Dual SGLT1 Research Articles

Role of Sotagliflozin in Managing Heart Failure in Diabetes

A chronic illness that impairs heart function is heart failure. This malfunction can put strain on other organs and be especially dangerous for those who have long-term conditions like diabetes and high blood pressure. Patients with diabetes are more likely to develop heart failure. Sotagliflozin is an oral medication used to treat diabetes. A dual sodium drug called sotagliflozin shows promise in the treatment of heart failure. An essential new family of medications for the treatment of diabetes is the sodium-dependent glucose transporter 2 (SGLT2) inhibitors. The goal of developing SGLT2 inhibitors has been to achieve high SGLT2 protein selectivity compared to SGLT1 protein. Treating diabetes with a single drug that combines the inhibition of SGLT1 and SGLT2 would offer complementing insulin-independent strategies. Thus, sotagliflozin (LX4211) was created as a dual SGLT1 and SGLT2 inhibitor. Large postprandial glucose decrease, increase of glucagon-like peptide 1, and mild urine glucose excretion are the distinguishing clinical aspects of dual inhibitor of SGLT1 and SGLT2. These characteristics might have an impact on how sotagliflozin is used clinically to treat diabetes.

A Review of Sotagliflozin: The First Dual SGLT-1/2 Inhibitor.

Sotagliflozin (trade name INFEPA) is a novel dual sodium-glucose cotransporter-1 and -2 (SGLT-1/2) inhibitor that was developed by Lexicon Pharmaceuticals. It has emerged as a promising therapy for managing heart failure and other cardiovascular complications associated with type 2 diabetes mellitus (T2DM). Its dual inhibition of SGLT-1 and SGLT-2 receptors uniquely decreases glucose absorption in the intestine in addition to decreasing renal glucose reabsorption, leading to improved glycemic control and cardio-reno protection. Clinical trials have demonstrated its efficacy in reducing cardiovascular death, heart failure hospitalizations, and urgent visits, particularly in T2DM patients with chronic kidney disease (CKD). The drug was approved in 2023 by the Food and Drug Administration for reducing cardiovascular death and heart failure in T2DM patients with CKD and those with heart failure, irrespective of diabetic status or ejection fraction. However, despite its considerable therapeutic potential, sotagliflozin does pose notable adverse effects, including diabetic ketoacidosis, genital infections, and diarrhea. As a result, it has faced regulatory challenges in certain regions, notably the United States. The Food and Drug Administration has so far withheld approval for sotagliflozin in the treatment of type 1 diabetes due to concerns about its safety profile, specifically the risk of diabetic ketoacidosis, although Lexicon Pharmaceuticals plans to submit another new drug application for this use in 2024. Further investigation and clinical trials are warranted to fully elucidate sotagliflozin's impact on diabetes and CKD.

Role of Sotagliflozin in Managing Heart Failure in Diabetes`

A persistent illness called heart failure lowers heart function. Patients with chronic illnesses like diabetes and hypertension are especially vulnerable to the damage caused by this failure, which can put strain on other organs. Heart failure is more common in those with diabetes. An oral antidiabetic medication is called sotagliflozin. A dual sodium drug used to treat heart failure, sotagliflozin shows great promise. An important new family of drugs being developed to treat diabetes is the sodium-dependent glucose transporter 2 (SGLT2) inhibitors. The goal of high selectivity for the SGLT2 protein in comparison to the SGLT1 protein has guided the development of SGLT2 inhibitors. Treating diabetes through complementary insulin-independent pathways could be made possible by combining SGLT1 and SGLT2 inhibition in a single drug. Consequently, a dual SGLT1 and SGLT2 inhibitor called sotagliflozin (LX4211) has been developed. A significant reduction in postprandial glucose, an increase in glucagon-like peptide 1, and a moderate excretion of glucose in the urine are the distinguishing clinical aspects of dual inhibitors of SGLT1 and SGLT2. The usage of sotagliflozin in the treatment of diabetes may be affected clinically by these characteristics.

A Review of the Potential Role of Sotagliflozin: A Dual SGLT2 and SGLT1 Inhibitor-in the Treatment of Heart Failure.

Objective: This review provides an overview of the pharmacology, efficacy, and safety of sotagliflozin, a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), to reduce the risk of cardiovascular death and hospitalization in those with heart failure. Data sources: A search of Embase via Elsevier, PubMed, Web of Science-All Databases, and The Cochrane Library for clinical trials in CENTRAL, as well as the MedRxiv and BioRxiv pre-print servers, was conducted from inception through December 1, 2023. Search terms included sotagliflozin, lx 4211, lp 802034, sar 439954, and (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. Study selection and data extraction: Published phase 1, phase 2, and phase 3 clinical trials, meta-analyses, and systematic reviews. Studies were included if they were published in English and evaluated sotagliflozin pharmacology, pharmacokinetics, efficacy, or safety. Data synthesis: The Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF) and Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) phase 3 trials compared sotagliflozin with placebo in patients with type 2 diabetes mellitus. In both the SCORED and SOLOIST-WHF trials, treatment with sotagliflozin resulted in a statistically significant reduction in the primary composite outcome of death from cardiovascular causes, hospitalizations due to heart failure (HF), and urgent visits for HF. Conclusions: Dual SGLT1 and SGLT2 inhibition with sotagliflozin is efficacious in reducing myocardial infarction (MI), stroke, and HF hospitalizations and urgent visits in the SCORED and SOLOIST-WHF trials. However, its impact on reducing cardiovascular mortality remains uncertain due to premature study discontinuation. Owing to these factors and lack of generalizability, further studies are needed to establish its role in renal protection and cardiovascular mortality in broader populations. At this time, more evidence is warranted to definitively establish sotagliflozin in HF.

Dual SGLT1 and SGLT2 inhibition: more than the sum of its parts

Dual SGLT1 and SGLT2 inhibition: more than the sum of its parts

Mediators of the benefit of sotagliflozin in patients with worsening heart failure in SOLOIST-WHF

Abstract Background In SOLOIST-WHF, the dual SGLT1 and SGLT2 inhibitor sotagliflozin (SOTA) reduced primary endpoint events – total occurrences of cardiovascular (CV) death and hospitalizations and urgent visits for heart failure (HF) – by 33% relative to placebo (PBO) among 1222 patients hospitalized for worsening HF. The extent to which treatment group differences in biomarkers assessed during study follow-up contributed to this benefit of SOTA is unknown. Purpose The contributions of 20 biomarkers (identified in published mediation analyses of SGLT2 inhibitors: HbA1c; weight; BMI; systolic and diastolic BP; heart rate; serum creatinine, urate, albumin, sodium, and magnesium; eGFR; hematocrit; hemoglobin; erythrocytes; total cholesterol; LDL-C; HDL-C; non-HDL-C; triglycerides) to the reduction of primary endpoint events by SOTA relative to PBO were quantified via mediation analyses to describe the mechanisms of SOTA. Methods Patients were randomized 1:1 to SOTA 200 mg/day (with possible increase to 400 mg/day) or PBO and followed for a median 9 months. Two conditions must be met for a biomarker to be a mediator: there had to be a treatment group difference on the biomarker and an association between the biomarker and risk of primary endpoint events. For the first condition, treatment group differences in change from baseline in each biomarker were analyzed by mixed effects repeated measures models. For the second condition, time-varying values of each biomarker were related to the risk of primary endpoint events by calculating the time-weighted moving average (TWMA) for each variable, using all values for a given patient. Each was analyzed in a competing risks marginal model for total events (stratified according to left ventricular ejection fraction at baseline and geographic region of enrollment), in which non-CV deaths were treated as competing terminal events and TWMA values were included as a time-varying covariate. The individual and joint mediation of those biomarkers determined to be mediators were assessed in competing risks marginal models that included treatment assignment. If biomarkers that would otherwise be included in multivariable models were strongly correlated (baseline values R2>0.5), the marker with the greatest univariate mediation was included. All analyses were intention-to-treat. Results Among the biomarkers considered, serum urate, hemoglobin, and total cholesterol met the criteria for being mediators. Serum urate was the strongest single mediator, while the joint mediation for these three biomarkers was 22.3% (Figure 1). Conclusion In SOLOIST-WHF, a fraction of the benefit of SOTA was attributable to effects on biomarkers accounting for most of the treatment benefits of other SGLT2 inhibitors on CV death and HF events. Further investigation is therefore needed to identify what unique biomarker treatment effects might account for the majority of SOTA benefit.Figure 1

Abstract 16947: Sotagliflozin, a Dual SGLT 1 and 2 Inhibitor, Has High Membrane Affinity and Hydrocarbon Core Location Compared With Empagliflozin

Background: The dual SGLT-1 and 2 inhibitor sotagliflozin (sota) reduced atherothrombotic events and hospitalization for worsening heart failure in patients with diabetes in clinical trials (SCORED, SOLOIST). Unlike selective SGLT2 inhibitors such as empagliflozin (empa), sota binds with higher affinity to SGLT1, which is located in the intestine, kidney, heart, brain, and vascular endothelial cells. To elucidate the physico-chemical basis for differences in tissue distribution and receptor affinity, we compared the effects of these drugs on membrane binding and molecular location. Methods: Membranes reconstituted from cardiac phospholipid and cholesterol were used to measure drug partitioning across a range of cholesterol concentrations. Multilamellar vesicles were prepared as mixtures of cardiac phospholipid (CPL), cholesterol, and each agent at 30 μM or vehicle. Drug-membrane partitioning was determined by rapid centrifugation and UV/Vis spectrophotometry. In parallel experiments, we used small angle x-ray scattering (SAXS) to identify drug location in model membranes containing phosphatidylcholine and cholesterol. Results: Sota had a membrane partition coefficient (8590 ± 2078) that was 16-fold higher than empa (519 ± 195, p<0.001) in CPL membranes. This high membrane affinity was preserved over a range of cholesterol levels compared to empa (p<0.001). Consistent with high membrane affinity, SAXS analysis showed that sota had a location evidenced by a broad increase in electron density in the hydrocarbon core extending to approximately 20 Å from the membrane center. By contrast, empa had a location limited to the polar headgroup region, consistent with its lower lipophilicity and tissue penetration. Conclusions: Sota had high membrane affinity and distinct location in the hydrocarbon core compared to empa. This may contribute to the effect of its dual SGLT-1 and 2 inhibition in vivo across various tissues including the heart. These distinct membrane interactions may also partially explain the reduced atherothrombotic risk as demonstrated in outcome trials with sota but not selective SGLT-2 inhibitors.

Abstract 13696: Sotagliflozin is Associated With Early Clinical Benefit for Heart Failure and Atherosclerotic Events

Background: SGLT inhibitors reduce cardiovascular (CV) death and heart failure (HF)-related outcomes in HF patients, with benefits observed within 1 month. Less data exist for the time to clinical benefit for reducing HF or major cardiovascular events (MACE; CV death, myocardial infarction, and stroke) with SGLT inhibitors in patients with chronic kidney disease at high CV risk. Objective: This analysis evaluates the time to clinical benefit for HF-related events and MACE with sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, in SCORED. Methods: SCORED was a randomized, double-blind study of 10,584 patients with type 2 diabetes, chronic kidney disease, and other CV risk factors, where patients were randomized 1:1 to sotagliflozin or placebo. The primary endpoint was total CV death, hospitalization for HF, or urgent visit for HF. A prespecified secondary endpoint was total MACE. The present post hoc analysis calculated the sotagliflozin:placebo hazard ratios (HR) and 95% confidence intervals (CI) for each of these outcomes and determined the day after randomization where the treatment effect reached statistical significance (p<0.05) and remained statistically significant for the duration of follow-up. Results: The overall risk of the primary endpoint was reduced by 26% (HR (95% CI) = 0.74 (0.63, 0.88); p<0.001) with sotagliflozin, with a sustained significant reduction 95 days after randomization (HR (95% CI) = 0.70 (0.50, 0.98) at 95 days; Figure A). For MACE, the overall risk reduction with sotagliflozin was 23% (HR (95% CI) = 0.77 (0.65, 0.91); p<0.001), with a sustained significant reduction 94 days after randomization (HR (95% CI) = 0.69 (0.47, 0.99) at 94 days; Figure B). Conclusion: In this stable, outpatient population at high risk for CV events, the time to clinical benefit with sotagliflozin was very early at approximately three months for both HF- and MACE-related outcomes.

Comparison of SGLT1, SGLT2, and Dual Inhibitor biological activity in treating Type 2 Diabetes Mellitus.

Diabetes Mellitus Type 2 (T2D) is an emerging health burden in the USand worldwide, impacting approximately 15% of Americans. Current front-line therapeutics for T2D patients include sulfonylureas that act to reduce A1C and/or fasting blood glucose levels, or Metformin that antagonizes the action of glucagon to reduce hepatic glucose production. Next generation glucomodulatory therapeutics target members of the high-affinity glucose transporter Sodium-Glucose-Linked-Transporter (SGLT) family. SGLT1 is primarily expressed in intestinal epithelium, whose inhibition reduces dietary glucose uptake, whilst SGLT2 is highly expressed in kidney - regulating glucose reabsorption. A number of SGLT2 inhibitors are FDA approved whilst SGLT1 and dual SGLT1 & 2 inhibitor are currently in clinical trials. Here, we discuss and compare SGLT2, SGLT1, and dual inhibitors' biochemical mechanism and physiological effects.

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

Sotagliflozin, A Dual SGLT1 And SGLT2 Inhibitor, Reduces First And Subsequent Heart Failure-related Events In Patients Admitted For Worsening Heart Failure

Sotagliflozin, A Dual SGLT1 And SGLT2 Inhibitor, Reduces First And Subsequent Heart Failure-related Events In Patients Admitted For Worsening Heart Failure

Abstract 13422: Sotagliflozin, a Dual SGLT-1/2 Inhibitor, Modulated Expression of Endothelial Proteins That Inhibit Reactive Oxygen Species During Inflammation Compared With Empagliflozin

Background: Reactive oxygen species (ROS) generated during endothelial cell (EC) dysfunction contributes to progression of atherosclerosis. The SGLT1/2 inhibitor sotagliflozin (sota) reduced atherothrombotic events and hospitalization for worsening heart failure in patients with diabetes (SCORED, SOLOIST). Unlike selective SGLT2 inhibitors, sotagliflozin significantly reduced ischemic events, including myocardial infarction and stroke. We compared the effects of sota and empagliflozin (empa) on expression of ROS signaling proteins in human vein ECs (HUVECs) challenged with interleukin-6 (IL-6) or lipopolysaccharide (LPS). Methods: HUVECs were treated with sota or empa (100 nM) for 30 minutes and the challenged with IL-6 (12 ng/mL) or LPS (100 ng/mL) for 24 hours. Global proteomic analysis was performed using LC/MS to measure relative expression levels of >1,000 proteins. Only significant (p<0.05) changes in expression between treatment groups >1-fold were included in gene set enrichment analysis (GSEA) of biological pathways. Results: Sota significantly changed expression of 166 and 274 proteins in ECs challenged with IL-6 and LPS, respectively. Empa significantly modulated fewer proteins - 122 and 93 proteins - following challenge with IL-6 and LPS, respectively. GSEA revealed that sota, not empa, modulated proteins related to ROS detoxification within the “cellular response to oxidative stress” pathway (GO:0034599) compared to both IL-6 and LPS (pathway adjusted p-values = 0.0016 and 0.036, respectively). Within this pathway, sota increased expression of peroxiredoxin (PRDX) 5 and PRDX6 (1.2 and 1.1-fold) and glutathione peroxidase-1 (GPX1, 1.1-fold) relative to IL-6 alone. Relative to LPS, sota decreased expression GPX1 (1.2-fold), PRDX1 (1.1-fold), and increased thioredoxin (1.1-fold). None of these proteins were modulated significantly by empa. Conclusions: Sota significantly modulated expression of proteins linked to ROS detoxification and signaling in human ECs during inflammation compared to a selective SGLT2 inhibitor. These favorable effects of dual SGLT1/2 inhibition may have implications for inflammation and reduced atherothrombotic risk as demonstrated in outcome trials.

Abstract 10209: The Effect of the Dual SGLT1 and 2 Inhibitor Sotagliflozin on Cardiovascular Mortality and Hospital Readmission Rates for Heart Failure at 30 and 90 Days Post Discharge in Patients With Type 2 Diabetes Hospitalized for Worsening Heart Failure in the SOLOIST-WHF Trial

Introduction: SGLT inhibitors demonstrate reductions in CV mortality and HHF in patients with diabetes and chronic HF. Despite therapy, patients hospitalized for worsening HF (WHF) are at high risk of death or readmission. Hypothesis: The SOLOIST-WHF trial admitted patients for their index WHF event and initiated randomized therapy during hospitalization. This study evaluated the effect of the SGLT1 and 2 inhibitor sotagliflozin on 30- and 90-day CV death and HF readmission rates after discharge. Methods: Of 1222 randomized patients with T2D, 86% were admitted for their index WHF event. Of them, 46% (n = 563) started study drug prior to or at discharge. In post hoc exploratory analyses, CV death and HF readmission (HHF or urgent visits for HF) rates were determined 30- or 90-days post discharge. Comparisons were done by Cochran-Mantel-Haenszel test stratified by region and baseline LVEF (<50%, ≥50%). Results: Treatment with sotagliflozin showed significant relative risk reduction of >50% for readmission for non-fatal HF-related events or the composite of CV death and readmission for HF-related events within 30 or 90 days of discharge vs placebo (Table 1). The sotagliflozin safety profile in those windows was generally consistent with the overall study duration. Incidence of adverse events (AEs) and serious AEs was similar between groups. Increased incidence of diarrhea and volume-related AEs was noted with sotagliflozin. No appreciable eGFR change from baseline occurred at 30 days, but there was lower incidence of AEs linked to acute kidney injury with sotagliflozin. Conclusions: Sotagliflozin, given to patients with T2D prior to or at hospital discharge after an episode of WHF, was well tolerated and resulted in a significant >50% reduction in CV mortality or readmission for a HF event at 30 and 90 days post-discharge.

Effect of sotagliflozin on ventricular arrhythmias in mice with myocardial infraction

BackgroundVentricular arrhythmias (VAs) after myocardial infarction (MI) are an important cause of death in patients. Inhibition of sodium-glucose ligand transporter type 2 (SGLT-2) has been shown to reduce cardiovascular mortality in myocardial infarction independent of glycemic sham and prevent ventricular arrhythmias, and it is unclear whether these effects can be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1 and 2 inhibitor sotagliflozin (Sto) on VAs and their underlying mechanisms after MI. MethodsMI was induced by ligation of the left anterior coronary artery in 6–8 weeks-old male mice, which were fed Sto at a dose of 30 mg/kg/day for 4 weeks after surgery. The effects were assessed by echocardiography, histopathology, Langendorff Heart Perfusion System, ambulatory electrocardiography, and Western blot. In vitro experiments were performed to assess the effect of Sto on cardiomyocytes subjected to hypoxic. ResultsCompared to the MI group, Sto treatment significantly improved cardiac function and reduced infarct size and fibrosis levels. Sto also decreased action potential duration (APD) and APD alternation thresholds. Ambulatory ECG and BURST stimulation showed that Sto reduced the incidence of VAs. In addition, Sto significantly improved the expression levels of ion channels and CX43 and ameliorated the abnormal expression of Ca2+ handling proteins after MI. Mechanistically, in vivo and in vitro experiments confirmed that TLR4/CaMKII activation was enhanced after MI, while Sto significantly inhibited the activation of the TLR4/CaMKII signaling pathway. ConclusionSto improved LV remodeling and reduced the incidence of VAs after MI, which was regulated by modulating the TLR4/CaMKII signaling pathway.

Sodium-Glucose Cotransporter Inhibitors as Antidiabetic Drugs: Current Development and Future Perspectives.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.

Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study.

OBJECTIVEInhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.RESEARCH DESIGN AND METHODSUsing a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.RESULTSChanges from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.CONCLUSIONSChanges from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

864-P: Glycemic Control across eGFR Categories with the Dual SGLT1 and 2 Inhibitor Sotagliflozin in SCORED

In cardiovascular (CV) outcome trials (OT) of glucose-lowering medications (GLM) , glycated hemoglobin (A1c) is typically treated according to local standard of care, with aim of glycemic equipoise between the randomized groups. However, in SGLT inhibitor CVOTs, larger A1c reductions are consistently seen in the active therapy vs. placebo (PBO) groups, since the former has access to an additional class of GLM. SCORED was a multicenter, double-blind, placebo-controlled CVOT of the dual SGLT1 and 2 inhibitor sotagliflozin (SOTA) , which may have preserved antihyperglycemic effects even in those with advanced chronic kidney disease (CKD.) We assessed the association between A1c lowering and assignment to SOTA vs. PBO in the overall trial population and across various pre-specified subgroups, including CKD categories. 10,584 type 2 diabetes (T2D) (A1c ≥7%) patients with CKD (eGFR 25-60 mL/min/1.73 m2) and increased CV risk were randomized to SOTA vs. PBO and followed for a median of 15.9 months. We previously reported that the risk for the primary composite outcome of total CV deaths and hospitalizations or urgent visits for heart failure was reduced by 26% in the SOTA group (p<0.001) . In the overall population, from a baseline A1c of 8.7%, the least-squares mean change in A1c was -0.60% with SOTA and -0.17% with placebo (mean difference [95% CI] = -0.42% [-0.47, -0.38]; p<0.0001) . Differences were larger with increasing baseline A1C: <8%: -0.31%; 8-<9%: -0.40%; and ≥9%: -0.57% (all p<0.0001) . The association between SOTA use and A1c lowering vs. placebo was consistent across strata of baseline eGFR, including those with CKD stage 4 (eGFR>45, 30-<45, and <30: -0.47%. -0.38%, and -0.31%, respectively [all p<0.001]) . These results were similarly consistent across age, sex, race/ethnicity, age, and BMI subgroups. In SCORED, SOTA consistently reduced A1c across all pre-specified subgroups, including patients with the lowest baseline eGFR, possibly reflecting SOTA’s dual mechanism of action. Disclosure S.E.Inzucchi: Advisory Panel; Abbott Diagnostics, ESPERION Therapeutics, Inc., vTv Therapeutics, Consultant; Merck & Co., Inc., Pfizer Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk. J.P.Dwyer: Consultant; Akebia Therapeutics, Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Cincor, Inc, CSL Behring, FibroGen, Inc., Reata Pharmaceuticals, Inc., Sanofi, Tricida, Inc. B.M.Scirica: Consultant; Allergan, Boehringer Ingelheim International GmbH, ESPERION Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Novo Nordisk, Research Support; Better Therapeutics, Eisai Co., Ltd., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Stock/Shareholder; Heath At Scale. C.J.Bailey: None. P.L.Banks: Employee; Lexicon Pharmaceuticals, Inc. R.Diaz: None. K.K.Ray: Consultant; Abbott, AstraZeneca, Cargene, CSL Behring, Daiichi Sankyo, Eli Lilly and Company, ESPERION Therapeutics, Inc., GlaxoSmithKline plc., Kaleido, Kowa Company, Ltd., New Amsterdam Pharma, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals Inc., Roche Diagnostics, The Medicines Company, Research Support; Amgen Inc., Daiichi Sankyo, Regeneron Pharmaceuticals Inc., Sanofi, Speaker's Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Medscape, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Viatris Inc., Stock/Shareholder; Cargene, PEMI31. J.A.Udell: Consultant; Boehringer Ingelheim International GmbH, Novartis AG, Sanofi, Other Relationship; GlaxoSmithKline plc., Sanofi, Research Support; Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. R.D.Lopes: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, GlaxoSmithKline plc., Medtronic, Pfizer Inc., Portola Pharmaceuticals, Inc., Other Relationship; Bristol-Myers Squibb Company, Sanofi, Research Support; Medtronic, Pfizer Inc. L.A.Leiter: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; AstraZeneca, Bayer AG, Lexicon Pharmaceuticals, Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Servier Laboratories. P.G.Steg: Advisory Panel; AstraZeneca, Bristol-Myers Squibb Company, Board Member; Novartis AG, Consultant; Amarin Corporation, Amgen Inc., Bayer AG, Idorsia Pharmaceuticals Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., Sanofi. D.L.Bhatt: Research Support; Afimmune Limited, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Novartis AG, Sanofi. Scored investigators: n/a. B.Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Funding Sanofi/Lexicon

Sodium-glucose co-transporter 1 and 2 expression in the mammary artery of patients with bypass surgery: role of the pro-inflammatory response and contribution to oxidative stress

Abstract Background Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection independently of glycemic control. Angiotensin II (Ang II) and H2O2 induced the expression of SGLT1 and 2 in cultured endothelial cells and isolated arteries to promote oxidative stress and endothelial dysfunction. However, the expression level and role of SGLT1 and 2 in human arteries remain poorly studied. Purpose This study examined the expression level of SGLT1 and 2 in the human internal mammary artery (IMA) obtained from bypass surgery patients, and, if so, determined the underlying mechanism and function. Methods IMAs were obtained from 40 bypass surgery patients (age 45 to 82). The expression level of target factors was assessed by Western blot analysis, immunofluorescence staining and RT-PCR, and the level of oxidative stress using dihydroethidium staining. Human kidney was used as a control tissue known to express SGLT1 and 2. Porcine coronary artery endothelial cells (CAEC) were cultured and studied at passage 1. Results Western blot analysis of 40 IMA samples indicated a high level of both SGLT1 and 2 in 16 and 17 IMAs, an intermediate level in 8 and 6 IMAs, and a low one in 16 and 17 IMAs, respectively. Immunofluorescence staining of IMA sections indicated that SGLT1 and 2 immunofluorescence signals were observed predominantly in the intima thickening and the media. The expression levels of SGLT1 and 2 were associated with p-p65 NF-kB signals but not angiotensin-converting enzyme (ACE), AT1R, MCP-1, VCAM-1. IMAs with a high expression level of SGLT1 and 2 had a high level of ROS throughout the arterial wall including the intima thickening and endothelium, which was inhibited by the antioxidant N-acetylcysteine, the ACE inhibitor perindoprilat, the AT1R antagonist losartan, and also by the dual SGLT1 and 2 inhibitor sotagliflozin and the selective SGLT2 inhibitor empagliflozin. Pro-inflammatory cytokines mRNA levels of IL-1β, TNF-α and IL-6 were detected in IMAs. Exposure of CAEC to either TNF-α, IL-1β or IL-6 caused a concentration-dependent upregulation of SGLT1 and 2. Conclusion The present findings indicate that SGLT1 and 2 expression is observed in some but not all IMAs of bypass surgery patients predominantly in the media, the intima thickening and the endothelium. High expression levels of SGLT1 and 2 are associated with NF-kB activation and oxidative stress that is prevented by a selective SGLT2 inhibitor and by a dual SGLT1/2 inhibitor. Since pro-inflammatory cytokines triggered SGLT1 and 2 expression in endothelial cells, the inflammatory burden of patients appears to be an important trigger regulating SGLT1/2 expression and the subsequent pro-oxidant response prompting pro-inflammatory and pro-thrombotic responses. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This work was supported by an unrestricted research grant from Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

BackgroundSodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.Methods17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable.ResultsSotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition.ConclusionThe SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

Dapagliflozin as an Adjunct Therapy to Insulin in Patients with Type 1 Diabetes Mellitus: Efficacy and Safety of this Combination.

The prevalence of type 1 diabetes (T1D) is increasing worldwide. T1D reduces life expectancy due to complications including cardiovascular disease. Sodium-glucose co-transporter (SGLT) inhibitors are a new class of drugs developed to treat type 2 diabetes (T2D), and now they can be used as an adjunct to insulin in T1D. In clinical trials, they have been shown to improve glycaemic control and decrease body weight without the risk of increased hypoglycaemia and with a reduction in insulin dose. Four SGLT2 inhibitors have been approved in Europe for the treatment of T2D, while only dapagliflozin and sotagliflozin, a dual SGLT1 and SGLT2 inhibitor approved in 2019, have been approved for the treatment of T1D. Both can be used as an adjunct therapy in combination with insulin in adults with a body mass index (BMI) of ≥27 kg/m2, inadequately controlled with insulin. In Europe, dapagliflozin is the only currently available SGLT2 inhibitor indcated as adjunct therapy for patients with T1D. The subgroup of patients with a BMI of ≥27 kg/m2 from the DEPICT-1 and -2 trials (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 diabetes) showed similar reduction in hyperglycaemia and body weight but no significant increased risk of diabetic ketoacidosis (DKA) than the overall trial population. The risk of DKA has been shown to increase in patients with T1D treated with adjunct therapy with SGLT2 inhibitors, and studies on sotagliflozin and empagliflozin have suggested a dose response. Thus, it is important to educate patients and doctors how to recognize symptoms of upcoming DKA and mitigate it. An independent DKA education programme has recently been developed to instruct patients with T1D being treated with SGLT inhibitor therapies with and without insulin pumps to prevent, identify and treat DKA. Despite these considerations, clinical trials support the use of SGLT2 inhibitors in the management of T1D. The benefits and potential risks of dapagliflozin as an adjunct therapy to insulin in adults with T1D should be considered in each individual case. Here we discuss the efficacy and safety of dapagliflozin as adjunct therapy in patients with T1D.