Sotagliflozin and Kidney Outcomes, Kidney Function, and Albuminuria in Type 2 Diabetes and CKD: A Secondary Analysis of the SCORED Trial.

BACKGROUND: In the initial analysis of the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial, because of early trial termination and suspension of adjudication, reconciliation of eGFR laboratory data and case report forms had not been completed. This resulted in a small number of kidney composite events and a nominal effect of sotagliflozin versus placebo on this outcome. This exploratory analysis uses laboratory eGFR data, regardless of case report form completion, to assess the effects of sotagliflozin on the predefined kidney composite end point in the SCORED trial and additional cardiorenal composite end points. METHODS: SCORED was a multicenter, randomized trial evaluating cardiorenal outcomes with sotagliflozin versus placebo in 10,584 patients with type 2 diabetes and CKD. This exploratory analysis used laboratory data to derive the eGFR components and case report form data for the non-laboratory-defined components that together made up the kidney and cardiorenal composites. AKI was also assessed in this dataset. RESULTS: Using laboratory data, 223 events were identified, and sotagliflozin reduced the risk of the composite of first event of sustained ≥50% decline in eGFR, eGFR <15 ml/min per 1.73 m 2 , dialysis, or kidney transplant with 87 events (1.6%) in the sotagliflozin group and 136 events (2.6%) in the placebo group (hazard ratio [95% confidence interval], 0.62 [0.48 to 0.82]), P < 0.001). Sotagliflozin reduced the risk of a cardiorenal composite end point defined as the abovementioned composite plus cardiovascular or kidney death with 239 events (4.5%) in the sotagliflozin group and 306 events (5.7%) in the placebo group (hazard ratio [95% confidence interval], 0.77 [0.65 to 0.91], P = 0.0023). The results were consistent when using different eGFR decline thresholds and when only including kidney death in composites (all P < 0.01). The incidence of AKI was similar between treatment groups. CONCLUSIONS: In this exploratory analysis using the complete laboratory dataset, sotagliflozin reduced the risk of kidney and cardiorenal composite end points in patients with type 2 diabetes and CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03315143 .

[Mechanism of Qiwei Guibao Granules in treatment of premature ovarian failure based on proteomics].

In this study, the underlying mechanism of Qiwei Guibao Granules(QWGB) in the treatment of premature ovarian fai-lure(POF) was explored by the proteomics technique. Firstly, the POF model was induced in mice by intragastric administration of Tripterygium wilfordii glycosides solution at 50 mg·kg~(-1) for 14 days. Ten days prior to the end of the modeling, the estrous cycle of mice was observed every day to evaluate the success of modeling. From the 1st day after modeling, the POF model mice were treated with QWGB by gavage every day and the treatment lasted four weeks. On the 2nd day after the end of the experiment, blood was collected from the eyeballs and the serum was separated by centrifugation. The ovaries and uterus were collected and the adipose tissues were carefully stripped. The organ indexes of the ovaries and uterus of each group were calculated. The serum estrogen(E_2) level of mice in each group was detected by ELISA. Protein samples were extracted from ovarian tissues of mice, and the differential proteins before and after QWGB intervention and before and after modeling were analyzed by quantitative proteomics using tandem mass tags(TMT). As revealed by the analysis of differential proteins, QWGB could regulate 26 differentially expressed proteins related to the POF model induced by T. wilfordii glycosides, including S100A4, STAR, adrenodoxin oxidoreductase, XAF1, and PBXIP1. GO enrichment results showed that the 26 differential proteins were mainly enriched in biological processes and cellular components. The results of KEGG enrichment showed that those differential proteins were involved in signaling pathways such as completion and coalescence cascades, focal adhesion, arginine biosynthesis, and terpenoid backbone biosynthesis. The complement and coalescence cascades signaling pathway was presumably the target pathway of QWGB in the treatment of POF. In this study, the proteomics technique was used to screen the differential proteins of QWGB in the treatment of POF in mice induced by T. wilfordii glycosides, and they were mainly involved in immune regulation, apoptosis regulation, complement and coagulation cascade reactions, cholesterol metabolism, and steroid hormone production, which may be the main mechanisms of QWGB in the treatment of POF.

Efficacy and safety of Tripterygium glycosides as an add-on treatment in adults with chronic urticaria: a systematic review and meta-analysis.

CONTEXT: Tripterygium glycosides (TG), a traditional Chinese medicine, has been used to treat chronic urticaria (CU) in China, and the evidence of TG for CU needs to be updated thoroughly. OBJECTIVE: To systematically evaluate the efficacy and safety of TG combined with H1-antihistamine (H1-AH) in adults with CU. METHODS: Eligible randomized controlled trials were searched in eight databases until May 31, 2022, including CNKI, WanFang, VIP, SinoMed, PubMed, Cochrane Library, Embase, and Web of Science. The search terms included urticaria, Tripterygium, Lei Gong Teng, and Leigongteng. Rev Man 5.3 and Stata 12.0 were used for statistical analysis. RESULTS: A total of 27 studies with 2788 patients were included. The pooled results showed that TG plus H1-AH was superior to H1-AH alone in cure rate (RR = 1.37, 95% CI = 1.15 to 1.63, p = 0.0003), total efficacy rate (RR = 1.40, 95% CI = 1.30 to 1.50, p < 0.00001), pruritus (MD = -0.32, 95% CI = -0.54 to -0.11, p = 0.003), wheal number (MD = -0.31, 95% CI = -0.55 to -0.07, p = 0.01), wheal size (MD = -0.32, 95% CI = -0.46 to -0.19, p < 0.00001), and the serum level of immunoglobulin E (SMD = -1.39, 95% CI = -2.42 to -0.36, p = 0.008). Moreover, adverse events between two groups were mild, and their incidences were not significantly different. CONCLUSIONS: The combination of TG and H1-AH is a promising and safe treatment for adults with refractory CU. Further high-quality studies are needed to confirm the evidence.

Mechanism of Qiwei Guibao Granules in treatment of premature ovarian failure based on proteomics / 中国中药杂志

In this study, the underlying mechanism of Qiwei Guibao Granules(QWGB) in the treatment of premature ovarian fai-lure(POF) was explored by the proteomics technique. Firstly, the POF model was induced in mice by intragastric administration of Tripterygium wilfordii glycosides solution at 50 mg·kg~(-1) for 14 days. Ten days prior to the end of the modeling, the estrous cycle of mice was observed every day to evaluate the success of modeling. From the 1st day after modeling, the POF model mice were treated with QWGB by gavage every day and the treatment lasted four weeks. On the 2nd day after the end of the experiment, blood was collected from the eyeballs and the serum was separated by centrifugation. The ovaries and uterus were collected and the adipose tissues were carefully stripped. The organ indexes of the ovaries and uterus of each group were calculated. The serum estrogen(E_2) level of mice in each group was detected by ELISA. Protein samples were extracted from ovarian tissues of mice, and the differential proteins before and after QWGB intervention and before and after modeling were analyzed by quantitative proteomics using tandem mass tags(TMT). As revealed by the analysis of differential proteins, QWGB could regulate 26 differentially expressed proteins related to the POF model induced by T. wilfordii glycosides, including S100A4, STAR, adrenodoxin oxidoreductase, XAF1, and PBXIP1. GO enrichment results showed that the 26 differential proteins were mainly enriched in biological processes and cellular components. The results of KEGG enrichment showed that those differential proteins were involved in signaling pathways such as completion and coalescence cascades, focal adhesion, arginine biosynthesis, and terpenoid backbone biosynthesis. The complement and coalescence cascades signaling pathway was presumably the target pathway of QWGB in the treatment of POF. In this study, the proteomics technique was used to screen the differential proteins of QWGB in the treatment of POF in mice induced by T. wilfordii glycosides, and they were mainly involved in immune regulation, apoptosis regulation, complement and coagulation cascade reactions, cholesterol metabolism, and steroid hormone production, which may be the main mechanisms of QWGB in the treatment of POF.

Therapeutic Effect and Safety of Tripterygium Glycosides Combined With Western Medicine on Type 2 Diabetic Kidney Disease: A Meta-Analysis.

PURPOSE: Tripterygium glycosides (TG) are widely used for the treatment of kidney disease in China. However, the application of TG in clinical practice is limited, as the therapeutic window is narrow, and the therapeutic dose is close to the toxic dose. In addition, the therapeutic effect of TG combined with Western medicine has not been fully elucidated. This study sought to explore standardized treatment, efficacy, and safety of TG combined with Western medicine for patients with type 2 diabetic kidney disease (T2DKD). METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, Chinese Scientific Journal, and Wan Fang databases were searched for randomized controlled trials of TG combined with Western medicine on T2DKD from their inception until May 4, 2021. A random effects model was used to explore heterogeneity of studies. FINDINGS: A total of 33 studies with 2034 patients were included in the current meta-analysis. The findings showed that TG combined with Western medicine effectively reduced urinary albumin excretion rates (standardized mean difference, -2.55; 95% CI, -4.70 to -0.40; P = 0.02), 24-hour urinary protein level (mean difference, -0.79; 95% CI, -1.22 to -0.36; P = 0.0003), and serum creatinine level (mean difference, -8.23; 95% CI, -14.48 to -1.99; P = 0.01) and increased albumin level (mean difference, 4.70; 95% CI, 3.27 to 6.13; P < 0.00001) in patients with T2DKD. No serious adverse reactions occurred, and the incidence of adverse events in the TG combined with Western medicine treatment group was slightly higher than in the control group (8.14% vs 2.65%). The results were stable, and a significant publication bias was not detected (P > 0.05). IMPLICATIONS: Based on our results, TG combined with Western medicine may be an effective and safe therapy for T2DKD; the best treatment duration may be 3 to 6 months. Nevertheless, larger, longer multicenter studies should be conducted for clinical application of the regimen to patients in more countries and regions. PROSPERO registration number: CRD42021259466.

Iron supplementation ameliorates aloin-induced iron deficiency anemia in rats.

Aloin, an anthraquinone glycoside, is one of other C-glycosides found in the leaf exudate of Aloe plant. Aloin possesses several biologic activities, including antitumor activity in vitro and in vivo. However, aloin treatment has shown iron deficiency anemia and erythropoiesis in vivo. The present study was undertaken to verify if iron supplementation could alleviate these perturbations, compared to doxorubicin, an anthracycline analog. Oral iron supplementation (20.56 mg elemental Fe/kg bw) to aloin-treated rats normalized red blood corpuscles count, hemoglobin concentration, and serum levels of total iron binding capacity and saturated transferrin, as well as hepatic iron content, hepcidin level, and mRNA expression of ferritin heavy chain (Ferr-H) and transferrin receptor-1 (TfR-1) genes. Although, serum hyperferremia, and leukocytosis were maintained, yet the spleen iron overload was substantially modulated. However, combined aloin and iron treatment increased iron storage levels in the heart and bone marrow, compared to aloin treatment per se. On other hand, oral iron supplementation to rats treated with doxorubicin (15 mg/kg bw) lessened the increase in the spleen iron content concomitantly with hepatic hepcidin level, rebound hepatic iron content to normal level, and by contrast augmented serum levels of iron and transferrin saturation. Also, activated Ferr-H mRNA expression and repressed TfR-1 mRNA expression were recorded, compared to doxorubicin treatment per se. Histopathological examination of the major body iron stores in rats supplemented with iron along with aloin or doxorubicin showed an increase in extramedullary hematopoiesis. In conclusion, iron supplementation restores the disturbances in iron homeostasis and erythropoiesis induced by aloin treatment.

Sotagliflozin for patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs comprising 16 411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42%, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09), and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. CONCLUSIONS: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium-glucose co-transporter-2 inhibitors.

Efficacy of tripterygium glycosides for diabetic nephropathy: a meta-analysis of randomized controlled trials.

BACKGROUNDS: Diabetic nephropathy (DN) is one of the most important clinical complications of diabetes mellitus (DM) and is the most common cause of end-stage renal disease. Currently, there is no highly effective medicine that can prevent, halt, or reverse the progressive course of DN. Initial clinical data showed that Tripterygium glycosides (TGs), a traditional Chinese medicine, can decrease proteinuria in patients with DN. OBJECTIVES: The objective of the present study is to investigate the efficacy and safety of TGs for the treatment of DN through meta-analysis of randomized controlled trials (RCTs). METHODS: All RCTs of TGs for DN were collected from The China National Knowledge Infrastructure (CNKI), PubMed, Web of Science, Wanfang Data, Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP) by setting the study inclusion and elimination standards. Two reviewers evaluated the quality of the trials and extracted the data independently. RevMan 5.4 software was used for meta-analyses. The primary outcome was a change in 24-hours urinary total protein (24 h TUP). RESULTS: 26 RCTs with 1824 participants were identified. Studies were assessed using the Cochrane risk of bias tool. The overall effects showed that TGs was compared with the controls, TGs showed significant effects in reducing 24 h TUP [WMD = -0.84, 95 % CI (-1.09, -0.59)], elevating serum albumin [WMD = 2.88, 95 % CI (1.87, 3.90)], and the total efficiency [OR = 4.08, 95 % CI (2.37, 7.04)]. This effect was consistent across the subgroups of period of intervention. CONCLUSIONS: The present research showed that TGs was significantly associated with improvement of renal function in patients with DN. TGs offers a novel approach to the treatment of DN, more high-quality RCTs are needed for a better understanding of the role of TGs in DN therapy.

Effect and safety evaluation of tacrolimus and tripterygium glycosides combined therapy in treatment of Henoch-Schönlein purpura nephritis.

OBJECTIVE: Henoch-Schönlein purpura nephritis has become a significant threat to children's health. Traditional combined therapy of glucocorticoids and cyclophosphamide leads to severe toxicity and complications. Therefore, identifying a feasible and effective strategy with low side-effects for the treatment of Henoch-Schönlein purpura nephritis is of great significance. METHODS: A randomized, controlled trial was carried out. A total of 279 children with Henoch-Schönlein purpura nephritis were recruited and randomly divided into three groups: control group (receiving the current standard therapy), TA group (receiving tacrolimus) and TA + tripterygium glycosides group (receiving tacrolimus + tripterygium treatment). The total duration of the trial was 6 months, and the duration of follow-up observation was 9 months. RESULTS: Various therapies showed similar therapeutic effects in the third and sixth months. The relief of Henoch-Schönlein purpura nephritis symptoms caused by TA + tripterygium glycosides was slower than the TA and control groups. The incidence of adverse reactions in the TA + tripterygium glycosides group was lower in the control and TA groups. The final treatment effect of the experimental groups was better than the control group. The recurrence rate in the TA + tripterygium glycosides group was also significantly lower. CONCLUSION: Tacrolimus and tripterygium glycosides combined therapy had better effects and safety for long-term treatment of Henoch-Schönlein purpura nephritis.

A case of tripterygium glycosides-associated AGEP-like drug reaction combined with bullous pemphigoid.

Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous drug reaction. Bullous pemphigoid (BP) is an acquired autoimmune disease that might be associated with drugs. There is currently no report of tripterygium glycosides (TG)-induced AGEP-like lesions combined with BP. A 66-year-old male with a 20-year history of psoriasis was prescribed oral TG at 1 mg/kg, three times a day, due to aggravated psoriasis. Seven days later, erythemas, and blisters appeared. After another 3 days, there were two types of blisters: (1) numerous small tension blisters with a lot of neutrophils on the top similar to AGEP combined with BP; (2) a BP. After intravenous injection of methylprednisolone and gamma globulin, the lesions were controlled. This patient developed two types of lesions, including one similar to AGEP combined BP (AGEP-like) and a BP. It is a rare drug reaction induced by TG.

Efficacy of combined angiotensin II receptor blocker with tripterygium glycosides on diabetic nephropathy: A protocol for meta-analysis.

BACKGROUND: Several studies have reported good results for angiotensin II receptor blockers (ARB) combined with tripterygium glycosides (TGs) in the treatment of diabetic nephropathy (DN). However, because a small number of cases were included in each study, the statistical power was limited. Therefore, we performed a protocol for meta-analysis to further evaluate the clinical efficacy and safety of combined ARB and TGs in treatment of DN. METHODS: The protocol was written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, Science Direct up to April 2021. Outcome measures were 24-h urinary total protein, urinary albumin excretion rate, serum creatinine, blood urea nitrogen, albumin, hemoglobin A1c, ß2-microglobulin and serum glutamic pyruvic transaminase. The risk of bias assessment of the included studies was performed by two authors independently using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). We performed meta-analysis using STATA 11.0. RESULTS: The review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings. CONCLUSION: The findings will provide helpful evidence for the application of combined ARB and TGs in the treatment of DN. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/ARGE3.

A review of pharmacological and pharmacokinetic properties of Forsythiaside A.

Traditional Chinese medicine plays a significant role in the treatment of various diseases and has attracted increasing attention for clinical applications. Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a widely used Chinese medicinal herb in clinic for its extensive pharmacological activities. Forsythiaside A is the main active index component isolated from Forsythiae Fructus and possesses prominent bioactivities. Modern pharmacological studies have confirmed that Forsythiaside A exhibits significant activities in treating various diseases, including inflammation, virus infection, neurodegeneration, oxidative stress, liver injury, and bacterial infection. In this review, the pharmacological activities of Forsythiaside A have been comprehensively reviewed and summarized. According to the data, Forsythiaside A shows remarkable anti-inflammation, antivirus, neuroprotection, antioxidant, hepatoprotection, and antibacterial activities through regulating multiple signaling transduction pathways such as NF-κB, MAPK, JAK/STAT, Nrf2, RLRs, TRAF, TLR7, and ER stress. In addition, the toxicity and pharmacokinetic properties of Forsythiaside A are also discussed in this review, thus providing a solid foundation and evidence for further studies to explore novel effective drugs from Chinese medicine monomers.

Effect of sotagliflozin as an adjunct to insulin therapy on blood pressure and arterial stiffness in adults with type 1 diabetes: A post hoc pooled analysis of inTandem1 and inTandem2.

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 < 0.0001), respectively. DBP decreased by 1.1 and 0.9 mm Hg, MAP by 1.4 and 1.6 mm Hg, and double product by 202.5 and 221.1 bpm × mm Hg, respectively (p < 0.05 for all). No increases in heart rate were observed. CONCLUSION: In adults with T1D, adding sotagliflozin to insulin significantly reduced blood pressure and other markers of arterial stiffness and vascular resistance.

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown. METHODS: We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor. RESULTS: A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose. CONCLUSIONS: In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.

BACKGROUND: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).

Perturbation of the human gastrointestinal tract microbial ecosystem by oral drugs to treat chronic disease results in a spectrum of individual specific patterns of extinction and persistence of dominant microbial strains.

BACKGROUND: Oral drugs can have side effects such as diarrhea that indicate the perturbation of the gut microbial community. To further understand the dynamics of perturbation, we have assessed the strain relatedness of samples from previously published data sets from pre and post bowel evacuation, episodes of diarrhea, and administration of oral drugs to treat diabetes and rheumatoid arthritis. METHODS: We analyzed a total of published five data sets using our strain-tracking tool called Window-based Single Nucleotide Variant (SNV) Similarity (WSS) to identify related strains from the same individual. RESULTS: Strain-tracking analysis using the first data set from 8 individuals pre and 21-50 days post iso-osmotic bowel wash revealed almost all microbial strains were related in an individual between pre and post samples. Similarly, in a second study, strain-tracking analysis of 4 individuals pre and post sporadic diarrhea revealed the majority of strains were related over time (up to 44 weeks). In contrast, the analysis of a third data set from 22 individuals pre and post 3-day exposure of oral metformin revealed that no individuals had a related strain. In a fourth study, the data set taken at 2 and 4 months from 38 individuals on placebo or metformin revealed individual specific sharing of pre and post strains. Finally, the data set from 18 individuals with rheumatoid arthritis given disease-modifying antirheumatic drugs methotrexate or glycosides of the traditional Chinese medicinal component Tripterygium wilfordii showed individual specific sharing of pre and post strains up to 16 months. CONCLUSION: Oral drugs used to treat chronic disease can result in individual specific microbial strain change for the majority of species. Since the gut community provides essential functions for the host, our study supports personalized monitoring to assess the status of the dominant microbial strains after initiation of oral drugs to treat chronic disease.

An up-to-date evaluation of sotagliflozin for the treatment of type 1 diabetes.

INTRODUCTION: The majority of patients with type 1 diabetes mellitus (T1DM) do not achieve glycemic targets. In addition, treatment with insulin is associated with increased risk for hypoglycemia and weight gain. Accordingly, there is an unmet need for new safe and effective glucose-lowering agents in this population. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, has been recently approved for use in patients with T1DM. AREAS COVERED: The authors review the major trials that have evaluated the safety and efficacy of sotagliflozin and provide their expert opinion. EXPERT OPINION: Even though sotagliflozin reduces HbA1 c levels and does not appear to increase the risk for hypoglycemia in most patients, the substantially increased risk for diabetic ketoacidosis limits the use of this agent to a carefully selected subgroup of patients with T1DM. Based on the existing evidence, sotagliflozin should be considered only in patients who have failed to achieve adequate glycemic control despite optimal insulin therapy, are at low risk for diabetic ketoacidosis, have been adequately trained to recognize this complication and are able to be in close contact with their physician.