and sotagliflozin 200 and 400 mg groups, respectively. Conclusions: After 26 weeks, HbA1c reductions with sotagliflozin were not statistically significant versus placebo in adults with T2D and CKD4. The 52‐week safety profile was consistent with results of the SCORED outcomes trial (NCT03242018). [ABSTRACT FROM AUTHOR]

Results from recent randomized controlled trials on inhibitors of the sodium-glucose cotransporter 2 (SGLT2) have determined a paradigm shift in the treatment of patients with type 2 diabetes mellitus. These agents have been shown not only to ameliorate metabolic control, but also to independently protect from cardiovascular events and to reduce the progression of chronic kidney disease (CKD) in these patients. The magnitude of the nephroprotective effect observed in these studies is likely to make SGLT2 inhibitors the most impactful drug class for the treatment of diabetic patients with CKD since the discovery of renin–angiotensin system inhibitors. Even more surprisingly, SGLT2 inhibitors have also been shown to slow CKD progression in non-diabetic individuals with varying degrees of proteinuria, suggesting that activation of SGLT2 is involved in the pathogenesis of CKD independent of its etiology. As indications continue to expand, it is still unclear whether the observed benefits of SGLT2 inhibitors may extend to CKD patients at lower risk of progression and if their association with other agents may confer additional protection.

Background: Diabetic retinopathy (DR) is a major cause of blindness globally. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have been demonstrated to exert cardiorenal protection in patients with diabetes. However, their potential beneficial effect on DR is less well studied. The aim of the present study was to determine the effects of the SGLT2 inhibition with Dapagliflozin (DAPA) on DR in well-characterised DR mouse models and controls. Methods: Dapagliflozin was administered to mice with and without diabetes for 8 weeks via their drinking water at 25 mg/kg/day. Urine glucose levels were measured weekly and their response to glucose was tested at week 7. After 8 weeks of treatment, eye tissue was harvested under terminal anaesthesia. The retinal vasculature and neural structure were assessed using immunofluorescence, immunohistochemistry and electron microscopy techniques. Results: Dapagliflozin treated DR mice exhibited metabolic benefits reflected by healthy body weight gain and pronounced glucose tolerance. Dapagliflozin reduced the development of retinal microvascular and neural abnormalities, increased the beneficial growth factor FGF21 (Fibroblast Growth Factor 21). We highlight for the first time that SGLT2 inhibition results in the upregulation of SGLT1 protein in the retina and that SGLT1 is significantly increased in the diabetic retina. Conclusions: Blockade of SGLT2 activity with DAPA may reduce retinal microvascular lesions in our novel DR mouse model. In conclusion, our data demonstrates the exciting future potential of SGLT1 and/or SGLT2 inhibition as a therapeutic for DR.

Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide. [Display omitted] • Subjects with type 2 diabetes have a substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. • The understanding of the pathogenetic mechanisms of atherosclerosis is critical for improving clinical outcomes. • Multiple CVOTs with GLP-1 RA and SGLT2i have demonstrated significant reduction of the risk of ASCVD in type 2 diabetes. • Early use of these drugs offers the opportunity to rate CV events closer to nondiabetic subjects. [ABSTRACT FROM AUTHOR]

A meta‐analysis of cardiorenal outcomes of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) available in Europe or the United States in patients with type 2 diabetes (T2D) is presented. An electronic search up to 6 January 2021 was conducted to determine eligible trials. A total of eight cardiorenal outcomes trials of SGLT‐2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) were identified, with 65,587 patients. Data were analysed using a random effects model. Overall, SGLT‐2is were associated with a 12% reduced risk of major adverse cardiovascular events (MACE; HR = 0.88; 95% CI, 0.83–0.93; Q statistic, p =.19), with no significant heterogeneity (p for interaction =.465) between subgroups of patients with or without cardiovascular disease (CVD). The risk of the composite renal outcome was significantly reduced by treatment with SGLT‐2is (HR = 0.61, 95% CI, 0.54–0.70), with no significant heterogeneity of associations with outcome (I2 = 37%, p =.11), and no difference in the risk between patients with or without CVD (p for interaction =.665). SGLT‐2is have moderate benefits on MACE and major benefits on the progression of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Given the mode of action of the drug, this is not surprising - but would also position omecamtiv mecarbil as a possible add-on therapy in patients with severe systolic dysfunction, in whom hypotension is often a complicating issue for conventional treatment. While the COVID-19 sensitivity analysis was meaningful in view of reported associations of the pandemic with reduced HF hospitalization rates 8 that may particularly impact recurrent HF events in the trial, how such analyses will be viewed in guidelines remains unknown. Perhaps most tantalizing are the implications of SOLOISTWHF for the safe initiation of SGLT inhibitors in hospitalized patients, as well as possible benefit in patients with HF and preserved LVEF. Biography: Dr Lam is a Senior Consultant at NHCS specializing in heart failure and recognized globally for expertise in heart failure with preserved ejection fraction. [Extracted from the article]

The article analyzes the new results of randomized clinical trials on the use of sodium-glucose co-transporter-2 inhibitors in patients with cardiovascular diseases, heart failure with and without type 2 diabetes. The data of the latest studies (EMPEROR reduced, VERTIS CV, SOLOIST-WHF, SCORED) are presented in more detail.

Sotagliflozin (SOTA) is a dual inhibitor of SGLT1 and SGLT2 used in adults with type 1 diabetes. The mechanism of action, based on the inhibition of both the SGLT1 and SGLT2 cotransporters, allows simultaneous increase of glucose excretion and slowing down the absorption of glucose in the intestine. Recently, test results have been published showing a beneficial effect of sotagliflozin on type 1 diabetes control [1,2,3]. Sotagliflozin use leads to a significant reduction in glycosylated haemoglobin (HbA1c) [1,2,3] , postprandial glucose reduction [1,2,3], weight loss [1,2,3], systolic blood pressure reduction [1,2,3] and reducing the risk of hypoglycaemia during the treatment [1,2,3]. Treatment of type 1 diabetes is based on a model of intensive, functional insulin therapy with the use of human insulin preparations or analogues of this insulin [10]. The therapy is carried out by multiple, subcutaneous injections of insulin doses or in the form of continuous insulin infusion with a personal insulin pump [10]. According to the recommendations of the Polish Diabetes Association (PTD) for patients with type 1 diabetes in terms of glycemic control, the primary goal is to maintain HbA1C  7% (53mmol / mol) and when the goal is not associated with the risk of hypoglycaemia, the target value is  6.5%. The use of proper treatment and sustaining HbA1C at the level recommended by PTD allows to prevent acute and chronic complications of the disease and at the same time allows patients to live actively and, consequently, improves their life quality [10]. According to recently published studies, preparations from SGLT-1 and SGLT-2 inhibitor groups may be helpful in obtaining and sustaining the treatment objective recommended by PTD.

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]

Background: Diabetes-related distress is common among persons affected by diabetes and is associated with suboptimal glycemic control and complications, thus constituting a relevant patient-report outcome (PRO). Improving glycemic control may reduce diabetes distress and improve treatment satisfaction. This post hoc analysis evaluated PRO data for a pooled cohort of adults with type 1 diabetes (T1D) receiving sotagliflozin as adjunct to optimized insulin in the inTandem1 and inTandem2 studies. Methods: Clinically meaningful changes in the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) and the two-item Diabetes Distress Scale (DDS2) total and individual scores were examined in the pooled data from the first 24 weeks of the studies. Results: In the cohort of patients with a baseline DTSQs total score ≤32 (∼76% of entire cohort), nearly twice as many patients treated with sotagliflozin 200 (45.9%) or 400 mg (42.3%) experienced a >3-point improvement from baseline versus those treated with placebo (24%). Treatment with sotagliflozin led to statistically significant (P < 0.05) improvements across all DTSQs items. Approximately 42% of all patients were considered to have a high risk of diabetes distress (total DDS2 score ≥6) at baseline following insulin optimization. More patients shifted from high to low risk with sotagliflozin compared with placebo (∼40% vs. 23%; P ≤ 0.0002). The baseline-adjusted difference in DDS2 from placebo was significantly (P < 0.001) reduced by -0.5 and -0.6 for sotagliflozin 200 and 400 mg, respectively. Conclusions: Patients with T1D treated with sotagliflozin in addition to optimized insulin therapy reported meaningful improvements in treatment satisfaction and diabetes distress. NCT02384941 and NCT02421510. [ABSTRACT FROM AUTHOR]