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Context: Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies., Objective: We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA + SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs)., Design: 24-week substudy of a randomized, open-label, 2-arm, parallel-group, phase 3b study., Setting: Multicenter study (112 centers in 11 countries)., Patients: 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea., Interventions: DAPA + SAXA vs INS., Main Outcome Measures: Changes in CGM profiles, HbA1c, and PROs., Results: Changes from baseline in HbA1c with DAPA + SAXA were similar to those observed with INS, with mean difference [95% confidence interval] between decreases of -0.12% [-0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA + SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (-0.7 ± 0.1 vs -0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being., Conclusion: DAPA + SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA + SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Gastric cancer (GC) is a common malignant disease that has a fifth highest incidence and fourth highest mortality worldwide. The Warburg effect is a common phenomenon observed in tumors, which suggests that tumor cells would enhance glucose uptake by overexpressing multiple glucose transporters. Sodium glucose transporter 2 (SGLT2) is one of glucose transporters which highly expressed in several cancers, but its role in gastric cancer is still unclear. Our research found that there was a high expression level of SGLT2 in gastric cancer tissues. We found that Dapagliflozin (a SGLT2 inhibitor) could suppress gastric cancer cell proliferation and migration in vitro and tumor growth in vivo. In present study, we revealed how dapagliflozin would suppress gastric cancer progression in a novel mechanism. We proved that dapagliflozin decreased the expression level of OTU deubiquitinase 5 (OTUD5), which further increased the ubiquitination and degradation of YAP1. Overexpression of OTUD5 in gastric cancer cells partly reversed the anti-tumor effect of dapagliflozin. Our findings revealed a novel mechanism by which dapagliflozin has an antitumor effect on gastric cancer and proposed a beneficial strategy for the application of dapagliflozin in gastric cancer patients., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The pathway of Janus-activated kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) (termed as JAK2/STAT3) plays an active role in stroke-related inflammation induced by ischemic stress. Gastrodin, the primary compound in Gastrodia elata Bl, has been identified for its notable neuroprotective effects and demonstrated to ameliorate cerebral ischemia-reperfusion but its exact mechanisms governing this defense are still unclear. This study aims to investigate whether gastrodin can regulate mitochondrial function via the JAK2/STAT3 pathway to limit cerebral ischemia-reperfusion. In vivo, gastrodin significantly reduced infarct volume, improved neurobiological function, attenuated neuronal apoptosis, oxidative stress, mitochondrial impairment, mtDNA leakage, and inflammatory responses. At the cellular level, gastrodin administration rescued OGD/R-induced cell apoptosis, oxidative stress, and mitochondrial dysfunction. Mechanistically, gastrodin notably suppressed Toll-like receptor 9 (TLR9) expression, important for the recognition of disrupted endogenous DNA to produce inflammatory reactions. Furthermore, gastrodin mitigated inflammation by inhibiting JAK2/STAT3 signaling, influencing inflammatory factors to aggravate inflammation. Notably, the effects of gastrodin were abolished by Coumermycin A1 (C-A1), a JAK2 agonist, validating the role of JAK2/STAT3 signaling. In summary, gastrodin enhances the protective effect against mitochondrial damage in ischemic stroke by inhibiting JAK2/STAT3 signaling. Gastrodin is a possible therapy for cerebral ischemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Prior research has demonstrated an association between sodium-glucose cotransporter 2 (SGLT2) inhibitor and a reduced incidence of atrial fibrillation (AF). Given the established link between mitochondrial dysfunction and AF, this study aimed to explore the impact of SGLT2 inhibitors on AF burden and plausible antiarrhythmic mechanisms in patients with cardiovascular implantable electronic devices (CIEDs). Patients with atrial high-rate episodes (AHREs) detected by CIEDs were randomized to receive either 10 mg of dapagliflozin or a placebo for 3 months. AF burdens were quantified via CIEDs interrogations as AHREs duration, percentage, and number of episodes at baseline and after 3 months of treatment. Mitochondrial parameters, cellular oxidative stress, and norepinephrine levels were measured in peripheral blood mononuclear cells (PBMCs). A total of 54 patients with CIEDs were enrolled in the study. Among them, 36 patients (66.7%) had a history of clinical AF, and 9 patients (16.7%) had diabetes mellitus. After 3 months of the assigned treatment, the median longest AHRE duration decreased similarly in both the dapagliflozin and placebo groups (-77.0 vs. -162.0 min, p = 0.442). Clinical AF, as opposed to subclinical AF, was independently linked to decreased basal respiration and adenosine triphosphate (ATP) production. Although the changes in AHREs burden over the 3 months did not significantly differ between the dapagliflozin and placebo groups, dapagliflozin significantly decreased the number of AHREs per month by 2.2 episodes among patients with clinical AF, whereas the placebo group experienced an increase of 0.6 episodes (p = 0.048). Additionally, dapagliflozin significantly reduced cellular oxidative stress (from 26840 to 18164 arbitrary units, p = 0.049) and improved mitochondrial spare respiratory capacity (SRC) percentage (from 166 to 202%, p = 0.016) in patients with clinical AF. Dapagliflozin did not significantly reduce the longest AHRE duration in patients with CIED. However, in the subgroup of patients with clinical AF, dapagliflozin reduced the number of AHREs potentially via reduction of cellular oxidative stress and enhancement of mitochondrial function.The study protocol was registered at the Thai Clinical Trials Registry (TCTR identification number TCTR20210315003) on March 15, 2021., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate The study protocol was approved by the Research Ethics Committee, Chiang Mai University (certificate of approval No.041/2021). The investigations were carried out in accordance with the Declaration of Helsinki. The informed consent was obtained from all subjects and/or their legal guardian(s)., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined., Objectives: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure., Methods: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously., Results: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same., Conclusions: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977)., Competing Interests: Funding Support and Author Disclosures The authors met criteria for authorship as described by the International Committee of Medical Journal Editors (ICMJE). No author received payment related to the development of the manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The study was supported and funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. To ensure independent interpretation of clinical trial results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically 1 year after the approval has been granted by major regulatory authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information. Dr Packer has received consulting fees from 89bio, Abbvie, Actavis, Altimmune, Ardelyx, ARMGO Pharma, Attralus, Amgen, Alnylam, AstraZeneca, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, Cytokinetics, Eli Lilly & Company, Imara, Moderna, Medtronic, Novartis, Pharmacosmos, Reata, Regeneron, and Salamandra. Dr Ferreira has served as consultant for Boheringer Ingelheim and AstraZeneca. Dr Butler has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Filippatos has received consulting fees from Bayer, Boehringer Ingelheim, and Servier; has received lecture fees from Novartis; has received trial committee membership fees from Impulse Dynamics, Vifor, and Medtronic; has served on trial committee for Cardior; and has received consulting fees from Novo Nordisk. Dr Maldonado has received consulting fees from Boehringer Ingelheim Pharma GmbH & Co KG. Dr Saadati has served as freelance statistician for Boehringer. Dr Sattar has served in advisory positions for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics; has received consulting fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novo Nordisk, Pfizer, and Sanofi; has received speaker fees from Abbott Laboratories, AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; and has received research grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr Anker has received grants and personal fees from Vifor and Abbott Laboratories; has received personal fees for consultancies, trial committee work and lectures from Actimed, AstraZeneca, Bayer, Bioventrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 & DE 102007022367), but he does not benefit personally from the related issued patents. Drs Gonzalez Maldonado, Panova-Noeva, Prochaska, Saadati, and Sumin are employees of Boehringer Ingelheim. Dr Zannad has served on the Steering Committee or Data Safety Monitoring Board for or served as a consultant to 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Cardior, Cereno, Cellprothera, CEVA, Merck, Northsea, Novartis, NovoNordisk, Otsuka, Owkin, Salubris, and Servier; has equity in Cardior, G3Pharmaceutical, Cereno Pharmaceutical, and CVCT; and has lectured for Bayer, Boehringer Ingelheim, CVRx, CEVA, Merck, and Novartis. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Currently, there is no comprehensive systematic review available to comprehensively assess the efficacy and safety of Empagliflozin and other sodium-glucose cotransporter 2 inhibitors in the treatment of heart failure (HF). This study employed a meta-analysis approach to systematically evaluate the therapeutic effects of Empagliflozin in HF patients and its impact on cardiac function., Method: The keywords including "heart failure," "HF," "cardiac failure," "cardiac disease," "Empagliflozin," and "sodium-glucose cotransporter 2 inhibitors" were utilized to search for relevant clinical studies on Empagliflozin in the treatment of HF in various databases, such as China National Knowledge Infrastructure, Wanfang, VIP Chinese Medical Journal Database, PubMed, MEDLINE, Embase, Cochrane Library, Springer, and Science Direct. The studies included patients with HF who received drug treatment. Data on baseline characteristics and posttreatment outcomes, including HF hospitalization (HHF), cardiovascular mortality, all-cause mortality, estimated glomerular filtration rate changes, Kansas City Cardiomyopathy Questionnaire quality of life (QoL) scores, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, hematocrit, and other relevant indicators were collected. Meta-analysis was conducted using RevMan5.3 to analyze the extracted data., Results: A total of 15 studies were included in the final analysis, comprising 36,917 patients with HF. Among them, 18,486 patients were in Empagliflozin group, and 18,431 patients were in control (Ctrl) group. The results of the meta-analysis demonstrated that, relative to Ctrl group, Empagliflozin group showed a substantially lower HHF rate, a substantial improvement in estimated glomerular filtration rate changes, a reduced cardiovascular mortality rate, a higher Kansas City Cardiomyopathy Questionnaire QoL score, increased hematocrit values, reduced N-terminal pro-B-type natriuretic peptide changes, and enhanced left ventricular ejection fraction changes. These findings suggest that remarkable improvements in various outcomes compared to the Ctrl group., Conclusion: The sodium-glucose cotransporter 2 inhibitor Empagliflozin markedly reduces the HHF rate and cardiovascular mortality in HF patients. It also improves patients' QoL, enhances renal function, and increases cardiac function while reducing both, the preload and afterload., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate the association between sodium-glucose cotransporter-2 (SGLT-2) inhibitor use and risk of all cause mortality among patients with heart failure with reduced ejection fraction., Design: Linked database study., Setting: National registers in Denmark, July 2020 to June 2023., Participants: Patients with heart failure, aged ≥45 years, with left ventricular ejection fraction ≤40%., Main Outcome Measures: The primary outcome was all cause mortality comparing initiation and continued treatment with SGLT-2 inhibitors versus continued treatment with other standard-of-care heart failure drugs and non-use of SGLT-2 inhibitors; secondary outcomes were the composite of cardiovascular mortality or admission to hospital with heart failure and its individual components. Hazard ratios were estimated using Cox regression adjusted using inverse probability of treatment weighting based on propensity scores., Results: The study included 6776 patients who started SGLT-2 inhibitors (79% dapagliflozin; 21% empagliflozin) and 14 686 patients who remained on other standard-of-care heart failure drugs and did not use SGLT-2 inhibitors. Most SGLT-2 inhibitor users were male (70%), the mean age was 71.2 (standard deviation 10.6) years, and 20% had type 2 diabetes. During follow-up, 374 deaths occurred among SGLT-2 inhibitor users (incidence rate 5.8 per 100 person years) and 1602 among non-users (8.5 per 100 person years). The weighted hazard ratio for all cause mortality was 0.75 (95% confidence interval 0.66 to 0.85); the weighted incidence rate difference was -1.6 (95% confidence interval -2.5 to -0.8) per 100 person years. Secondary outcomes showed a weighted hazard ratio of 0.94 (0.85 to 1.04) for cardiovascular mortality or hospital admission with heart failure, 0.77 (0.64 to 0.92) for cardiovascular mortality, and 1.03 (0.92 to 1.15) for hospital admission with heart failure. The weighted hazard ratios for all cause mortality were consistent in patients with and without diabetes (0.73 (0.58 to 0.91) and 0.73 (0.63 to 0.85); P=0.99)., Conclusions: In this large database study among patients with heart failure with reduced ejection fraction, SGLT-2 inhibitor use was associated with a 25% lower risk of all cause mortality, supporting their effectiveness in routine clinical practice., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Novo Nordisk Foundation and Karolinska Institutet; HS is a former employee of IQVIA; AH is a scientific advisory board member of VAC4EU and receives unrelated grant support from the Novo Nordisk Foundation, the Lundbeck Foundation, and the Independent Research Foundation Denmark; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors produce cardioprotective effects on heart failure (HF), even in the absence of diabetes. However, the underlying mechanisms of this cardioprotective effect remain unexplored. The purpose of this study was to examine the effects of SGLT2 inhibitors on serum MOTS-c, humanin levels, nitrosative stress, and ferroptosis parameters in diabetic patients with HF with reduced ejection fraction (HFrEF). A total of 74 adult diabetic patients with HFrEF and 37 healthy controls were included in this prospective study. Half of the patients were using SGLT2 inhibitors (empagliflozin or dapagliflozin) for at least two months. Serum nitric oxide and 3-nitrotyrosine levels were markedly higher in diabetic patients with HFrEF than the control (P < 0.001), but these elevations were inhibited with SGLT2 inhibitors. Although SGLT2 inhibitors had no marked effect on humanin levels, they significantly augmented MOTS-c levels when compared to the control. SGLT2 inhibitors augmented GPX4 but inhibited ACSL4 levels when compared to diabetic patients with HF. However, TFRC levels were increased in the patient group (P < 0.001 for all) but not modified with SGLT2 inhibitors. Our results suggest that increased nitrosative stress is significantly depressed by SGLT2 inhibitors. This study was the first to show that SGLT2 inhibitors can stimulate MOTS-c, but not humanin, in diabetic patients with HFrEF. SGLT2 inhibitors reduced ferroptosis through elevation of GPX4 and suppression of ACSL4 levels. Our data suggest that SGLT2 inhibitors could produce cardioprotective effects through relieving ferroptosis, inhibiting nitosative stress, and stimulating mitochondrial MOTS-c release., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The kidneys are essential for glucose homeostasis, as they perform gluconeogenesis, utilize glucose, and reabsorb glucose. Reabsorption is performed by SGLT2, which is responsible for about 90%. However, little is known about how renal glucose handling is altered in patients with chronic kidney disease (CKD). SGLT2 inhibitors have demonstrated efficacy in suppressing CKD progression in clinical trials, but their mechanisms are not fully understood. Therefore, this study aimed to evaluate how each uninephrectomy (UNx) and SGLT2 inhibitor affects blood glucose concentrations and SGLTs dynamics in rats with type 2 diabetes mellitus. Male rats were divided into four treatment groups: sham + placebo, sham + dapagliflozin, UNx + placebo, and UNx + dapagliflozin. There were few group differences in food intake or body weight, but blood glucose concentrations continued to rise in the sham + placebo, whereas this rise was delayed for several weeks in the UNx + placebo, and largely suppressed by dapagliflozin. SGLT2 mRNA expression was significantly lower in the UNx group, but SGLT1 mRNA expression did not significantly differ. Dapagliflozin did not alter SGLT1 or SGLT2 mRNA expression. In animal models of diabetes, renal glucose reabsorption appears likely to be a major contributor to the development of hyperglycemia., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background and Objective: The efficacy and safety of empagliflozin in the treatment of chronic kidney disease (CKD) were demonstrated in the EMPA-KIDNEY trial, which showed a 28% reduction in combined risks of kidney disease or death from cardiovascular causes (hazard ratio, 0.72; 95% confidence interval, 0.64-0.82; p < 0.001) compared with placebo. Based on these results, the present study aimed to assess the cost-effectiveness of empagliflozin + standard of care (SoC) compared with SoC alone in the treatment of CKD in France., Methods: A Markov state microsimulation model was adapted to compare the health and economic outcomes in France, considering a healthcare system perspective, in patients treated with empagliflozin in addition to SoC versus patients treated with SoC alone. The model simulated the intention-to-treat population of the trial, transitioning between 18 mutually exclusive and collectively exhaustive health states defined based on the Kidney Disease: Improving Global Outcomes classification. For each arm, the model estimated (over a 25-year time horizon) the number of events and deaths, and the costs associated with these events, to calculate the incremental cost-effectiveness ratio. The resources used were derived using French authorities reports, literature, and French CKD guidelines. Both economic and health outcomes were discounted at a 2.5% annual rate according to French guidelines., Results: The model predicted that using empagliflozin + SoC to treat patients with CKD would prevent CKD-related complications and deaths associated with a cardiovascular event or all-cause deaths while in kidney replacement therapy, resulting on average in a discounted gain of 1.29 years in overall survival (9.48 years vs. 8.19 with SoC alone). Empagliflozin costs (treatment, events, and disease management) were completely offset by the cost savings from avoided kidney failure events. Overall, empagliflozin + SoC would be more effective and less costly than SoC alone and would therefore be the dominant treatment strategy. The sensitivity analyses conducted support the results' robustness in showing the dominance of empagliflozin + SoC over SoC alone., Conclusions: The base-case results indicate that empagliflozin + SoC is a dominant strategy compared with the current SoC for the management of CKD in France. Empagliflozin + SoC would have a positive impact on patients with CKD by slowing CKD progression and leading to the prevention of kidney failure events on top of all-stages CKD complications., Competing Interests: Declarations Competing Interests Harinala Groyer and Denis San were employed by Boehringer Ingelheim France at the time of manuscript submission. Romain SUPIOT, Jean TARDU, Nicolas VIRELY, and Marine SIVIGNON were employed by Putnam at the time of manuscript submission. Pierre Lévy reports serving on a consultancy or paid advisory board for Bayer, Boehringer Ingelheim, Newcard. Anastasia Ustyugova is employed by Boehringer Ingelheim International GmbH, Ingelheim, Germany. Ziad Massy reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Sanofi- Genzyme, Lilly, Otsuka, AstraZeneca, Vifor, and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. The sponsors had no role in the design, execution, interpretation, or writing of the present study. Ethics Approval Not applicable. Consent to Participate Not applicable. Consent for Publication Not applicable. Availability of Data and Material: No other data or material are available than the ones published in this article. Code Availability No code or information from the cost-effectiveness model is available. Authors' Contributions The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Harinala Groyer managed the project on the Boehringer Ingelheim side and proofread the manuscript. Romain Supiot managed the project on the Putnam side and wrote the manuscript. Jean Tardu, Nicolas Virely, Marine Sivignon, Denis San, and Anastasia Ustyugova contributed to the analysis and proofread the manuscript. Pierre Lévy was consulted as an economic expert and proofread the manuscript. Ziad Massy was consulted as a clinical expert to validate assumptions and key inputs of the model and proofread the manuscript. Funding The study was supported and funded by Boehringer Ingelheim., (© 2024. The Author(s).)

This is a summary of the original article 'Dapagliflozin Utilization in Chronic Kidney Disease and Its Real-World Effectiveness Among Patients with Lower Levels of Albuminuria in the USA and Japan'. The slowing down of kidney function decline is important for managing chronic kidney disease (CKD) and preventing its complications. Clinical trials of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT-2i), have shown reductions in disease progression and death in patients with CKD and elevated levels of albuminuria. This summary of research provides an overview of a previously published article that aimed to find out whether dapagliflozin is also effective in patients with lower levels of albuminuria [urinary albumin-to-creatinine ratio (UACR) below 200 mg/g]. Starting dapagliflozin was associated with slower kidney function decline in patients with CKD and UACR below 200 mg/g compared with not starting. This effect was also observed in a subgroup analysis of patients without type 2 diabetes. These results suggest that the established benefits of SGLT-2is may extend to patients with lower levels of albuminuria., (© 2024. The Author(s).)

We previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD). Therefore, we used this model to evaluate the effects of tofogliflozin on renal lipid metabolism and inflammation. Male 8-10-week-old C57Bl/6 mice were fed a high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or an HF/HC/HS/BA diet alone (SLD group). After eight weeks, serum lipid profiles, histology, lipid content, and mRNA/microRNA and protein expression levels in the kidney were examined. The Tofo group showed significant reductions in body (26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001) and kidney weight compared to those of the SLD group. Renal cholesterol (9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g; p < 0.05) and non-esterified fatty acid (NEFA) (12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g; p < 0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed the presence of fewer lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. MicroRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a.

Objective: To evaluate the comparative effects of dapagliflozin versus placebo in patients with heart failure (HF), focusing on functional capacity, symptoms, and safety outcomes., Background: Despite advancements in heart failure (HF) therapy, HF is still a significant cause of recurrent hospitalization and death worldwide. Dapagliflozin has demonstrated potential in lowering hospitalizations and mortality associated with heart failure; however, its impact on functional capacity, particularly the 6-min walk distance (6MWD), and the comprehensive assessment of safety outcomes in diverse HF populations, including those with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively), requires further investigation., Methods: PubMed, Web of Science, Cochrane Library, and Scopus databases were comprehensively searched to identify randomized controlled trials (RCTs) investigating the efficacy of dapagliflozin in comparison with control interventions for heart failure. The primary outcome was a change in the 6MWD, KCCQ score, and safety measures included hospitalization, all-cause mortality, and adverse events., Results: In our meta-analysis of ten studies involving 12,695 patients with heart failure, dapagliflozin showed significantly improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores [risk ratio (RR) of 2.75, 95% confidence interval (CI) (1.95-3.569), p < 0.00001] and no significant differences in 6-min walk distance [6MWD; RR of 3.59, 95% CI (- 1.44 to 8.63), p = 0.16]. Dapagliflozin demonstrated a notable reduction in hospitalization for heart failure [RR of 0.76, 95% CI (0.68-0.84), p < 0.00001], significant overall reduction on the effect of any cause mortality [RR of 0.90, 95% CI (0.83-0.99), p = 0.03). There was, however, no significant effect on adverse events [RR of 0.96, 95% CI (0.98-1.03), p = 0.39)., Conclusions: Our meta-analysis of ten trials concluded that dapagliflozin significantly improved KCCQ scores in both HFrEF and HFpEF. The improvement in 6MWD was not statistically significant but trended toward dapagliflozin. Dapagliflozin also showed a mortality benefit in patients with reduced ejection fraction; however, in patients with preserved ejection fraction, the result was not statistically significant. There was also a statistically significant reduction in heart failure hospitalizations across all classes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims/introduction: To assess whether the sodium-glucose cotransporter 2 inhibitor, henagliflozin, improves cognitive impairment in patients with type 2 diabetes., Materials and Methods: We carried out a prospective study on 290 patients with type 2 diabetes and cognitive impairment. Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels were used to assess cognition. The association between henagliflozin use and changes in cognition was examined using multivariable logistic regression analysis., Results: Montreal Cognitive Assessment scores at enrollment and after 6 months were 21 (interquartile range [IQR]19-23) versus 22 (IQR 20-25; P < 0.0001) in all patients, 21 (IQR 19-23) versus 24 (IQR 22-26; P < 0.0001) in the henagliflozin group and 21 (IQR 19-22) versus 21 (IQR 19-23; P > 0.05) in the non-sodium-glucose cotransporter 2 inhibitor group. Logistic regression analysis showed that henagliflozin treatment was associated with Montreal Cognitive Assessment score improvement independent of potential confounders (odds ratio [OR] 3.670, 95% confidence interval [CI] 2.224-6.056, P < 0.0001). Additionally, plasma phosphorylated tau181 levels significantly decreased at 6-month follow up in all patients (OR 11.5, 95% CI 9.9-13.7 vs OR 10.1, 95% CI 7.8-12.9, P < 0.0001) and in the henagliflozin group (OR 11.5, 95% CI 10.3-13.0 vs OR 9.2, 95% CI 7.1-10.7, P < 0.0001), but not in the non-sodium-glucose cotransporter 2 inhibitor group. Henagliflozin treatment was independently associated with decreased phosphorylated tau181 levels (OR 3.670, 95% CI 1.598-4.213, P < 0.0001)., Conclusions: Henagliflozin treatment was independently associated with improvements in Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels, indicating significant beneficial effects on cognitive impairment in patients with type 2 diabetes., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination., Patients and Methods: In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level., Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups., Conclusion: Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia., Methods: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials., Results: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%)., Conclusion: These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755)., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors in nephrotic patients on immunosuppression are underexplored. We evaluated dapagliflozin's impact in non-diabetic primary nephrotic syndrome., Methods: Randomized controlled clinical trial was conducted on 60 non-diabetic primary nephrotic syndrome patients, equally assigned to dapagliflozin and control groups. All patients received the standard of care medication and the Dapagliflozin group received 10 mg dapagliflozin in addition. Demographic data, nephrotic syndrome etiology, proteinuria levels, eGFR, and immunosuppression doses, were well-matched. After 6 months of follow up primary outcomes included changes in and eGFR., Results: Both groups exhibited significant reductions in proteinuria after 6 months, with the dapagliflozin group achieving a mean UPCR reduction of  - 94.7%, and the control group  - 86.7% (p < 0.001). However, the comparative change in proteinuria between both groups did not reach statistical significance (p = 0.158). Dapagliflozin initially led to a transient eGFR decline. Dapagliflozin also resulted in a significant mean body weight reduction (p < 0.001) and notable improvements in triglyceride levels compared to the control group (p = 0.045)., Conclusion: In primary nephrotic syndrome patients, adjunct dapagliflozin may enhance the standard of care. While notable, the reduction in proteinuria was comparable to that of the control group by the study's end. Furthermore, after 6 months, eGFR remained stable in both groups. However, significant weight loss and serum triglyceride reduction were particularly pronounced in the dapagliflozin group. Further long-term investigations are necessary to address potential immunosuppression-related confounding effects in patients with primary glomerular disease., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims/introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors effectively and safely reduce fasting and postprandial hyperglycemia while promoting weight loss. However, their unique mechanism of action contributes to concerns regarding their safety. We therefore carried out a large-scale, non-commercial, investigator-initiated study on the safety and effectiveness of the SGLT2 inhibitor tofogliflozin., Materials and Methods: This multicenter, open-label, uncontrolled, prospective observational study was carried out at hospitals and clinics across Japan in participants aged ≥20 years who were SGLT2 inhibitor-naïve and had an established diagnosis of type 2 diabetes. The primary endpoint was adverse drug reactions (ADRs) of special interest. Secondary endpoints included all other ADRs and adverse events, glycated hemoglobin (HbA1c), and weight loss., Results: The study, carried out from June 2014 through February 2020, enrolled 11,480 participants from 1,103 medical institutions; 6,967 participants completed the 104-week follow up. The most common ADRs of special interest were urinary and genital tract infections (1.53%), followed by volume depletion (1.25%). Hypoglycemia occurred in 27 participants (0.24%), adverse events in 1,054 (9.18%) and ADRs in 645 (5.62%). HbA1c decreased by 0.85% (95% confidence interval 0.82%-0.88%) and bodyweight decreased by 3.05 kg (95% confidence interval 2.94-3.17 kg). The HbA1c target was achieved by 51.70% of participants for target HbA1c <7.0%, 85.3% for <8.0% and 5.4% for <6.0% at week 104., Conclusions: Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Central nervous system (CNS)-related diseases have a high mortality rate, are a serious threat to physical and mental health, and have always been an important area of research. Gastrodin, the main active metabolite of Gastrodia elata Blume, used in Chinese medicine and food, has a wide range of pharmacological effects, mostly related to CNS disorders. This review aims to systematically summarize and discuss the effects and underlying mechanisms of gastrodin in the treatment of CNS diseases, and to assess its potential for further development as a lead drug in both biomedicine and traditional Chinese medicine. Studies on the pharmacological effects of gastrodin on the CNS indicate that it may exert anti-neurodegenerative, cerebrovascular protective, and ameliorative effects on diabetic encephalopathy, perioperative neurocognitive dysfunction, epilepsy, Tourette's syndrome, depression and anxiety, and sleep disorders through various mechanisms. To date, 110 gastrodin products have been approved for clinical use, but further multicenter clinical case-control studies are relatively scarce. Preclinical studies have confirmed that gastrodin can be used to treat CNS-related disorders. However, important concerns need to be addressed in the context of likely non-specific, assay interfering effects when gastrodin is studied using in vitro and in silico approaches, calling for a systematic assessment of the evidence to date. High-quality clinical trials should have priority to evaluate the therapeutic safety and clinical efficacy of gastrodin. Further experimental research using appropriate in vivo models is also needed, focusing on neurodegenerative diseases, cerebral ischemic and hypoxic diseases, brain damage caused by methamphetamine or heavy metals, and epilepsy., (© 2024 John Wiley & Sons Ltd.)

The effect of sitagliptin and empagliflozin on serum levels of asprosin and metabolic parameters in patients with type 2 diabetes mellitus (T2DM) was assessed in a non-randomized, prospective observational study. Seventy-nine T2DM patients, without adequate glycemic control with metformin monotherapy, were included in the study. In addition to the ongoing metformin treatment, patients received sitagliptin 100 mg and empagliflozin 10 mg once daily for 12 weeks. Anthropometric parameters, lipid and glycemic profile, insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), and asprosin serum levels were assessed at baseline and after 12 weeks of therapy. Both empagliflozin and sitagliptin treatments led to similar, significant improvement in fasting blood glucose (FBG) and hemoglobin A1C (HbA1C). Compared to baseline, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were improved with both treatments, but empagliflozin led to the more improvement. No significant change of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were observed in either group. Insulin resistance was significantly attenuated in both groups, but to a greater degree with empagliflozin treatment. The reduction in serum asprosin levels from baseline was significantly higher in patients taking empagliflozin compared to those receiving sitagliptin. Additionally, individuals on empagliflozin exhibited a more decrease in body mass index (BMI) and body weight compared to those on sitagliptin. According to our findings, the addition of empagliflozin to metformin appeared to offer greater benefits compared to the addition of sitagliptin in terms of decreasing asprosin levels and improving certain metabolic parameters in T2DM patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gastrodin (GAS), a bioactive compound derived from the orchid plant Gastrodia elata, exhibits numerous pharmacological effects. However, its effect on sleep deprivation (SD)-induced cardiac injury and the mechanisms are unknown. This study established SD mice model using a modified multiple platform water method and induced ferroptosis model in H9c2 cells using Erastin. The heart rate of mice was measured, and myocardial and mitochondrial structures were visualized using hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). Myocardial injury, oxidative stress indicators, and Fe 2+ levels were detected by the kit method. The reactive oxygen species (ROS) levels were detected by immunofluorescence, and SIRT6 and ferroptosis-associated protein expression levels were detected by Western blot. Reduced heart rate and abnormalities in myocardial tissue and mitochondrial structure were ameliorated in the SD group of mice after GAS treatment. GAS treatment reduced ROS levels in Erastin-induced H9c2 cells. GAS treatment reduced atrial natriuretic peptide (ANP), creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MAD), and Fe 2+ levels, and increased superoxide dismutase (SOD) and glutathione (GSH) levels in the SD and Erastin groups. Western blot showed that GAS treatment increased the expression of sirtuin 6 (SIRT6), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) and decreased the expression of P53 in SD and Erastin groups. The SIRT6 inhibitor OSS&#95;128167 (OSS) reversed GAS treatment of Erastin-induced ferroptosis in H9c2 cells. These observations propose that GAS prevents myocardial injury in sleep-deprived mice by suppressing ferroptosis through SIRT6., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Knee osteoarthritis (KOA) is one of the leading causes of disability. Polydatin has a potential effect on KOA treatment but the therapeutic mechanism is not clear. This study aims to investigate the therapeutic action of polydatin in KOA and its mechanism in activating autophagy via the AMP-activated protein kinase (AMPK)/mTOR signaling pathway., Methods: After a KOA rat model was established by anterior cruciate ligament transection surgery, model rats were treated with polydatin 40 mg/kg for 30 days. Subsequently, cartilage tissues were collected, and hematoxylin-eosin (HE), Safranin-O, and TUNEL staining, and western blotting were performed to evaluate the pathological damage and autophagy-related protein expression. Then, human chondrocyte C28/I2 cells were stimulated with lipopolysaccharide (LPS), and the effects of polydatin on C28/I2 cell viability, apoptosis, and autophagy-related protein expression were detected by MTT, Flow Cytometry, and western blot. In addition, an AMPK inhibitor (Dorsomorphin 2HCl) was used to probe the cell proliferation and apoptosis of polydatin-administered C28/I2 cells., Results: Polydatin ameliorated the pathological damage in rat cartilage tissues and inhibited cell apoptosis in KOA rats. Meanwhile, in C28/I2 cells, polydatin promoted viability and reduced apoptosis. In addition, the protein expression of collagen II, LC3II/LC3I, Beclin-1, and p-AMPK/AMPK were upregulated, and p62 and p-mTOR/mTOR were downregulated by polydatin treatment. Interestingly, relative results showed that the protective effect of polydatin in LPS-stimulated-C28/I2 cells was blocked by the AMPK/mTOR inhibitor, dorsomorphin 2HCl., Conclusion: Our research showed that polydatin reduced apoptosis and activated autophagy both in vivo and in vitro by the AMPK/mTOR signaling pathway to protect against KOA, which provided the basis for further investigation into the potential therapeutic impact of polydatin on KOA., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Objective: We compared health care resource utilization (HCRU) and costs for inpatient and outpatient services and dispensed medications in older adults with type 2 diabetes initiating empagliflozin versus dipeptidyl peptidase 4 inhibitors (DPP-4is)., Research Design and Methods: The study population included U.S. Medicare fee-for-service beneficiaries with diabetes (age ≥65 years) initiating empagliflozin or DPP-4is (August 2014 to September 2018). We estimated rate ratios (RRs) for HCRU outcomes using zero-inflated negative binomial regression and per-member per-year (PMPY) cost differences using generalized linear model with gamma distributions, overall and stratified by baseline cardiovascular disease (CVD), after adjusting for 143 baseline covariates using 1:1 propensity score matching., Results: We identified 23,335 matched pairs (mean age 72 years, 51% with baseline CVD). HCRU rates were lower in empagliflozin versus DPP-4i initiators (number of inpatient days, RR 0.89 [95% CI 0.82, 0.97]; number of emergency department [ED] visits, 0.86 [0.82, 0.91]; number of hospitalizations, 0.86 [0.79, 0.93]; number of office visits, 0.96 [0.95, 0.98]). Inpatient cost (-$713 PMPY [95% CI -847, -579), outpatient cost (-$198 PMPY [-272, -124]), and total cost of care (-$1,109 PMPY [-1,478, -739]) were lower for empagliflozin versus DPP-4is, although diabetes medication cost was higher in empagliflozin initiators ($454 PMPY [95% CI 284, 567]). In the CVD subgroup, total cost was lower for empagliflozin initiators (-$2,005 PMPY [-2,451, -1,337]), while the difference was attenuated in the non-CVD subgroup (-$296 PMPY [-740, 148])., Conclusions: Among older adults with diabetes, empagliflozin was associated with a lower number of inpatient days, hospitalizations, ED visits, and office visits and with lower costs of care compared with DPP-4is, especially in those with history of CVD., (© 2024 by the American Diabetes Association.)

Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as Empagliflozin, are increasingly recommended as part of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) in many developed nations. This recommendation is based on robust clinical evidence showing that adding Empagliflozin to GDMT improves heart failure symptoms, clinical outcomes, functional status, and overall quality of life. In Malaysia, where healthcare is predominantly public and heavily subsidized, the introduction of new treatments can significantly impact costs, requiring detailed economic assessments. This study evaluates the budget impact of incorporating Empagliflozin into GDMT for HFrEF from the perspective of the public healthcare system. A five-year budget impact model was developed, integrating local data such as population, drug use, costs, clinical outcomes, and healthcare expenses. In the current scenario (GDMT alone), the projected five-year expenditure is MYR 6.12 billion (USD 3.92 billion). With Empagliflozin, the total cost rises by 0.71% to MYR 6.16 billion (USD 3.95 billion), driven by drug acquisition costs of MYR 160.12 million (USD 102.64 million) and adverse event costs of MYR 211,543 (USD 135,604). However, these costs are offset by savings from reduced HF hospitalizations, fewer cardiovascular deaths, and improved renal outcomes. Sensitivity analysis identified hospitalization costs, the price of Empagliflozin, and cardiovascular deaths in diabetic patients as key factors influencing the budget impact. Policymakers can improve the affordability of Empagliflozin through strategies like price negotiations, cost-sharing, and focusing on high-risk groups to optimize healthcare expenditure while ensuring effective treatment access., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown., Methods: This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios, considering noncardiovascular death competing events, were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis., Results: There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32])., Conclusions: Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF., Competing Interests: Dr Hennessy consults for the Medullary Thyroid Cancer Registry Consortium (Novo Nordisk Inc, AstraZeneca Pharmaceuticals LP, and Eli Lilly and Company). The other authors report no disclosures.

Background: Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD., Methods: A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays., Results: Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012)., Conclusions: Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Lian Qiao (LQ), the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a well-documented traditional Chinese medicine known for its detoxifying and heat-clearing properties. Clinically, compounds containing LQ are widely used to treat thrombotic diseases, indicating that it may have antithrombotic effects. However, its exact mechanism of action remains unknown., Aim of the Study: This study aimed to verify the antithrombotic effect of LQ and further explore the material basis and target mechanism of its antithrombotic effect using various biological methods., Materials and Methods: An epinephrine-collagen-thrombin-induced mouse model of acute pulmonary embolism (APE) was established to study the effects of LQ on thrombus development. A UPLC/Q/TOF-MS screening and identification system based on the inhibition of platelet aggregation and Ca 2+ antagonism was established to determine the pharmacodynamic components of LQ that inhibit platelet activation. The inhibitory effect of active ingredients on platelet activation, and the determination of the target of their inhibitory effect on platelet activation have been studied using chemical proteomics. Furthermore, based on the structure and function of the target protein, a multidisciplinary approach was adopted to analyze the molecular mechanism of active ingredient binding to target proteins and to evaluate the effects of active ingredients on the downstream signaling pathways of target proteins., Results: LQ showed significant anticoagulant effects in APE model mice. Phillyrin and phillygenin were the antiplatelet-activating components of LQ. PLCβ3 was identified as a target for inhibiting platelet activation by phillyrin and its metabolites. The mechanism underlying the effect involves phillyrin and its metabolites inhibiting PLCβ3 activity by blocking the binding of PLCβ3 to Gαq through non-covalently targeting the ASN260 of PLCβ3, thus inhibiting the downstream Gαq-PLCβ3-Ca 2+ signaling pathway, effectively hindering platelet activation and therefore playing an anticoagulant role., Conclusion: This study not only proposes and validates the antithrombotic effect of LQ for the first time but also finds that phillyrin and phillygenin are the main pharmacological substances through which LQ exerts antithrombotic activity and reveals a novel mechanism by which they exert antiplatelet activity by directly targeting and inhibiting PLCβ3 activity. These findings significantly contribute to our understanding of the therapeutic potential of phillyrin and provide important clues for the discovery and development of new antiplatelet drugs., Competing Interests: Declaration of Competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study was aimed to evaluate whether the dose-response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)-canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin-can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Information on HbA1c reduction at various doses of each SGLT2i was collected from literatures on randomized controlled trials and was normalized based on the daily UGE data from phase I studies. After normalizing doses, the dose-response relationship of HbA1c reduction of most of SGLT2is was represented by a unified nonlinear mixed-effect model, with the estimated maximum HbA1c (%) reduction (E max ) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher E max than those of the other drugs. Other covariates included baseline HbA1c levels, body weight, disease duration, prior treatment, and renal function. Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials., (© 2024. The Author(s).)

Objective: To investigate the mechanism behind the protective effects of gastrodin against microglia-mediated inflammatory responses following hypoxic-ischemic brain damage (HIBD) in neonatal mice., Methods: Thirty-six 10-day-old C57BL/6J mice were randomized into sham-operated group, HIBD (induced by ligation of the left common carotid artery followed by hypoxia for 40 min) group, and HIBD with gastrodin treatment groups ( n =12). In gastrodin treatment group, 100 mg/kg gastrodin was injected intraperitoneally 1 h before and at 2 and 12 h after hypoxia. After the treatments, the expressions of CCR5, AKT, p-AKT, and TNF- α and the co-expression of IBA1 and CCR5 in the corpus callosum of the mice were detected with Western blotting and immunofluorescence double staining. In a BV2 microglial cell model of oxygen-glucose deprivation (OGD), the effects of pretreatment with gastrodin and Maraviroc (an CCR5 antagonist) on protein expressions of CCR5, AKT, p-AKT, TNF- α and IL-1β were evaluated using Western blotting and immunofluorescence double staining., Results: The neonatal mice with HIBD showed significantly increased expressions of CCR5 and TNF- α with lowered p-AKT expression in the brain tissues, and GAS treatment obviously reversed these changes. HIBD also significantly increased the co-expression of IBA1 and CCR5 in the corpus callosum of the mice, which was obviously lowered by gastrodin treatment. In BV2 cells, OGD significantly increased the expressions of CCR5, TNF- α , and IL-1β and decreased the expression of p-AKT, and these changes were inhibited by treatment with gastrodin, Maraviroc or their combination; the inhibitory effect of the combined treatment did not differ significantly from that of gastrodin or Maraviroc alone., Conclusion: Gastrodin can produce neuroprotective effects in neonatal mice with HIBD by inhibiting inflammatory cytokine production and activate AKT phosphorylation via inhibiting CCR5.

Background: Heart failure affects almost 64 million people, with more than half of it constituting heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) are in the first line for HFrEF, but no head-to-head trials are available. Moreover, growth differentiation factor-15 (GDF-15) has been demonstrated as a promising prognostic marker, specifically for HFrEF, but has not been explored much., Methods: This pragmatic randomised controlled trial recruits 100 patients with HFrEF (ejection fraction <40%) of New York Heart Association (NYHA) II-III and allocates them in a 1:1 ratio to the dapagliflozin and sacubitril/valsartan groups. The primary objective is to assess the difference in N-terminal pro-brain natriuretic peptide serum levels at the end of 16 weeks. The secondary efficacy objectives are to assess GDF-15, Kansas City Cardiomyopathy Questionnaire-overall summary score and estimated glomerular filtration rate. Patients will be assessed at baseline, fourth week and 16th week after randomisation. As health technology assessment practices widely differ in countries, cost assessment is a vital factor to consider. The cost needed to treat one cardiovascular event is also compared between both groups. The occurrence of safety events will also be evaluated at each follow-up point., Conclusion: This pragmatic study aims to compare the efficacy, safety and cost-effectiveness of dapagliflozin versus sacubitril/valsartan in patients with HFrEF in real-world settings. The study aims to provide clinicians with data to make informed decisions regarding the preferred drug class. Additionally, examining the impact of ARNI and SGLT2i on GDF-15 levels could offer better insights into prognosis among patients with HFrEF., Ethics and Dissemination: This study involves human participants and was approved by Institutional Ethics Committee at AlIMS Jodhpur with reference number AIIMS/IEC/2023/5842 approved this study. Participants gave informed consent to participate in the study before taking part. The research findings will be disseminated via closed group discussions at the site of study, scientific conferences, peer-reviewed published manuscripts, and social media., Trial Registration Number: CTRI/2023/12/060772., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To explore the construction of a diagnostic prediction model of diabetic nephropathy (DN) in type 2 diabetic patients for prognostic risk prediction and observe the therapeutic effect of Epalrestat combined with Dapagliflozin on DN., Methods: The study consisted of two phases, phase I: A retrospective analysis was conducted on the case information and clinical treatment related data of a total of 460 patients who underwent kidney biopsy from June 2018 to June 2021. They were randomly divided into validation queue and training queue. The predictive factors of the diagnostic prediction model were obtained through multivariate logistic regression., Phase Ii: An interventional study of 94 patients with DN admitted between January 2022 and August 2023 was conducted, and they were randomized into a control group (n = 47) receiving Dapagliflozin and a research group (n = 47) receiving Epalrestat combined with Dapagliflozin. The glucose metabolism, renal function, and treatment safety of the two groups before and after treatment were compared. In addition, the adverse reactions during the treatment of the two groups were counted., Results: In the phase I of the study, the DN risk model established showed a good performance in the diagnosis and risk assessment of patients with DN and could provide certain reference opinions for future clinical practice. In the phase II of the study, the research group showed better glucose metabolism and renal function than the control group after treatment (P < .05), but no statistical difference was identified between groups in the incidence of adverse reactions (P > .05).  Conclusion. Epalrestat combined with Dapagliflozin is significantly effective in the treatment of DN, which can effectively improve glucose metabolism and renal function in DN patients.

Background: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms., Methods: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-β) to investigate the effect of DAPA., Results: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels., Conclusions: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-β (Aβ), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aβ-induced oxidative stress, inflammatory injury, and β-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aβ production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aβ generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aβ generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease., Competing Interests: Declaration of competing interest No conflicts of interest are declared by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-β1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anthocyanins, found in various pigmented plants as secondary metabolites, represent a class of dietary polyphenols known for their bioactive properties, demonstrating health-promoting effects against several chronic diseases. Among these, cyanidin-3-O-glucoside (C3G) is one of the most prevalent types of anthocyanins. Upon consumption, C3G undergoes phases I and II metabolism by oral epithelial cells, absorption in the gastric epithelium, and gut transformation (phase II & microbial metabolism), with limited amounts reaching the bloodstream. Obesity, characterized by excessive body fat accumulation, is a global health concern associated with heightened risks of disability, illness, and mortality. This comprehensive review delves into the biodegradation and absorption dynamics of C3G within the gastrointestinal tract. It meticulously examines the latest research findings, drawn from in vitro and in vivo models, presenting evidence underlining C3G's bioactivity. Notably, C3G has demonstrated significant efficacy in combating obesity, by regulating lipid metabolism, specifically decreasing lipid synthesis, increasing fatty acid oxidation, and reducing lipid accumulation. Additionally, C3G enhances energy homeostasis by boosting energy expenditure, promoting the activity of brown adipose tissue, and stimulating mitochondrial biogenesis. Furthermore, C3G shows potential in managing various prevalent obesity-related conditions. These include cardiovascular diseases (CVD) and hypertension through the suppression of reactive oxygen species (ROS) production, enhancement of endogenous antioxidant enzyme levels, and inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway and by exercising its cardioprotective and vascular effects by decreasing pulmonary artery thickness and systolic pressure which enhances vascular relaxation and angiogenesis. Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are also managed by reducing gluconeogenesis via AMPK pathway activation, promoting autophagy, protecting pancreatic β-cells from oxidative stress and enhancing glucose-stimulated insulin secretion. Additionally, C3G improves insulin sensitivity by upregulating GLUT-1 and GLUT-4 expression and regulating the PI3K/Akt pathway. C3G exhibits anti-inflammatory properties by inhibiting the NF-κB pathway, reducing pro-inflammatory cytokines, and shifting macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. C3G demonstrates antioxidative effects by enhancing the expression of antioxidant enzymes, reducing ROS production, and activating the Nrf2/AMPK signaling pathway. Moreover, these mechanisms also contribute to attenuating inflammatory bowel disease and regulating gut microbiota by decreasing Firmicutes and increasing Bacteroidetes abundance, restoring colon length, and reducing levels of inflammatory cytokines. The therapeutic potential of C3G extends beyond metabolic disorders; it has also been found effective in managing specific cancer types and neurodegenerative disorders. The findings of this research can provide an important reference for future investigations that seek to improve human health through the use of naturally occurring bioactive compounds., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective : To evaluate the effectiveness of empagliflozin in reducing all-cause mortality (ACM), hospitalization for heart failure (HHF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), and end-stage renal disease (ESRD) in routine clinical practice in the Nordic countries of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study. Methods : This noninterventional, multicountry cohort study used secondary data from four Nordic countries (Denmark, Sweden, Finland, and Norway). Propensity score (PS) matched (1:1) adults with type 2 diabetes (T2D) initiating empagliflozin (a sodium-glucose cotransporter-2 inhibitor) during 2014-2018 who were compared to those initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i). Cox proportional hazards regression modelling was used to assess the risk for ACM, HHF, MI, stroke, CVM, and ESRD. Meta-analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) from random-effects models were calculated. Results : A total of 43,695 pairs of PS-matched patients were identified. Patients initiating empagliflozin exhibited a 49% significantly lower risk of ACM (HR: 0.51, 95% CI 0.40-0.64) compared to DPP-4i. Additionally, empagliflozin was associated with a 36% significantly lower risk of HHF (HR: 0.64, 95% CI 0.46-0.89), a 52% significantly lower risk of CVM (HR: 0.48, 95% CI 0.37-0.63), and a 66% significantly lower risk of ESRD (HR: 0.34, 95% CI 0.15-0.77) compared to DPP-4i. No significant differences were observed in the risk of stroke and MI between patients initiating empagliflozin compared with those initiating a DPP-4i. Results were generally consistent for subgroups (with/without pre-existing CV disease or congestive heart failure) and in sensitivity analyses. Conclusion : Empagliflozin initiation was associated with a significantly reduced risk of ACM, HHF, CVM, and ESRD compared with initiation of DPP-4i in patients with T2D when examining routine clinical practice data from Nordic countries., Competing Interests: Dorte Vistisen has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S, and Boehringer Ingelheim. She holds shares in Novo Nordisk A/S. Bendix Carstensen declares no conflicts of interest. Sigrun Halvorsen has received speaker fees from Sanofi, Novartis, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb. Gisle Langslet has received consulting/lecture fees from Sanofi and Boehringer Ingelheim. Thomas Nyström has received unrestricted grants from AstraZeneca and Novo Nordisk and has been a national adviser of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. Leo Niskanen has received speaker honoraria from Amgen, Boehringer Ingelheim, Novo Nordisk, Sanofi, MSD, and Astra Zeneca; research support from Novo Nordisk to the hospital; and has participated in the scientific advisory boards of Amgen, Boehringer Ingelheim, AstraZeneca, MSD, and Novo Nordisk. Paula Casajust is an employee of TFS Health Science. Giorgi Tskhvarashvili, Fabian Hoti, and Riho Klement are/were employees of IQVIA contracted by Boehringer Ingelheim to conduct the meta-analyses, interpret the results, review, and revise the manuscript. Christina Shay, Soulmaz Fazeli Farsani, Kristina Karlsdotter, Mikko Tuovinen, Anne Pernille Ofstad, and Maria Lajer were employees of Boehringer Ingelheim at the time of manuscript development. Lisette Koeneman is an employee of Eli Lilly and Company and owns stock in Eli Lilly and Company. Emilie Toresson Grip is an employee of Quantify Research that was contracted to conduct the country-specific studies in Finland, Norway, and Sweden., (Copyright © 2024 Gisle Langslet et al.)

Introduction: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in diabetes treatment is expanding; however, few studies have investigated the efficacy and safety of combining SGLT2is with insulin pump therapy. Notably, there is a scarcity of high-quality, multicentre, clinical trials. Therefore, we aim to conduct a prospective multicentre, randomised, controlled, study to investigate whether treatment of type 2 diabetes patients with continuous subcutaneous insulin infusion (CSII) combined with henagliflozin can reduce the time required for blood glucose control, decrease total insulin requirements, mitigate blood glucose fluctuations and enhance beta-cell function., Methods and Analysis: In this inpatient, open-label, multicentre, randomised, controlled trial, 200 patients with type 2 diabetes who have not received hypoglycaemic drugs will be randomly allocated at a 1:1 ratio to either the henagliflozin combined with CSII group or the CSII group. The efficacy and safety of treatment in both groups will be compared. We will use a real-time continuous glucose monitoring system for blood glucose monitoring. The primary aim of this study is to compare the time (% time in range (TIR)) in the range of 3.9~10.0 mmol/L blood glucose between the two treatment groups. The secondary outcome measures will include comparisons of the two treatment groups with respect to the (a) time at TIR >70%; (b) mean amplitude of glycaemic excursions; (c) time below range; (d) total insulin dosage; and (e) time above range., Ethics and Dissemination: This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and is to be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The study will be disseminated through peer-reviewed publications and conference presentations., Trial Registration Number: NCT05677334., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Diabetic osteoporosis (DOP) is a metabolic disease that occurs in patients with diabetes due to insufficient insulin secretion. This condition can lead to sensory neuropathy, nephropathy, retinopathy, and hypoglycemic events, which can increase the risk of fractures. This study aimed to assess the effectiveness of Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, in treating diabetic osteoporosis (DOP) and preventing fractures., Methods: This quasi-experimental study enrolled 100 patients with diabetic osteoporosis from February 2023 to February 2024. Participants were randomly assigned to an intervention group (n = 50) and a control group (n = 50). The intervention group received Empagliflozin in combination with symptomatic treatment, while the control group received only symptomatic treatment. The treatment duration was six months. Fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PG), glycosylated hemoglobin A1c (Hb A1c), bone mineral density (BMD), serum phosphorus and calcium concentration were measured after the intervention and the incidence of fracture was followed up for 12 months. The data were analyzed using SPSS 23. Descriptive statistics (mean, standard deviation, and percentage) and analytical methods (t test, Chi square) were also used to analyze the data., Results: After six months of treatment, the intervention group exhibited significantly lower levels of FBG (P < 0.001), 2 h-PG (P = 0.001), and HbA1c (P < 0.001) than the control group. Additionally, bone mineral density, serum phosphorus, and calcium levels were significantly higher in the intervention group (P < 0.001). After a 12-months follow-up, the incidence of fractures in the intervention group was 2%, while it was 16.33% in the control group (P < 0.05)., Conclusion: Empagliflozin, when combined with symptomatic treatment, demonstrates a positive clinical effect in patients with diabetic osteoporosis. The treatment effectively improves blood glucose metabolism, bone mineral density, and phosphorus and calcium metabolism, ultimately leading to a significant reduction in the incidence of fracture., (© 2024. The Author(s).)

Objectives: The objective of this study was to evaluate the effectiveness of the combined use of empagliflozin (EMPA) and topiramate (TPM) versus a placebo in overweight/obese individuals without diabetes on a calorie-restricted diet., Methods: In this study, 44 non-diabetic and overweight/obese subjects who were on a calorie restricted diet were randomly assigned into 2 groups: (1) Participants received a 10 mg EMPA tablet daily plus TPM tablet (at the 1st week 25 mg once a day and from the second week 25 mg twice a day); (2) Participants received an empagliflozin placebo (daily) plus a topiramate placebo (as mentioned for topiramate tablet in group 1), for 12 weeks. At baseline and weeks 4, 8, 12, weight, height, body mass index (BMI), waist circumference (WC), and body composition were evaluated. Before and after the intervention, blood pressure, C reactive protein, and glucose and lipid profile parameters were measured., Results: The EMPA/TPM group, compared to placebo, had a greater percent change of weight at week 12 (- 8.92 ± 1.80 vs. - 4.93 ± 1.17). The intervention group had a greater percent change of fat mass and fat percent at week 12 (P < 0.05). However, there was no difference in the percent of change in fat-free percent between the two groups at week 12 (P = 0.577). Within-group analysis found a significant reduction in SBP, DBP, FBS, insulin, HOMA-IR, TC, LDL, HDL, TG, and CRP in both groups (P < 0.05). At week 12, no statistically significant difference was observed between the two groups in any of mentioned variables (P > 0.05)., Conclusion: In non-diabetic overweight/obese individuals, the combination of EMPA/TPM and calorie restriction led to a notable decrease in body weight and was generally well-tolerated. Further research is required to evaluate the potential advantages of utilizing this combination for sustained weight management in the long run., Level I: Randomized clinical trial., (© 2024. The Author(s).)

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes 1,2 . Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia 3 . Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle 4 and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions., (© 2024. The Author(s).)

During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8 + T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8 + T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8 + T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8 + T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8 + T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8 + T cells and may be an effective strategy for treating MASH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations., Methods: In a voluntary substudy of the DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure), patients wore a waist-worn triaxial accelerometer for as long as possible (ideally for 24 h/d for 7 days) at 3 points during the trial, between the screening visit and randomization (baseline data), and during weeks 8 and 14 to 16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity, time spent in moderate-to-vigorous physical activity, movement intensity during walking, number of vector magnitude units' and total activity counts., Results: Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as ≥10 hours of wear time for ≥3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference, 778 [95% CI, 240-1315]), time spent in moderate-to-vigorous physical activity (0.16 [95% CI, 0.03-0.29] hours), and in the mean vector magnitude units (25 [95% CI, 0.1-49] counts per minute). There were no between-group differences in the other accelerometer outcomes of interest., Conclusions: In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with heart failure across the entire left ventricular ejection fraction spectrum, yet did not improve 6-minute walk distance, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6-minute walk distance and identify beneficial effects of treatment not detected by 6-minute walk distance., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224., Competing Interests: Dr Docherty’s employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials; he has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosmos, Translational Medical Academy, and Radcliffe Cardiology; has served on Advisory Boards for Us2.ai and holds stock in the company; has served on an advisory board and served on a clinical end point committee for Bayer AG; has performed consultancy for FIRE-1; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis, and Boehringer Ingelheim. Drs Buendia Lopez, Cowie, Hammarstedt, Langkilde, and Reicher and F. Folkvaljon are employees of AstraZeneca and may own stock or stock options. The institution of Dr de Boer has received research grants or fees from AstraZeneca, Abbott, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche; he has had speaker engagements with or received fees from or served on an advisory board for Abbott, AstraZeneca, Bristol Myers Squibb, Cardior Pharmaceuticals GmbH, NovoNordisk, and Roche; and has received travel support from Abbott, Cardior Pharmaceuticals GmbH, and Novo Nordisk. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingelheim, Novo Nordisk, Rivus, and St. Luke’s Medical Center; has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. Dr Senni has received honoraria or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr Shah was supported by research grants from the US National Institutes of Health (NIH; U54 HL160273; R01 HL140731; and R01 HL149423); has received research funding from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cytokinetics, Edwards Lifesciences, Eli Lilly, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Merck, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving grants or research support or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management Inc, and Sanofi. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/National Heart‚ Lung‚ and Blood Institute (NHLBI), Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr McMurray reports receiving support from British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund; payments through Glasgow University from work on clinical trials, consulting, and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline and Novartis, British Heart Foundation, NIH/NHLBI, Boehringer Ingelheim, SQ Innovations, and Catalyze Group; personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, Bristol Myers Squibb, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2 Renal Corp; personal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals Ltd, Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; and on the Data Safety Monitoring Board for WIRB-Copernicus Group Clinical Inc. He is a director of Global Clinical Trial Partners Ltd.

Diabetic cognitive dysfunction (DCD) is a complication of diabetes that seriously affects quality of life. Glucocorticoid-induced transcript 1 (GLCCI1) has been found to be involved in inflammation, apoptosis and autophagy in various diseases. However, the distribution of GLCCI1 in the brain and its role in DCD have not yet been revealed. In addition, the potential therapeutics effects of salidroside (SAL), a phenyl propyl glycoside compound known for its neuroprotective effects in treating DCD are unknow. In the present study, we found that GLCCI1 was localized in hippocampal neurons. C57BL/6 J mice with DCD presented downregulation of GLCCI1 and Bcl-2 and upregulation of p-STAT3/STAT3, Bax, Cleaved Caspase-3/Caspase-3. Overexpression of GLCCI1 or SAL administration relieved DCD, reversed the changes in the expression of these cytokines, and alleviated morphological alterations in hippocampal neurons. Interestingly, SAL alleviated DCD and attenuated the expression of GLCCI1 and p-STAT3, showing similar effects as GLCCI1 overexpression. These findings suggest that the GLCCI1/STAT3 axis plays a crucial role in DCD and is involved in SAL-mediated attenuation of DCD., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims/hypothesis: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV)., Methods: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI., Results: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10 -3 mm 2 /s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10 -3 mm 2 /s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10 -3 mm 2 /s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10 -3 mm 2 /s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA 1c ., Conclusions/interpretation: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis., Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38., (© 2024. The Author(s).)