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Randomized controlled trials (RCTs) have become the gold standard of clinical evidence and the staple of guided clinical practice. RCTs are based on a complex set of principles and procedures heavily strung by statistical analysis, primarily designed to answer a specific question in a clinical experiment. Readers of clinical trials need to apply critical appraisal skills before blindly accepting the results and conclusions of trials, lest they misinterpret and misapply the findings. We introduce the fundamentals of an RCT and discuss the relationship between relative risk (RR) and absolute risk (AR) in terms of the different information each conveys. The top results of some recent cardiovascular outcome trials using sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes are used to exemplify the merit of assessing both RR and AR changes for a balanced translation of findings into shrewd clinical judgment. We also suggest practical points to assist with a clinically useful interpretation of both within-trial and across-trial reports. Finally, we mention an alternative approach, namely, the restricted mean survival time, to obtaining unbiased estimates of the mean time of missed events in the treatment versus placebo arm for the duration of the trial.

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). Supplementary Information The online version contains supplementary material available at 10.1007/s13340-021-00515-4.

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.

Czapska Mirella, Babkiewicz Kamila, Pabis Szczepan, Skórzyńska-Dziduszko Katarzyna. Sotagliflozin, an inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 / 2), as a new therapeutic approach for patients with type 1 diabetes mellitus. Journal of Education, Health and Sport. 2018;8(12):335-351. eISNN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.2267488 http://ojs.ukw.edu.pl/index.php/johs/article/view/6378 The journal has had 7 points in Ministry of Science and Higher Education parametric evaluation. Part b item 1223 (26/01/2017). 1223 Journal of Education, Health and Sport eissn 2391-8306 7 © The Authors 2018; This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 10.11.2018. Revised: 20.11.2018. Accepted: 14.12.2018. Sotagliflozin, an inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 / 2), as a new therapeutic approach for patients with type 1 diabetes mellitus Mirella Czapska1, Kamila Babkiewicz1, Szczepan Pabis2, Katarzyna Skórzyńska-Dziduszko3 1Students Scientific Society at the Department of Human Physiology, Medical University of Lublin 2Departament of Urology University of Rzeszów 3Department of Human Physiology, Medical University of Lublin Sotaglifosine, a complex inhibitor of SGLT1 / 2 cotransporters, as a new therapeutic option for patients with type 1 diabetes Sotagliflozin, an inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 / 2), as a new therapeutic approach for patients with type 1 diabetes mellitus Summary Sotagliflozin (SOTA) is a dual inhibitor of SGLT1 and SGLT2 used in adultswith type 1 diabetes.The mechanism of action, based on theinhibition ofboth the SGLT1 and SGLT2 cotransporters, allows simultaneous increase of glucose excretion and slowing down the absorption of glucose in the intestine.Recently, testresults have been publishedshowinga beneficialeffect of sotagliflozin ontype 1 diabetes control[1,2,3]. Sotagliflozin use leads to a significant reduction inglycosylated 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. Keywords : SGLT-1 and SGLT-2 inhibitor, sotaglifosin, type 1 HbA1C diabetes, hypoglycaemia Keywords:SGLT1 and SGLT2 inhibitor, sotagliflozin, type 1 diabetes (T1D), HbA1C, hypoglycaemia

© Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high. We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment. The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment. This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade.

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.

Background: Sodium-glucose transport protein 2 (SGLT2) inhibitors are a novel class of drugs initially developed for the treatment of type II diabetes mellitus (T2DM) through the principal mechanism of glucose reabsorption inhibition at the proximal convoluted tubule. It was soon observed that SGLT2 inhibitors demonstrated potent cardioprotective effects beyond the hypoglycemic mechanism thus rendering their use in heart failure with reduced ejection fraction (HFrEF) to further reduce mortality and morbidity outcomes. In clinical trials, genital and urinary tract infection (UTI) and volume depletion associated with SGLT2 use have been commonly reported. Purpose: To determine the risk of UTI associated with SGLT2 use in patients with chronic or acutely worsened HF, compared to placebo. Methods: Three randomized clinical trials (RCTs) and a prespecified subanalysis of one major RCT were included in the analysis. Two included patients with HFrEF (DAPA-HF and EMPEROR-Reduced), one included patients with T2DM that were hospitalized for worsening HF (SOLOIST-WHF) while one was the subanalysis focused on a subgroup of patients that had HF and T2DM (DECLARE- TIMI 58). Two trials examined the use of dapagliflozin, one of empagliflozin and one of sotagliflozin. All trials reported on the incidence of urinary tract infections. Fixed-effects meta-analysis with Mantel Haenszel algorithm was performed with a relative risk (RR) and 95% confidence intervals (95% CI) reported as main outcome measures. Heterogeneity across studies was inspected by I2 statistic. Results: A total of four trials encompassing 26.838 patients with HF with pooled 569 UTI events were recorded. Of these, 285 UTI events were recorded in the SGLT2 group (2.12%) and 284 in the placebo group (2.11%). The observed heterogeneity across studies was low and non- significant (I2=11%) in the random- effects model, therefore, the main analysis was carried out by using a fixed-effects model. We found that the use of SGLT2 inhibitor was similar to placebo concerning the risk of UTI among patients with HF (RR 1.005, 95% CI 0.855-1.181 ; Figure 1) and this was based on the evidence of no significant heterogeneity across included studies (P=0.336). The leave- one-out fixed-effects analysis confirmed this finding (Figure 2). Conclusion: In patients with heart failure, treatment with SGLT2 inhibitors was not associated with an increased risk of urinary tract infections compared to placebo.

Objective: Evaluate the effect of sotagliflozin, a dual inhibitor of sodium glucose cotransporter (SGLT) 1 and 2, on arterial stiffness in patients with type 1 diabetes (T1D) treated with sotagliflozin as adjunct to optimized insulin therapy. Methods: In this post hoc analysis, indirect markers of arterial stiffness, including pulse pressure, mean arterial pressure (MAP), and double product, were calculated using observed systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse rate at 24 weeks using data from a pooled patient population from the inTandem1 and inTandem2 randomized controlled trials ( n = 1575). Results: Baseline characteristics were similar among groups. Relative to placebo at Week 24, sotagliflozin 200 mg and 400 mg reduced SBP by 2.03 mm Hg (95% CI −3.30 to −0.75; p = 0.0019) and 2.85 mm Hg (−4.12 to −1.57; p Conclusion: In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance.

Background: To systematically evaluate the efficacy and safety of sotagliflozin (SOTA) adjuvant therapy for type 1 diabetes mellitus (T1DM). Methods: Through April 2019, the Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure databases were electronically searched to identify randomized controlled trials exploring SOTA adjuvant therapy for T1DM. Strict screening and quality evaluations of the obtained literature were performed independently by 2 researchers. Outcome indexes were extracted, and a meta-analysis of the data was performed using Revman 5.3 software. Results: A total of 7 randomized controlled trials were included. The meta-analysis results showed that compared with the patients in the placebo group, the patients in the SOTA group had a lower hemoglobin A1c (mean difference [MD] = −0.28, 95% confidence interval [CI] [−0.34, −0.22], P

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

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

Many adults with T1D are not at glycemic goal and are overweight or obese and this trend appears to be worsening. SGLT inhibitors have been shown to improve metabolic outcomes in T1D. However, the glycemic efficacy of selective SGLT2 inhibitors depends on the amount of glucose filtered in the glomerulus and as such efficacy attenuates as renal function declines. The mechanism of action of sotagliflozin (SOTA) involves inhibition of SGLT2 in the kidney and SGLT1 in the gastrointestinal tract. This post-hoc analysis evaluated the efficacy and safety of SOTA by baseline eGFR (45- Disclosure Y. Handelsman: Advisory Panel; Self; Amgen, Applied Therapeutics, AstraZeneca. Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen, AstraZeneca. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M.J. Davies: Employee; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.

SOTA is a sodium-glucose linked cotransporter (SGLT)-1 in the GI tract and SGLT2 in the kidney. Compared to selective SGLT2 inhibitors, SOTA has the potential to retain glycemic-lowering efficacy in patients with renal insufficiency. In a 52-week, Phase 3 study, SOTA 200 and 400 mg QD, were evaluated in adults with T2D (HbA1C 7-11%) and Stage 3 CKD (eGFR ≥30-60 mL/min/1.73m2) to demonstrate statistical superiority vs. placebo (PBO) in reducing HbA1C at Week 26. Prespecified sequential testing of HbA1C reduction with SOTA 400 mg vs. PBO in the full CKD population was followed by Stage 3A and Stage 3B cohorts before testing SOTA 200 mg. ANCOVA models with retrieved dropouts and/or washout imputation methods were used for primary and prespecified secondary endpoints. In the full population (N=787), the least squares mean (LSM) difference between SOTA 400 mg and PBO for the change in HbA1C at Week 26 was −0.23% (p=0.002). In the CKD 3A (n=394) and CKD 3B cohorts (n=393), LSM differences for SOTA 400 mg vs. PBO were −0.31% (p=0.004) and −0.15% (p=0.158); respectively. SOTA 200 mg did not significantly reduce HbA1C in any cohort vs. PBO. In an exploratory analyses, PBO-corrected reductions in the urinary albumin-to-creatinine ratio were −38% (p Disclosure D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. G.E. Umpierrez: None. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. A.K. Carroll: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. W. Jiang: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.

Objective: To evaluate the effect of sotagliflozin (SOTA), a dual SGLT 1 and 2 inhibitor, on beta-hydroxybutyrate (BHB) over 52 weeks in adults with type 1 diabetes (T1D) on insulin therapy. Methods: Analyses were performed on pooled data from two, 52-week, placebo-controlled studies in 1575 adult patients with T1D on optimized insulin therapy, who were randomly assigned 1:1:1 to placebo (PBO), SOTA 200 mg, and SOTA 400 mg. Descriptive statistics were performed on serum BHB using results from scheduled visits at baseline and Weeks 4, 12, 24, and 52. A 2-sample Wilcoxon rank sum test was performed to test the distribution of change in BHB from baseline between SOTA and placebo. The proportion of patients experiencing ≥1 measurement meeting predefined limits of DKA risk based on BHB levels (≥0.6 mmol/L “ketonemia” and ≥1.5 mmol/L “impending DKA”) was assessed. Results: Median baseline BHB was 0.13 (IQR 0.10, 0.20), 0.13 (IQR 0.10, 0.22), and 0.14 mmol/L (IQR 0.10, 0.23) in the PBO, SOTA 200-mg, and SOTA 400-mg groups, respectively. While the median change in BHB was 0 mmol/L with PBO, median BHB increased from baseline by 0.03 to 0.05 mmol/L with SOTA, and generally remained stable over 52 weeks (p Conclusion: Treatment with SOTA was associated with small increases in BHB over time, which on average remained well below the clinically important level of 0.6 mmol/L. Although the DKA incidence was Disclosure A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi. S. Sawhney: None. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. M.J. Davies: Employee; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.

SOTA inhibits sodium-glucose cotransporter (SGLT) 1 in the GI tract and SGLT2 in the kidney. Compared to selective SGLT2 inhibitors, SOTA potentially retains glycemic lowering despite renal insufficiency. This is the first study of an SGLT-inhibitor to examine glycemic control in patients with T2D and Stage 4 CKD. In a 52-week, Phase 3 study, SOTA 200 and 400 mg QD were evaluated for superiority vs. placebo (PBO) in reducing HbA1C levels after 26 weeks. Adults had T2D, inadequate glycemic control (mean HbA1C, 8.0%), and severe CKD (mean eGFR, 23.6 mL/min/1.73 m2). Pre-specified efficacy endpoint data analyzed by an ANCOVA model combining retrieved dropout and washout imputation methods for missing data showed clinically meaningful HbA1C reduction with SOTA 400 mg vs. PBO of -0.30% (95% CI: −0.61, 0.02; p=0.062). In an analysis consistent with FDA recommendations applying an ANCOVA model using just the retrieved dropout imputation method, SOTA 400 mg (n=92) reduced HbA1C vs. PBO (n=92) by −0.33% (95% CI: 0.66, −0.001; p=0.049) at Week 26. SOTA 200 mg did not significantly reduce HbA1C vs. PBO. In key secondary endpoint analyses at Week 26, SOTA 400 mg reduced mean body weight vs. PBO by −1.53 kg (95% CI: −2.96, −0.09). In patients with baseline urinary albumin-to-creatinine-ratio (UACR) >30 mg/g, SOTA 400 mg reduced UACR vs. PBO by −27.04% (95% CI: −46.36, −0.75). At Week 12, SOTA 400 mg reduced SBP vs. PBO by −5.22 mm Hg (95% CI: −9.31, −1.13). The incidence of adverse events was 77.8% with SOTA vs. 74.2% with PBO. There were no treatment-group differences in mycotic infection (0% vs. 0%) or volume depletion (0% vs. 4.3%). Rates of level 1 and 2 hypoglycemia were lower with both doses of SOTA vs. PBO. At 26 weeks, SOTA 400 mg treatment resulted in meaningful reductions in HbA1C without unexpected safety concerns in adults with T2D and stage 4 CKD. The impact on renal and cardiovascular outcomes is being evaluated in a dedicated CVOT in patients with CKD. Disclosure D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. G.E. Umpierrez: None. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. A.K. Carroll: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. W. Jiang: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. S. Sawhney: None.

Diabetes mellitus is the global health issue and become an alarming threat in the modern era where human lifestyle gets compromised with modernization. According to the latest statistical report 2020, USA has 9.47% (31 million among 32.72 cr), China has 8.3% (116.4 million among 139.27 cr) and India has 5.6% (77 million among 135.26 cr) of the diabetic people, indicating that diabetes is more prevailing in developed countries as compared to the developing countries. The number of diabetic patients is rising day by day at a tremendous rate and soon it may affect each and every person in a family. So, there is an urgent need to develop novel entities that can meet the scarcity of present antidiabetic agents. In the last few decades, the sodium-glucose co-transporter 2 (SGLT2) has emerged as a prominent target for the treatment of Type 2 diabetes mellitus due to its novel mechanism of action & no involvement in insulin signaling pathway. Most of the inhibitors that target SGLT2 contain three basic moieties: glucose, two benzene rings (one is connected with glucose and the other with methylene), and the methylene bridge which are similar to dapagliflozin. Several SGLT2 inhibitors and their derivatives such as remogliflozin etabonate (phase-II), sotagliflozin (phase-III) and bexagliflozin (phase-III) are under different phases of clinical trial studies and some have been patented. The present review is focused on SGLT2 inhibitors, structure activity relationships (SARs) of dapagliflozin and its several analogues for their binding affinity with SGLT2. We have also presented and summarized the efforts made by various researchers in terms of the synthesis of various dapagliflozin derivatives till date.

Background: According to the centers for disease control and prevention, 14% of American adults have diabetes – 10% know it, and more than 4% go undiagnosed. Sotagliflozin is a new type of diabetes drug This study is to compare the efficacy of Sotagliflozin therapy for Diabetes Mellitus (DM) between week 24 with week 52. Methods and analysis: Through to October 2019, Web of Science, PubMed Database, Cochrane Library, EMBASE, Clinical Trials and CNKI will be searched to identify randomized controlled trials (RCTs) exploring SOTA therapy for DM. Strict screening and quality evaluation will be performed on the obtained literature independently by 2 researchers; outcome indexes will be extracted. The bias risk of the included studies will be evaluated based on Cochrane assessment tool. Meta-analysis will be performed on the data using Revman 5.3 software. We will provide practical and targeted results assessing the lost efficacy of SOTA therapy for DM from week 24 to week 52, to provide reference for clinicians. Ethics and dissemination: The stronger evidence about the lost efficacy of SOTA for DM from week 24 to week 52 will be provided for clinicians. Trial registration number: PROSPERO CRD42019133027. Strengths and limitations of this study: Whether the efficacy of SOTA could last for a long time is still inconclusive, high quality research is still lacking, and this study attempts to explore this issue; The efficacy of SOTA at different times will be compared by direct comparisons and indirect comparisons, this can lead to more accurate and reliable results; The quality of the included literatures are uneven, and some data might be estimated by calculation, which may affect the quality of this study.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic β cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes.

Background: Type 1 Diabetes Mellitus (T1DM) has long required insulin treatment. Sotagliflflozin (SOTA), as a dual SGLT-1/2 inhibitor, has the potential to be the first oral antidiabetic drug (OAD) to be approved for T1DM in the US market. It is important to evaluate the effectiveness of SOTA for T1DM. Methods: Web of Science, PubMed datebase, Cochrane Library, Embase, Clinical Trials, and CNKI will be searched to identify randomized controlled trials (RCTs) exploring SOTA adjuvant therapy for T1DM. Strict screening and quality evaluation will be performed on the obtained literature independently by 2 researchers; outcome indexes will be extracted. The bias risk of the included studies will be evaluated based on Cochrane assessment tool. Meta-analysis will be performed on the data using Revman 5.3 software. Result: We will provide practical and targeted results assessing the efficacy and safety of SOTA for T1DM patients, to provide reference for clinical use of SOTA. Conclusion: The stronger evidence about the efficacy and safety of SOTA for T1DM patients will be provided for clinicians. Trial registration number: PROSPERO CRD42019133099.

Purpose The purpose of this study was to conduct qualitative participant interviews to provide context to the meaningfulness of improvements in end points seen in 2 large-scale Phase III sotagliflozin trials in participants with type 1 diabetes. Methods Participants were eligible for an interview if they had exited one of the clinical trials within the previous 12 months. Participants were recruited by investigators at the clinical trial sites, and interviews were conducted by independent interviewers by telephone in accordance with a semistructured interview guide. Both interviewers and participants were blinded to treatment assignment. Qualitative analysis was conducted using ATLAS-ti version 7.5, and descriptive statistics were computed and summarized. Findings Across 3 countries, 41 participants were interviewed. Difficulty maintaining blood glucose within a desired range, described by participants as lack of blood glucose “stability,” was the most concerning symptom that they reported, wanting to see it improved during the clinical trial because it negatively impacted their physical, mental, and emotional lives. Participants who reported symptom improvement also reported a positive psychosocial impact while taking the clinical trial medication. All participants who monitored ketones described themselves as being “pretty confident” to “very confident” that they could avoid diabetic ketoacidosis by monitoring both ketone levels and understanding the physical signs and symptoms of hyperglycemia. Implications Improvements in glucose stability and control were important to participants with type 1 diabetes, as these improvements were correlated with improvements in the participants' lives. ClinicalTrials.gov identifiers: NCT02384941; NCT02421510.

Recent ADA/EASD recommendations emphasize the importance of the patient role in therapy decisions. Adjunct to insulin SGLT inhibitor (SGLTi) therapy for T1D has been evaluated in RCTs but patient reaction to the benefit-risk profile of these agents is unknown. We aimed to objectively evaluate patient preferences for different therapy options, using a Discrete Choice Experiment (DCE) form of conjoint analysis, a validated methodology. The DCE used an online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, 228 Germany), to present 6 hypothetical, masked pair-wise drug profile comparison choices composed of different benefit-risk attributes and clinical effect ranges (levels). Attributes and levels were derived from different combinations of phase 3 trial data for a low dose SGLTi (comparable to empagliflozin 2.5mg); a high dose SGLTi (comparable to sotagliflozin 400mg); and an available adjunct to insulin therapy (pramlintide 60µg TID). Based upon respondents’ choices, DCE calculated, in %, the relative importance of one attribute to another and the overall predicted therapy preferences. DKA risk was the most important attribute with a relative importance of 23% (z-test, p In conclusion, the DCE and head-to-head explicit choice identified low dose SGLTi as the favored patient preference for adjunct therapy to insulin in T1D. Disclosure B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. L.M. Laffel: Advisory Panel; Self; Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Janssen Pharmaceuticals, Inc., UpToDate. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. C. Pang: Consultant; Self; dQ&A Market Research, Inc. R. Wood: Other Relationship; Self; Multiple companies in the diabetes field (>10 companies). O. Kinduryte: Employee; Self; Boehringer Ingelheim International GmbH. Stock/Shareholder; Self; Novo Nordisk A/S, Zealand Pharma A/S. J. George: Employee; Self; Boehringer Ingelheim International GmbH. J. Marquard: Employee; Self; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Self; Boehringer Ingelheim Canada Ltd. Funding Boehringer Ingelheim; Eli Lilly and Company

Individuals with type 1 diabetes (T1D) face daily challenges in achieving optimal glycemic control by reducing hyperglycemia while avoiding hypoglycemia. Optimization is reflected by the High/Low Blood Glucose Indices (HBGI/LBGI) - established metrics using self-monitored blood glucose, or continuous glucose monitoring (CGM) data, to assess glycemic variability (GV) and predict the risks of hyper- and hypoglycemia with intensification of therapy. In the phase 3 inTandem1 and 2 studies, sotagliflozin (SOTA), a dual SGLT1 and 2 inhibitor used as adjunct to optimized insulin therapy in adults with T1D, reduced HbA1c vs. placebo. Significant improvement of glucose time in range (70-180 mg/dL) without increasing time Compared with placebo, HBGI values were lower with SOTA 400 mg at study weeks 4, 12, and 24, and SOTA 200 mg at weeks 4 and 12 (p The percentage of adults in moderate (4.5-9) or high-risk (>9) HBGI categories was reduced with SOTA throughout the study for both dosages, and minimal changes were seen in LBGI values and risk categories. The CGM profile showed that SOTA reduced GV through a favorable impact on HBGI without changing LBGI. Disclosure B. Kovatchev: Advisory Panel; Self; Sanofi. Board Member; Self; TypeZero Technologies, Inc. Consultant; Self; Sanofi, Tandem Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc. Stock/Shareholder; Self; TypeZero Technologies, Inc. Other Relationship; Self; Johnson & Johnson, Sanofi. S. Wang: Employee; Self; Sanofi US. J.H. Oliveira: Employee; Self; Sanofi. Employee; Spouse/Partner; Sanofi. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. R. Castro: Employee; Self; Sanofi US. Funding Lexicon Pharmaceuticals, Inc.; Sanofi

Hypoglycemia (HYPO) is a major barrier in achieving optimal glycemic control in T1D. Intensifying insulin therapy to lower HbA1c is frequently accompanied by an increased risk of HYPO. In two 52-week phase 3 studies (inTandem1 and 2), sotagliflozin (SOTA), a dual SGLT1 and 2 inhibitor as adjunct to optimized insulin therapy, demonstrated significant reduction in HbA1c and body weight without increasing the risk of severe hypoglycemia compared with placebo (PBO) in adults with T1D. To further evaluate the HYPO profile of SOTA added to insulin, we analyzed rates of confirmed HYPO (level 1, glucose ≤70 mg/dL in the study) and clinically important HYPO (level 2, glucose ≤55 mg/dL in the study) in a patient-level pooled analysis (n=1,368) using a negative binomial model adjusted for HbA1c at week 52. Rates of level 1 HYPO events per patient year were 99.48, 77.14, and 77.14 for PBO, SOTA 200mg, and 400mg, respectively (P In conclusion, at week 52 overall level 1 and 2 HYPO event rates were 22.5-30% lower with SOTA when used as adjunct to optimized insulin therapy vs. PBO and were reduced at any HbA1c level especially at lower HbA1c values. Disclosure T. Danne: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Dexcom, Inc. J. Pettus: Advisory Panel; Self; Diasome Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; MannKind Corporation. A. Giaccari: Advisory Panel; Self; Sanofi. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Merck Sharp & Dohme Corp., Sanofi. B. Cariou: Board Member; Self; Novo Nordisk A/S, Regeneron Pharmaceuticals. Consultant; Self; GENFIT, Sanofi-Aventis. Research Support; Self; Amgen Inc., Pfizer Inc. Speaker's Bureau; Self; Abbott, Akcea Therapeutics, Merck Sharp & Dohme Corp. H.W. Rodbard: Advisory Panel; Self; Bayer US, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Spouse/Partner; Eli Lilly and Company. Consultant; Self; Gan & Lee Pharmaceuticals. Research Support; Self; Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Merck & Co., Inc., Novo Nordisk Inc. S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. M. Bonnemaire: Employee; Self; Sanofi. S. Sawhney: Stock/Shareholder; Spouse/Partner; AstraZeneca, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck & Co., Inc., Pfizer Inc. S. Wang: Employee; Self; Sanofi US. R. Castro: Employee; Self; Sanofi US. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD. Funding Lexicon Pharmaceuticals Inc.; Sanofi

In people with type 2 diabetes (T2D), SGLT2 inhibitors reduce cardiovascular risk and diabetic kidney disease (DKD) progression. Because several mechanisms of DKD progression overlap in people with T2D and T1D, our aim was to assess if sotagliflozin (SOTA), a dual SGLT1 and 2 inhibitor, had favorable renal effects suggestive of kidney protection in adults with T1D. In this 52-week pooled analysis, 1575 adults enrolled in the InTandem 1 and 2 trials were randomized to SOTA 200 mg, 400 mg, or placebo (PBO) in addition to optimized insulin therapy. Mean changes of eGFR (MDRD), urinary albumin to creatinine ratio (UACR, geometric mean), systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline to week 52 were compared with PBO. From a baseline eGFR of 89.30±0.86 ml/min/1.73m2, mean eGFR reduction was -2.50±0.63 ml/min/1.73m2 vs. PBO after 4 weeks for SOTA 200 mg and similar change was observed with 400 mg (p In adults with T1D, SOTA 200 mg was associated with short and long-term hemodynamic changes in eGFR and lower UACR. SOTA 200 and 400 mg lowered SBP and DBP and induced mild hemoconcentration. These data suggest that the renal hemodynamic profile of SOTA in T1D is similar to that seen with SGLT2 inhibition in T2D. Further investigation around cardiorenal effects of SOTA in people with T1D is warranted. Disclosure D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. R. Castro: Employee; Self; Sanofi US. S. Wang: Employee; Self; Sanofi US. D.R. Powell: Employee; Self; Lexicon Pharmaceuticals, Inc. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi.

Context The effect of sotagliflozin (a dual sodium–glucose cotransporter [SGLT] 2 and SGLT1 inhibitor) on intestinal glucose absorption has not been investigated in humans. Objective To measure rate of appearance of oral glucose (RaO) using a dual glucose tracer method following standardized mixed meals taken after single sotagliflozin or canagliflozin doses. Setting Clinical research organization Design and participants In a double-blind, 3-period crossover study (NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 participants. Within each cohort, participants were randomly assigned single oral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on each of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing [6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 hours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours postdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All participants received a 10- to 15-hour continuous [U-13C6] glucose infusion starting 5 hours before their first [6,6-2H2] glucose-containing meal. Main Outcome RaO, postprandial glucose (PPG), and postprandial insulin. Results Sotagliflozin and canagliflozin decreased area under the curve (AUC)0–1 hour and/or AUC0–2 hours for RaO, PPG, and insulin after breakfast and/or the 4.25-hour postdose lunch (P Conclusions Sotagliflozin delayed and blunted intestinal glucose absorption after meals, resulting in lower PPG and insulin levels, likely due to prolonged local inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.

Sotagliflozin (Sota) inhibits sodium glucose cotransporter 2 (SGLT2; IC50=1.8 nM) and SGLT1 (IC50=36 nM). In humans, Sota improves glycemic control in part by increasing urinary glucose excretion via renal SGLT2 inhibition. Sota also lowers postprandial glucose (PPG), likely by inhibiting intestinal SGLT1 to delay the rate of appearance of oral glucose (RaO). To test the hypothesis that Sota delays SGLT1-mediated RaO, we performed a randomized, 3-period crossover study comparing effects of single doses of placebo (Pbo), Sota (400 mg) and canagliflozin (Cana, 300 mg), an SGLT2 inhibitor (IC50=4.2 nM) that inhibits SGLT1 (IC50=663 nM) with lower potency than Sota, on RaO using a dual-glucose tracer method in two cohorts of 12 healthy subjects each; plasma glucose, insulin and additional pharmacodynamic parameters were also evaluated. All subjects received a continuous [U-13C6] glucose infusion starting 5 hr before their first mixed meal (MM) test. Cohort 1 subjects had a MM breakfast containing [6,6-2H2] glucose starting 0.25 hr postdose and a MM lunch containing [1-2H1] glucose starting 5.25 hr postdose. Cohort 2 subjects had a MM breakfast containing no labeled glucose starting 0.25 hr postdose and a MM lunch containing [6,6-2H2] glucose starting 4.25 hr postdose. Plasma glucose, and labeled glucose as a fraction of plasma glucose, were measured frequently for 5 hr after any MM containing labeled glucose, while plasma levels of insulin, intestinal hormones and other analytes were measured frequently after any MM containing [6,6-2H2] glucose. For the Cohort 1 MM breakfast, Sota and Cana: 1) lowered RaO AUC[0-1 hr] and RaO AUC[0-2 hr], and also lowered AUC[0-4hr] for insulin, c-peptide and gastric inhibitory peptide (GIP), all p

学位記番号：医博甲1731

Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood–brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.