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Background: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have demonstrated associations with lowering cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). However, the impact of SGLT-2is on individuals at dialysis commencement remains unclear. The aim of this real-world study is to study the association between SGLT-2is and outcomes in patients with T2DM at dialysis commencement., Methods: This is a retrospective cohort study of electronic health records (EHRs) of patients with T2DM from TriNetX Research Network database between January 1, 2012, and January 1, 2024. New-users using intention to treatment design was employed and propensity score matching was utilized to select the cohort. Clinical outcomes included major adverse cardiac events (MACE) and all-cause mortality. Safety outcomes using ICD-10 codes, ketoacidosis, urinary tract infection (UTI) or genital infection, dehydration, bone fracture, below-knee amputation, hypoglycemia, and achieving dialysis-free status at 90 days and 90-day readmission., Results: Of 49,762 patients with T2DM who initiated dialysis for evaluation, a mere 1.57% of patients utilized SGLT-2is within 3 months after dialysis. 771 SGLT-2i users (age 63.3 ± 12.3 years, male 65.1%) were matched with 771 non-users (age 63.1 ± 12.9 years, male 65.8%). After a median follow-up of 2.0 (IQR 0.3-3.9) years, SGLT-2i users were associated with a lower risk of MACE (adjusted Hazard Ratio [aHR] = 0.52, p value < 0.001), all-cause mortality (aHR = 0.49, p < 0.001). SGLT-2i users were more likely to become dialysis-free 90 days after the index date (aHR = 0.49, p < 0.001). No significant differences were observed in the incidence of ketoacidosis, UTI or genital infection, hypoglycemia, dehydration, bone fractures, below-knee amputations, or 90-day readmissions., Conclusions: Our findings indicated a lower incidence of all-cause mortality and MACE after long-term follow-up, along with a higher likelihood of achieving dialysis-free status at 90 days in SGLT-2i users. Importantly, they underscored the potential cardiovascular protection and safety of SGLT-2is use in T2DM patients at the onset of dialysis., (© 2024. The Author(s).)

Aims/introduction: We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone., Materials and Methods: In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated., Results: At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone., Conclusions: Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/hypothesis: Although the benefits of sodium-glucose cotransporter 2 inhibitor (SGLT2i) use in chronic kidney disease (CKD) are well established, the effects of these therapeutic agents in patients with advanced CKD are less certain. We hypothesised that the continued use of these drugs, even when renal function deteriorates to stage 4 CKD or worse, is safe and associated with improved cardiorenal survival., Methods: This is a retrospective cohort study utilising data from medical records from two institutions. All patients with type 2 diabetes mellitus who were prescribed an SGLT2i between 1 January 2016 and 31 December 2021, who subsequently had eGFR <30 ml/min per 1.73 m 2 recorded on two occasions at least 90 days apart, were identified. The date on which the eGFR first reached any level less than 30 ml/min per 1.73 m 2 was defined as the index date. Individuals were then categorised into the SGLT2i continuation group or the discontinuation group according to the use of SGLT2i after the index date. Inverse probability of treatment weighting (IPTW) was performed to minimise confounding. Outcomes of interest included heart failure outcomes, cardiovascular outcomes, renal outcomes and safety outcomes., Results: According to the eligibility criteria, 337 patients in the continuation group and 358 in the discontinuation group were identified. After IPTW, continuation of SGLT2i use was associated with significantly lower risks of the composite of major adverse cardiovascular events compared with discontinuation of SGLT2i use (HR 0.65 [95% CI 0.43, 0.99]), largely driven by reduced risk of myocardial infarction during follow-up (subdistribution HR [SHR] 0.43 [95% CI 0.21, 0.89]). The incidences of an eGFR decline of 50% or more (SHR 0.58 [95% CI 0.42, 0.81]) and all-cause hospital admission (SHR 0.77 [95% CI 0.64, 0.94]) were also significantly lower in the continuation group. None of the studied safety outcomes were significantly different when comparing the two groups. Blood haemoglobin levels were significantly higher in the continuation group at the end of follow-up (114.6 g/l vs 110.4 g/l, with a difference of 4.12 g/l; p=0.047)., Conclusions/interpretation: In patients with CKD who were treated with an SGLT2i, continuation of SGLT2i use after eGFR declined to 30 ml/min per 1.73 m 2 or less was associated with lower risks of cardiovascular and renal events compared with discontinuation of SGLT2i use. Continued use of SGLT2i throughout the course of CKD should be considered to optimise patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2I) have been suggested to reduce new-onset cancer amongst type-2 diabetes mellitus (T2DM) patients. This study aims to compare the risks of prostate cancer between SGLT2I and dipeptidyl peptidase-4 inhibitors (DPP4I) amongst T2DM patients., Design, Setting and Participants: This was a retrospective population-based cohort study of prospectively recorded data on male patients with T2DM who were prescribed either SGLT2I or DPP4I between 1 st January 2015 and 31 st December 2020 from Hong Kong., Methods: The primary outcome was new-onset prostate cancer. The secondary outcomes included cancer-related mortality and all-cause mortality. Propensity score matching (1:1 ratio) using the nearest neighbor search was performed and multivariable Cox regression was applied. A three-arm analysis including the glucagon-like peptide-1 receptor agonist (GLP1a) cohort was conducted., Results: This study included 42129 male T2DM patients (median age: 61.0 years old [SD: 12.2]; SGLT2I: n = 17,120; DPP4I: n = 25,009). In the propensity score matched cohort, the number of prostate cancers was significantly lower in SGLT2I users (n = 60) than in DPP4I (n = 102). Over a follow-up duration of 5.61 years, SGLT2I was associated with lower prostate cancer risks (HR: 0.45; 95% CI: 0.30-0.70) than DPP4I after adjustments. The subgroup analyses showed that the interactions between SGLT2I and age, hypertension, heart failure, and GLP-1a were not statistically significant. The result remained consistent in the sensitivity analysis., Conclusion: The study demonstrated SGLT2I was associated with lower risks of new-onset prostate cancer after propensity score matching and adjustments compared to DPP4I amongst T2DM patients., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Masson SAS.)

Background/Objectives : The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods : The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results : During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions : Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

Background: Emerging data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve kidney outcomes for people with type 2 diabetes (T2D). Direct comparisons of the kidney and cardiovascular effectiveness of GLP-1 RA with sodium-glucose cotransporter 2 inhibitors (SGLT2i), a first-line therapy for this population, are needed., Objectives: The authors compared kidney and cardiovascular outcomes for new users of SGLT2i and GLP-1 RAs with T2D., Methods: Using propensity score overlap weighting, we analyzed electronic health record data from 20 U.S. health systems contributing to PCORnet between 2015 and 2020. The primary kidney outcome was a composite of sustained 40% estimated glomerular filtration rate (eGFR) decline, incident end-stage kidney disease, or all-cause mortality over 2 years or until censoring. In addition, we examined cardiovascular and safety outcomes., Results: The weighted study cohort included 35,004 SGLT2i and 47,268 GLP-1 RA initiators. Over a median of 1.2 years, the primary outcome did not differ between treatments (HR: 0.91; 95% CI: 0.81-1.02), although SGLT2i were associated with a lower risk of 40% eGFR decline (HR: 0.77; 95% CI: 0.65-0.91). Risks of mortality (HR: 1.08; 95% CI: 0.92-1.27), a composite of stroke, myocardial infarction, or death (HR: 1.03; 95% CI: 0.93-1.14), and heart failure hospitalization (HR: 0.95; 95% CI: 0.80-1.13) did not differ. Genital mycotic infections were more common for SGLT2i initiators, but other safety outcomes did not differ. The results were similar regardless of chronic kidney disease status., Conclusions: SGLT2i and GLP-1 RAs led to similar kidney and cardiovascular outcomes in people with T2D, though SGLT2i initiation was associated with a lower risk of 40% eGFR decline. (Evaluating Comparative Effectiveness of Empagliflozin in Type 2 Diabetes Population With and Without Chronic Kidney Disease; NCT05465317)., Competing Interests: Funding Support and Author Disclosures This study was funded by the Boehringer Ingelheim & Lilly Diabetes Alliance. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Dr Butler has received consultant honoraria 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, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Pagidipati has received research support from Alnylam, Amgen, Boehringer Ingelheim, Eggland’s Best, Eli Lilly, Novartis, Novo Nordisk, and Verily Life Sciences; has served on consultation/advisory panels for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk; has served as an executive committee member for trials sponsored by Novo Nordisk and Amgen; has served on the Data Safety Monitoring Boards for trials sponsored by Johnson and Johnson and Novartis; and has served on the medical advisory board for Miga Health. Dr Fonseca has received research support (to Tulane) from Fractyl and Jaguar Gene Therapy; has received consultant honoraria from Asahi, Bayer, Abbott, Boehringer Ingelheim, and Corcept; has stock or stock options in Mellitus Health, BRAVO4Health, Amgen, and Abbott; and has patents pending for BRAVO risk engine for predicting diabetes complications and PAX4 gene therapy for type 1 diabetes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations, recurrent cardiovascular events, and chronic kidney disease (CKD) progression, and thus constitute a Class 1a recommendation in people with diabetes and atherosclerotic cardiovascular disease, HF, or CKD and in people with severe albuminuria or HF, regardless of diabetes status., Objectives: The purpose of this study was to comprehensibly characterize the rate of SGLT2 inhibitor prescriptions among people with a Class 1a recommendation for SGLT2 inhibitor use., Methods: Among 3,189,827 adults from 28 U.S. health systems within Optum Labs Data Warehouse between April 1, 2022, and March 31, 2023, we assessed SGLT2 inhibitor prescription rates, stratified by presence of diabetes and Class 1a recommendation., Results: Among 716,387 adults with diabetes, 63.4% had a Class 1a recommendation for SGLT2 inhibitor therapy. There was little difference by Class 1a recommendation status (present: 11.9%; 95% CI: 11.9%-12.0% vs absent: 11.4%; 95% CI: 11.3%-11.6%; standardized mean difference: 1.3%). Among 2,473,440 adults without diabetes, 6.2% had a Class 1a recommendation for SGLT2 inhibitor therapy, and 3.1% (3.0%-3.2%) of those received a prescription. Internists/family practitioners initiated SGLT2 inhibitor prescriptions most commonly among people with diabetes, whereas specialists initiated SGLT2 inhibitor prescriptions most commonly among people without diabetes. No health system had >25% SGLT2 inhibitor prescription rate among people with a Class 1a recommendation. Health systems with higher proportions of patients with commercial insurance and lower proportions with Medicare had higher SGLT2 inhibitor prescription rates., Conclusions: In this analysis of U.S. data from 2022 to 2023, SGLT2 inhibitor prescription among people with a Class 1a recommendation is low. Interventions are needed to increase uptake of guideline-recommended SGLT2 inhibitor use., Competing Interests: Funding Support and Author Disclosures This study was funded by R01 DK115534, K24HL155861, and K01DK121825 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: This nationwide cohort study evaluated the impact of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on patients with type 2 diabetes mellitus (T2DM) after ischaemic stroke (IS), aiming to compare clinical outcomes between SGLT2i-treated patients and those not receiving SGLT2i., Materials and Methods: Utilizing Taiwan's National Health Insurance Research Database, we identified 707 patients with T2DM treated with SGLT2i and 27 514 patients not treated with SGLT2i after an IS, respectively, from 1 May 2016 to 31 December 2019. Propensity score matching was applied to balance baseline characteristics. The follow-up period extended from the index date (3 months after the index acute IS) until the independent occurrence of the study outcomes, 6 months after discontinuation of the index drug, or the end of the study period (31 December 2020), whichever came first., Results: After propensity score matching, compared with the non-SGLT2i group (n = 2813), the SGLT2i group (n = 707) exhibited significantly lower recurrent IS rates (3.605% per year vs. 5.897% per year; hazard ratio: 0.55; 95% confidence interval: 0.34-0.88; p = 0.0131) and a significant reduction in all-cause mortality (5.396% per year vs. 7.489% per year; hazard ratio: 0.58; 95% confidence interval: 0.39-0.85; p = 0.0058). No significant differences were observed in the rates of acute myocardial infarction, cardiovascular death, heart failure hospitalization, or lower limb amputation., Conclusions: Our findings indicate significantly lower risks of recurrent IS and all-cause mortality among patients with T2DM receiving SGLT2i treatment. Further studies are required to validate these results and investigate the underlying mechanisms behind the observed effects., (© 2024 John Wiley & Sons Ltd.)

Purpose: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients., Methods: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO 3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis., Results: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%)., Conclusions: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases., (© 2024. The Author(s).)

The sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that is located within the proximal tubule of the kidney's nephrons. While it is typically associated with the kidney, it was later identified in various areas of the central nervous system, including areas modulating cardiorespiratory regulation like blood pressure. In the kidney, SGLT2 functions by reabsorbing glucose from the nephron's tubule into the bloodstream. SGLT2 inhibitors are medications that hinder the function of SGLT2, thus preventing the absorption of glucose and allowing for its excretion through the urine. While SGLT2 inhibitors are not the first-line choice, they are given in conjunction with other pharmaceutical interventions to manage hyperglycemia in individuals with diabetes mellitus. SGLT2 inhibitors also have a surprising secondary effect of decreasing blood pressure independent of blood glucose levels. The implication of SGLT2 inhibitors in lowering blood pressure and its presence in the central nervous system brings to question the role of SGLT2 in the brain. Here, we evaluate and review the function of SGLT2, SGLT2 inhibitors, their role in blood pressure control, the future of SGLT2 inhibitors as antihypertensive agents, and the possible mechanisms of SGLT2 blood pressure control in the central nervous system., (© 2024. The Author(s).)

Aim: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first., Methods: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only., Results: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001)., Conclusion: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes., (© 2024 John Wiley & Sons Ltd.)

Real-life data on the impact of sacubitril-valsartan and sodium-glucose cotransporter type 2 (SGLT-2) inhibitors on heart failure (HF) in France is lacking. Using French health insurance databases, we examined the ten-year evolution in HF medication use, focusing on SGLT-2 inhibitors and sacubitril/valsartan, and incidence of HF hospitalizations during the same period. We conducted a repeated cross-sectional study using medical-administrative data from French health insurance databases between 2014 and 2023. These included "OpenMedic" for outpatient medication reimbursements and "ScanSanté" for annual hospitalization data. Medications were classified using ATC codes, and hospitalizations were identified using ICD-10 codes. Statistical analyses encompassed annual rates of users and boxes dispensed for HF medications, along with HF, ischemic heart disease and ischemic stroke hospitalization rates. Prevalence of SGLT-2 inhibitors and sacubitril-valsartan use was also studied regionally, with direct standardization by age and sex, with the French population as the standard population. Between 2014 and 2023, HF drug use increased significantly, with beta-blockers and ACE inhibitors/ARBs leading in prevalence of use. ARNi and SGLT-2 inhibitors, introduced later, showed remarkable rises: +506% and +3766% in users since their market introduction, respectively. Meanwhile, HF hospitalizations slightly increased by +3.6% between 2016 and 2019, followed by a notable decline of -12.5% during 2019-2023, coinciding with the introduction of SGLT-2 inhibitors. In contrast, hospitalizations for ischemic heart disease rose by 11.6% over the period 2016-2019 and by +5.2% over the period 2019-2023, and hospitalizations for ischemic stroke rose by 8.2% over the period 2016-2019 and declined by -0.6% over the period 2019-2023. We observed regional disparities in SGLT-2 inhibitors use, with prevalence ranging from 0.9% in Bretagne to 1.5% in Hauts-de-France. The data suggests a temporal correlation between the increase in SGLT-2 inhibitors use and the decline in HF hospitalizations since 2019. More studies are needed to measure real life effectiveness of SGLT-2 inhibitors in heart failure., (Copyright © 2024. Published by Elsevier Masson SAS.)

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).)

Background and Objectives : Peritoneal dialysis (PD) is a renal replacement therapy modality in which the dialysis dose can be individually adapted according to the patients' residual kidney function (RKF). RKF is a crucial factor for technique and patient survival. Pharmacological strategies aimed at slowing the loss of RKF in patients on PD are limited. Therefore, we aimed to assess the potential effects and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on the preservation of RKF in patients with and without type 2 diabetes mellitus (T2DM) on PD during an average follow-up of 6 months. Materials and Methods : In this retrospective observational, single-center study on real-world data, we included patients from the Peritoneal Dialysis Unit of the Hospital General Universitario de Ciudad Real, who started treatment with SGLT-2 inhibitors during the period from December 2022 to December 2023. Data on analytical and clinical parameters, RKF, and peritoneal membrane transport function were retrospectively collected at months 0, 3, and 6. Results : Out of 31 patients in our unit, 16 prevalent patients initiated treatment with SGLT-2 inhibitors (13 empagliflozin and 3 dapagliflozin). A total of 62.5% were male and the mean age was 67.3 years. The baseline peritoneal ultrafiltration was higher in the non-diabetic patient (NDMP) group than in the diabetic patient (DMP) group. However, the residual diuresis volume, 24 h residual renal clearance rate of urea in urine, and 24 h proteinuria were higher in the DMP group than in the NDMP group. At the sixth month, patients in both groups preserved RKF and diuresis, with a trend towards a non-significant reduction in proteinuria and blood pressure. Only two patients of the DMP group presented adverse effects. Conclusions : The use of SGLT-2 inhibitors in our sample of patients with and without T2DM on PD appears to be safe and effective to preserve RKF.

Dapagliflozin has been associated with euglycemic ketoacidosis in adults with diabetes contributing to poor outcomes when continued prior to surgery. It is unknown if preoperative use of dapagliflozin may lead to adverse events (AE) in nondiabetic children with advanced heart failure (HF) undergoing heart transplantation (HTx). We performed a single-center, matched case-control analysis of nondiabetic primary pediatric HTx recipients < 21 years-old who underwent HTx and followed through postoperative day (POD) 3. Cases who received dapagliflozin leading up to HTx (n = 22) were matched by age and cardiac diagnosis to two historical controls who did not receive dapagliflozin (n = 44). Median age at HTx was 13.8 years (range 0.36-20.7) and 48% were female. Cardiac diagnoses included cardiomyopathy (45%), Fontan failure (41%), and single ventricle status post stage I palliation (14%). Cases received median dapagliflozin dose of 0.17 mg/kg once daily; therapy was stopped one day prior to HTx. There were no significant differences in blood glucose nadirs, arterial blood gas indices including nadirs of pH, bicarbonate, or peaks of arterial blood lactic acid POD0-3. Vasopressor, inotrope, and insulin infusion usage were not different. No patients were treated for severe hypoglycemia, euglycemic ketoacidosis, or urinary tract infections. There were no deaths. Length of stay in ICU and time from HTx to hospital discharge did not differ between cohorts. Use of dapagliflozin in children with advanced HF until HTx is not associated with AE in the immediate postoperative period nor increased length of hospitalization post-HTx. Potential cardiovascular benefits of dapagliflozin in patients awaiting HTx should be prioritized., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are both recommended for patients with diabetes, yet their effects on the development or progression of diabetic retinopathy (DR) are largely unknown., Methods: In this retrospective cohort study, data were collected from a nationwide database. Patients with diabetes who initiated treatment with a GLP1RA or SGLT2i between 1 May 2016 and 31 December 2017, were identified. Patients were divided into those with or without a previous diagnosis of DR and then categorized into the GLP1RA and the SGLT2i groups according to drug use. The primary outcome of interest in the DR group was the composite of new-onset proliferative DR, vitreous haemorrhage and tractional retinal detachment (RD). In the non-DR group, the primary outcome was the composite of newly diagnosed DR of any severity, vitreous haemorrhage and RD., Results: In total, 97 413 patients were identified. After matching, 1517 patients were treated with a GLP1RA and 3034 with an SGLT2i in the DR cohort. In the non-DR cohort, 9549 initiated a GLP1RA and 19 098 initiated an SGLT2i. In patients with pre-existing DR, the incidence of any DR progression event was significantly higher in the GLP1RA group than the SGLT2i group (subdistribution hazard ratio 1.50, 95% confidence interval 1.01-2.23), primarily because of the increased risk of tractional RD. In patients without DR at baseline, the risks of all ocular outcomes were similar between the GLP1RA and SGLT2i groups., Conclusions: In patients with diabetes mellitus and established DR, GLP1RA treatment was associated with increased risks of DR progression compared with SGLT2i use., (© 2024 John Wiley & Sons Ltd.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

Background: The impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the postoperative recurrence of atrial fibrillation (AF) in patients with persistent AF undergoing an initial radiofrequency ablation is not yet established. The objective of this study is to assess the impact of SGLT2 inhibitors on the recurrence of AF after radiofrequency ablation in patients with type 2 diabetes complicated persistent AF., Methods: A total of 182 patients with type 2 diabetes and persistent AF, who underwent their first radiofrequency ablation for AF at our center, were enrolled and divided into two groups: the SGLT2 inhibitor group and the non-SGLT2 inhibitor group. The main outcome of the follow-up was the postoperative recurrence of AF., Results: A total of 49 participants experienced AF recurrence. The use of SGLT2 inhibitors in patients with type 2 diabetes who underwent AF ablation was associated with a significantly lower risk of AF recurrence (adjusted hazard ratio: 0.65; 95% confidence interval: 0.28-0.83; p < .01)., Conclusions: The use of SGLT2 inhibitors is associated with a decreased risk of arrhythmia recurrence after AF ablation in patients with type 2 diabetes complicated with persistent AF., (© 2024 Wiley Periodicals LLC.)

Introduction: It is unclear how dietary intake changes after sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is started in patients with type 2 diabetes., Methods: We performed a non-controlled, open-label study that enrolled 51 patients with type 2 diabetes. The patients were newly administered empagliflozin, and their dietary habits were examined using a self-administered diet history questionnaire at the beginning of the study and after 24 weeks. We investigated the association of changes in HbA1c and body weight with changes in energy, nutrient, and food group intakes., Results: At 24 weeks after the start of the study, HbA1c improved significantly and body weight decreased. In the food group, only the intake of confectionery increased, and there were no significant differences in the association between changes in HbA1c and body weight and changes in energy, nutrient, and food group intakes after 24 weeks. However, a significant negative correlation was found between change in HbA1c after 4 weeks and change in energy intake after 24 weeks, and principal component analysis showed an association between change in HbA1c levels after 4 weeks and change in energy intake and some food group intakes including confectionery after 24 weeks., Conclusion: In this study, after 24 weeks of treatment with empagliflozin, only intake of confectionery increased. Early assessment by dietitians after initiation of SGLT2i treatment might be important because our data suggested that the reduction in blood glucose levels after the start of empagliflozin was associated with a subsequent increase in energy intake., Trial Registration: University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on September 5, 2016 (registration ID, UMIN000002309|| http://www.umin.ac.jp/ctr/ )., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter 2 inhibitors were shown to reduce morbidity and mortality in patients with heart failure., Objectives: This study aims to assess potential effects of dapagliflozin in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) on cardiac function assessed by speckle tracking echocardiography (STE)., Methods: This randomized, prospective, single-center, open-label trial compared consecutive nondiabetic outpatients with HFrEF or HFmrEF receiving dapagliflozin with patients treated with optimal medical therapy (OMT) except sodium-glucose cotransporter type 2 inhibitors. Primary endpoint was the presence of a significant modification of left ventricular global longitudinal strain, diastolic function (as peak atrial longitudinal strain) and right ventricular function by STE from baseline to 6 months. Cardiovascular events and parameters of congestion were assessed as safety-exploratory endpoints., Results: Overall, 88 patients (38% HFmrEF) were enrolled and randomized to start dapagliflozin on top of OMT (n = 44) or to continue with OMT (n = 44). All STE values improved in the dapagliflozin group after 6 months, whereas there was a nonsignificant improvement in OMT group. Moreover, when comparing the modification of STE parameters at follow-up in patients with HFrEF and HFmrEF, only the main treatment effect resulted statistically significant in both groups (P < 0.0001), indicating a significant difference between dapagliflozin and OMT., Conclusions: This study provided randomized data on the beneficial effect of dapagliflozin in nondiabetic patients with HFrEF and HFmrEF in terms of myocardial performance measured by the most sensitive echocardiographic technique, ie, STE. This suggests its usefulness for left ventricular reverse remodeling and better quality of life in patients with HFrEF and HFmrEF. (Effects of Dapagliflozin on cardiac deformation and clinical outcomes in heart failure with reduced and mildly reduced ejection fraction [DAPA ECHO trial]; EudraCT number: 2021-005394-66)., Competing Interests: Funding Support and Author Disclosures The study has been supported with an unrestricted grant by AstraZeneca. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved., Methods and Results: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models., Conclusions: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a neuroprotective effect. This study compared the risks of carpal tunnel syndrome and carpal tunnel release surgery between new users of SGLT2is and new users of glucagon-like peptide-1 receptor agonists (GLP-1RAs)., Methods: A retrospective new-user active comparator cohort study with a target trial design was conducted by using the TriNetX platform. Patients with type 2 diabetes mellitus prescribed SGLT2is or GLP-1RAs were identified. Covariates were balanced using propensity score matching to form 2 homogenous treatment groups. Outcomes were the risk of carpal tunnel syndrome and the risk of carpal tunnel release surgery. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated using the TriNetX platform., Results: The crude cohort included 86,188 and 100,244 patients in the SGLT2is group and GLP-1RAs group, respectively. After matching, each group included 65,464 patients. The SGLT2is group had an average age of 59.6 years, and 46 % were women. The GLP-1RAs group had an average age of 59.5 years, and 45.9 % were women. The incidences of carpal tunnel syndrome (HR: 0.928; 95 % CI: 0.869 to 0.991) and carpal tunnel release surgery (HR: 0.840; 95 % CI: 0.726 to 0.971) were significantly lower in the SGLT2is group than in the GLP-1RAs group., Conclusion: In patients with type 2 diabetes mellitus, SGLT2is seem to decrease the risk of carpal tunnel syndrome and the need for carpal tunnel release surgery. Prospective studies are required to confirm our results., 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 Masson SAS.)

Background: Dapagliflozin and empagliflozin are antidiabetic medications. They are the first two sodium-glucose cotransporter-2 inhibitors (SGLT2i) to receive the US Food and Drug Administration approval to manage heart failure. Emerging new trials have examined changes in the 6-min walk distance as a clinically significant response to dapagliflozin and empagliflozin in patients with heart failure with reduced ejection fraction (HFpEF) and heart failure with preserved ejection fraction (HFrEF). This meta-analysis aims to evaluate the effects of dapagliflozin and empagliflozin on the 6-min walk distance in patients with HFpEF and HFrEF. To our knowledge, no such meta-analysis has been published., Methods: Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) to identify eligible studies reported up to December 16, 2023. Using Review Manager software, we reported outcomes as risk ratios (RRs) or mean difference (MD) and confidence intervals (CIs). A p-value ≤ 0.05 is considered as statistically significant., Results: The meta-analysis included a total of 8 studies with 2624 patients. Overall, the results showed insignificant differences in the 6-min walk between the SGLT2i and placebo (MD 24, 95% CI -0.30 to 18.78, p = 0.06). Results became significant after resolving the heterogeneity (MD 6.72, 95% CI 0.13 to 13.31, p = 0.05). Notably, the results of each drug separately were insignificant. More robust observations occurred in the HFpEF group (MD 10.73, 95% CI 1.08 to 20.39, p = 0.03). Compared to placebo, patients on dapagliflozin reported significant improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary (KCCQ-CS) and Overall Summary (KCCQ-OS) with values of MD 5.18 (95% CI 2.80 to 7.57, p < 0.0001) and MD 4.06 (95% CI 1.66 to 6.46, p = 0.0009), respectively. The dapagliflozin group and patients with HFpEF had reported a significant reduction in their weight compared with the control group (MD -0.59 CI -1.09 to -0.08, p = 0.02) and (MD -0.80 CI -1.47 to -0.13, p = 0.02), respectively. No significant side effects were observed for dapagliflozin or empagliflozin., Conclusion: Patients with HFpEF experienced benefits from SGLT2i administration, as evidenced by improved 6-min walk distances and weight reduction. Dapagliflozin demonstrated clinical and overall improvements in KCCQ scores and was more effective in reducing weight than the placebo. Both Dapagliflozin and Empagliflozin were well-tolerated and exhibited favorable safety profiles. Future studies could benefit from a larger patient population, a longer follow-up period, and a broader range of SGLT2i., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The conventional sequence of guideline-directed medical therapy (GDMT) initiation in heart failure with reduced ejection fraction (HFrEF) assumes that the effectiveness and tolerability of GDMT agents mirror their order of discovery, which is not true. In this review, the authors discuss flexible GDMT sequencing that should be permitted in special populations, such as patients with bradycardia, chronic kidney disease, or atrial fibrillation. Moreover, the initiation of certain GDMT medications may enable tolerance of other GDMT medications. Most importantly, the achievement of partial doses of all four pillars of GDMT is better than achievement of target dosing of only a couple., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a newly developed class of anti-diabetics which exert potent hypoglycemic effects in the diabetic milieu. However, the evidence suggests that they also have extra-glycemic effects. The renin-angiotensin-aldosterone system (RAAS) is a hormonal system widely distributed in the body that is important for water and electrolyte homeostasis as well as renal and cardiovascular function. Therefore, modulating RAAS activity is a main goal in patients, notably diabetic patients, which are at higher risk of complications involving these organ systems. Some studies have suggested that SGLT2is have modulatory effects on RAAS activity in addition to their hypoglycemic effects and, thus, these drugs can be considered as promising therapeutic agents for renal and cardiovascular disorders. However, the exact molecular interactions between SGLT2 inhibition and RAAS activity are not clearly understood. Therefore, in the current study we surveyed the literature for possible molecular mechanisms by which SGLT2is modulate RAAS activity., 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 Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure., Methods: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m 2 , n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed., Results: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects., Conclusions: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure., (© 2024. The Author(s).)

Type 2 diabetes (T2DM) is a chronic metabolic disease with a steadily increasing prevalence worldwide. Diabetes affects the function of many organs, including the skin. Pharmacotherapy for T2DM is mainly based on oral hypoglycemic drugs. The therapeutic strategy is chosen taking into account the individual patient's characteristics, among other comorbidities. Antidiabetic drugs can induce cutaneous adverse reactions (CADRs) ranging in severity from mild erythema to serious disorders such as DRESS or Stevens-Johnson syndrome. CADRs can result from hypersensitivity to the drug but can also be related to the mechanism of action of the drug or cross-reactivity with drugs of similar structure. This paper reviews CADRs induced by oral antidiabetic drugs, considering their dermatological manifestations and possible pathomechanisms. Particular attention was paid to specific dermatological conditions such as dipeptidylpeptidase 4 inhibitor-associated bullous pemphigoid or Fournier's gangrene associated with sodium-glucose cotransporter 2 inhibitor therapy. Knowledge of the dermatological manifestations of CADRs is important in clinical practice. Recognition of a skin lesion resulting from an adverse drug reaction allows for appropriate management, which in this case is primarily related to drug discontinuation. This is particularly important in the treatment of T2DM since this disease has a high prevalence in the elderly, who are at higher risk of adverse drug reactions.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias., (© 2024. The Author(s).)

Metabolic syndrome (MetS) is a multifactorial condition that significantly increases the risk of cardiovascular disease and chronic kidney disease (CKD). Recent studies have emphasized the role of lipid dysregulation in activating cellular mechanisms that contribute to CKD progression in the context of MetS. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated efficacy in improving various components of MetS, including obesity, dyslipidemia, and insulin resistance. While SGLT2i have shown cardioprotective benefits, the underlying cellular mechanisms in MetS and CKD remain poorly studied. Therefore, this review aims to elucidate the cellular mechanisms by which SGLT2i modulate lipid metabolism and their impact on insulin resistance, mitochondrial dysfunction, oxidative stress, and CKD progression. We also explore the potential benefits of combining SGLT2i with other antidiabetic drugs. By examining the beneficial effects, molecular targets, and cytoprotective mechanisms of both natural and synthetic SGLT2i, this review provides a comprehensive understanding of their therapeutic potential in managing MetS-induced CKD. The information presented here highlights the significance of SGLT2i in addressing the complex interplay between metabolic dysregulation, lipid metabolism dysfunction, and renal impairment, offering clinicians and researchers a valuable resource for developing improved treatment strategies and personalized approaches for patients with MetS and CKD.

Background: Rabson-Mendenhall syndrome (RMS), a rare disorder characterized by severe insulin resistance due to biallelic loss-of-function variants of the insulin receptor gene (INSR), presents therapeutic challenges (OMIM: 262190). This case study explores the efficacy of adjunctive therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2is) in the management of RMS in an 11-year-old male patient with compound heterozygous pathogenic variants of INSR. Methods: Despite initial efforts to regulate glycemia with insulin therapy followed by metformin treatment, achieving stable glycemic control presented a critical challenge, characterized by persistent hyperinsulinism and variable fluctuations in glucose levels. Upon the addition of empagliflozin to metformin, notable improvements in glycated hemoglobin (HbA1c) and time in range (TIR) were observed over a 10-month period. Results: After 10 months of treatment, empagliflozin therapy led to a clinically meaningful reduction in HbA1c levels, decreasing from 8.5% to 7.1%, along with an improvement in TIR from 47% to 74%. Furthermore, regular monitoring effectively averted normoglycemic ketoacidosis, a rare complication associated with SGLT2 inhibitor therapy. Conclusion: This case highlights the potential of SGLT2i as adjunctive therapy in RMS management, particularly in stabilizing glycemic variability. However, further research is warranted to elucidate the long-term efficacy and safety of this therapeutic approach in RMS and similar insulin resistance syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Foglino, Barbetti, Morotti, Castorani, Rigamonti, Frontino, Barera and Bonfanti.)

Background: Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i)., Objectives: This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM., Methods: Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different-age and N-terminal pro-B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables., Results: The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003)., Conclusions: SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM., Competing Interests: Funding Support and Author Disclosures Dr Fontana is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/21/33447). Dr Cappelli has received consulting income from Pfizer, Alnylam, Astra Zeneca, Novo Nordisk, and BridgeBio. Dr Urey has received consulting income from Pfizer, BridgeBio, AstraZeneca, Ionis, and Alnylam. Dr Hawkins has received consulting income from Alnylam. Dr Gillmore has received consulting income from Ionis, Alexion, Eidos, Intellia, Alnylam, and Pfizer. Dr Fontana has received consulting income from Intellia, Novo Nordisk, Pfizer, Eidos, Prothena, Alnylam, Alexion, Janssen, AstraZeneca, Attralus, Lexeo, and Ionis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research., Competing Interests: Authors GC and KU were employed by CEINGE-Advanced Biotechnologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Riemma, Mele, Donniacuo, Telesca, Bellocchio, Castaldo, Rossi, De Angelis, Cappetta, Urbanek and Berrino.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have noted benefits in the treatment of type 2 diabetes, cardiovascular disease, heart failure, and chronic kidney disease. Despite these benefits, the adoption of SGLT2i in clinical practice has been slow. Early initiation of SGLT2i during hospitalization has been proposed to address this gap for 2 important reasons: 1) it provides early clinical benefit in multiple disease states; and 2) hospitalization presents an opportunity for medication optimization and patient education, thereby overcoming clinical inertia. Challenges in SGLT2i adoption necessitate innovative strategies for integration into clinical practice. Ongoing trials and novel care delivery models are anticipated to further elucidate effective strategies for SGLT2i implementation and adherence. This review synthesizes the accrued evidence of SGLT2i across various chronic diseases. It emphasizes the rationale for early in-hospital initiation and discusses barriers and potential solutions for widespread implementation of SGLT2i in hospitalized patients., Competing Interests: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Lilly USA, LLC. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no payment related to the development of the manuscript. Graphical support was provided by Envision Pharma Group, contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. BIPI and Lilly were given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Dr Unlu has received funding from the 10.13039/100000050National Heart Lung and Blood Institute under award number T32HL007604. Dr Bhatt has received grant support to his institution from 10.13039/100000002National Institutes of Health/10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health/10.13039/100000049National Institute on Aging, 10.13039/100005485American College of Cardiology Foundation, and the 10.13039/100000030Centers for Disease Control and Prevention and has received consulting fees from Sanofi Pasteur, Novo Nordisk, and the Kinetix Group. Dr Blood has received grant support from Novo Nordisk, 10.13039/100001003Boehringer Ingelheim, GE Healthcare, 10.13039/100004312Eli Lilly; consulting fees from Walgreens Health, Color Health, Flare Capital, Arsenal Capital Partners, Novo Nordisk, Milestone Pharmaceuticals; and has equity holdings in Knownwell; and has received grant support from National Institutes of Health/ National Heart, Lung, and Blood Institute and under Equity “Signum Technologies and Porter Health”., (© 2024 The Authors.)

Aim: To describe the epidemiological, clinical and laboratory characteristics and clinical progress of patients hospitalized with heart failure (HF) who started treatment with empagliflozin before discharge. Methods: We performed a retrospective observational study of patients aged ≥18 years admitted to the Internal Medicine Department of University Hospital Jaen, Jaen, Spain with acute HF between 1 May 2022 and 31 May 2023. Patients had to have a life expectancy of ≥1 year and have started treatment with empagliflozin during admission. Results: We included 112 patients (mean age, 85.2 ± 6.5 years; 67.9% women; 35.7 and 31.3% in NYHA functional classes III and IV; 73.2% with HF and preserved ejection fraction). Before admission, 80.4% were taking loop diuretics, 70.6% renin-angiotensin-aldosterone system inhibitors, 49.1% betablockers and 25% mineralocorticoid receptor antagonists. At admission, 94.6% were taking furosemide (15.2% at high doses, 36.6% at intermediate doses). The dose of furosemide was reduced at initiation of empagliflozin. At the end of follow-up, 13.4% of patients had died, 93.8% of the survivors continued treatment with empagliflozin and 26.8% had attended the emergency department with signs and symptoms of HF. Conclusion: Introduction of empagliflozin before discharge from hospital in patients admitted with HF made it possible to reduce the dose of diuretics during admission. The frequency of complications was as expected, and treatment was largely maintained.

Background: Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood., Objective: The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD., Methods: We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m 2 ), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m 2 ). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82 Rubidium positron emission tomography-computed tomography ( 82 Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99m Technetium-diethylene-triamine-pentaacetate ( 99m Tc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system., Results: Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published., Conclusions: This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively., Trial Registration: EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50., International Registered Report Identifier (irrid): DERR1-10.2196/56067., (©Steffen Flindt Nielsen, Camilla Lundgreen Duus, Niels Henrik Buus, Jesper Nørgaard Bech, Frank Holden Mose. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 29.05.2024.)

Introduction: Kidney transplantation (KT) improves the cardiovascular outcomes of patients with end-stage kidney disease. However, cardiovascular disease remains the leading cause of premature death and graft loss in KT recipients (KTRs) with diabetes. We evaluated the cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in KTRs with diabetes., Methods: A total of 750 KTRs with diabetes were enrolled from 6 tertiary hospitals. Among them, 129 patients (17.2%) were prescribed SGLT2i. The primary outcome was the incidence of major adverse cardiovascular events (MACE), which comprised myocardial infarction (MI), death from cardiovascular causes, hospitalization for heart failure, and stroke. Multivariable Cox regression analysis and propensity score matching were used to investigate the effect of SGLT2i on clinical outcomes., Results: In the matched cohort, MACE occurred in 5 patients (3.9%) in the SGLT2i group and 15 patients (11.8%) in the non-SGLT2i group, out of 127 patients in each group over 55.3 months. The incidence of MACE and MI was lower in the SGLT2i group than in the non-SGLT2i group ( P  = 0.036 and 0.008, respectively). In multivariate analysis, the SGLT2i group had a lower risk of MACE and MI than the non-SGLT2i group (adjusted hazard ratio [HR], 0.30 and 0.04; 95% confidence interval [CI], 0.10-0.88 and 0.004-0.40; P  = 0.028 and 0.006, respectively). There was no difference in the incidence of urinary tract infection (UTI) between the 2 groups., Conclusion: SGLT2i significantly decreased the risk of cardiovascular events in KTRs with diabetes, particularly lowering the incidence of MI and death from cardiovascular causes. SGLT2i can be used to reduce the burden of cardiovascular disease in KTRs with diabetes., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: This systematic review and meta-analysis aimed to explore the effects of different sodium-glucose cotransporter-2 inhibitors (SGLT2i) on prognosis and cardiac structural remodeling in patients with heart failure (HF)., Methods: Relevant studies published up to 20 March 2024 were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library CNKI, China Biomedical Literature Service, VIP, and WanFang databases. We included randomized controlled trials of different SGLT2i and pooled the prognosis data of patients with HF. We compared the efficacy of different SGLT2i in patients with HF and conducted a sub-analysis based on left ventricular ejection fraction (LVEF)., Results: We identified 77 randomized controlled trials involving 43,561 patients. The results showed that SGLT2i significantly enhanced outcomes in HF, including a composite of hospitalizations for HF and cardiovascular death, individual hospitalizations for HF, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, left atrial volume index (LAVi), and LVEF among all HF patients ( P  < 0.05) compared to a placebo. Sotagliflozin was superior to empagliflozin [RR = 0.88, CI (0.79-0.97)] and dapagliflozin [RR = 0.86, CI (0.77-0.96)] in reducing hospitalizations for HF and CV death. Dapagliflozin significantly reduced hospitalizations [RR = 0.51, CI (0.33-0.80)], CV death [RR = 0.73, CI (0.54-0.97)], and all-cause mortality [RR = 0.69, CI (0.48-0.99)] in patients with HF with reduced ejection fraction (HFrEF). SGLT2i also plays a significant role in improving cardiac remodeling and quality of life (LVMi, LVEDV, KCQQ) ( P  < 0.05). Among patients with HF with preserved ejection fraction (HFpEF), SGLT2i significantly improved cardiac function in HFpEF patients ( P  < 0.05). In addition, canagliflozin [RR = 0.09, CI (0.01-0.86)] demonstrated greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF patients., Conclusion: Our systematic review showed that SGLT2i generally enhances the prognosis of patients with HF. Sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in a composite of hospitalization for HF and CV death in the overall HF patients. Canagliflozin exhibited greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF. Overall, the efficacy of SGLT2i was greater in HFrEF patients than in HFpEF patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lan, Zhu, Cao, Hu, Fan, Zhang and Wu.)

Background: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, is an epochal oral antidiabetic drug that improves cardiorenal outcomes. However, the effect of early dapagliflozin intervention on left ventricular (LV) remodeling in patients with type 2 diabetes free from cardiovascular disease remains unclear., Methods and Results: The ELUCIDATE trial was a prospective, open-label, randomized, active-controlled study that enrolled 76 patients with asymptomatic type 2 diabetes with LV ejection fraction ≥50%, randomized to the dapagliflozin 10 mg/day add-on or standard-of-care group. Speckle-tracking echocardiography-based measurements of the cardiac global longitudinal strain were performed at baseline and 24 weeks after treatment initiation. Patients who received dapagliflozin had a greater reduction in LV dimension (1.68 mm [95% CI, 0.53-2.84]; P =0.005), LV end-systolic volume (5.51 mL [95% CI, 0.86-10.17]; P =0.021), and LV mass index (4.25 g/m 2.7 [95% CI, 2.42-6.09]; P <0.0001) compared with standard of care in absolute mean differences. Dapagliflozin add-on therapy led to a significant LV global longitudinal strain increment (0.74% [95% CI, 1.00-0.49]; P <0.0001) and improved LV systolic and early diastolic strain rates (0.27/s [95% CI, 0.17-0.60]; and 0.11/s [95% CI, 0.06-0.16], respectively; both P <0.0001) but not in global circumferential strain. No significant changes were found in insulin resistance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, or other biomarkers at 6 months after the dapagliflozin administration., Conclusions: Dapagliflozin add-on therapy could lead to more favorable cardiac remodeling accompanied by enhanced cardiac mechanical function among patients with asymptomatic type 2 diabetes. Our findings provide evidence of the efficacy of dapagliflozin use for the primary prevention of diabetic cardiomyopathy., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871621.

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for type 2 diabetes mellitus (DM) treatment, have shown potential benefits beyond glycemic control, including a positive impact on the blood pressure (BP). This meta-analysis aimed to evaluate their effects on patients with type 2 DM and hypertension., Methods: We searched the PubMed, Google Scholar, and Cochrane databases for relevant randomized controlled trials published until May 31, 2023. Ten randomized controlled trials involving participants with confirmed type 2 DM were selected. The intervention group received SGLT2i, whereas the control group received a placebo or standard care. The primary outcomes were the 24-hour ambulatory systolic BP (SBP) and diastolic BP (DBP)., Results: The results showed a significant reduction in the 24-hour ambulatory SBP (weighted mean difference, -5.08 mm Hg; 95% confidence interval, -7.02 to -3.14; P <.00001) and DBP (weighted mean difference, -2.73 mm Hg; 95% confidence interval, -4.25 to -1.20; P =.0005) with the use of SGLT2i compared with that using the placebo. However, a high-heterogeneity level was observed in both analyses (SBP, I 2  = 83%; DBP, I 2  = 91%). Sensitivity analysis excluding specific studies reduced heterogeneity while maintaining statistically significant and clinically relevant reductions in the BP., Conclusion: In conclusion, this meta-analysis proves that SGLT2i significantly reduce the 24-hour ambulatory BP. SGLT2i may be considered an effective treatment option for lowering the BP in addition to standard care in patients with hypertension and type 2 DM., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Background: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes., Methods and Results: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65., Conclusions: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

Background: Heart failure (HF) is the principal cause of morbidity and mortality in adults with congenital heart disease (ACHD). Robust evidence-based treatment options are lacking., Objectives: This study aims to evaluate the safety, tolerability, and short-term HF-related effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a real-world ACHD population., Methods: All patients with ACHD treated with SGLT2i in 4 European ACHD centers were included in this retrospective study. Data were collected from 1 year before starting SGLT2i to the most recent follow-up. Data on side effects, discontinuation, mortality, and hospitalizations were collected., Results: In total, 174 patients with ACHD were treated with SGLT2i from April 2016 to July 2023. The mean age was 48.7 ± 15.3 years, 72 (41.4%) were female, and 29 (16.7%) had type 2 diabetes mellitus. Ten (5.7%) patients had mild, 75 (43.1%) moderate, and 89 (51.1%) severe congenital heart disease. HF was the most frequent starting indication (n = 162, 93.1%), followed by type 2 diabetes (n = 11, 6.3%) and chronic kidney disease (n = 1, 0.6%). At median follow-up of 7.7 months (Q1-Q3: 3.9-13.2 months), 18 patients (10.3%) reported side effects, 12 (6.9%) permanently discontinued SGLT2i, and 4 (2.3%) died of SGLT2i-unrelated causes. A significant reduction in the HF hospitalization rate was observed from 6 months before to 6 months after starting SGLT2i (relative rate = 0.30; 95% CI: 0.14-0.62; P = 0.001)., Conclusions: SGLT2i generally seem safe, well-tolerated, and potentially beneficial in patients with ACHD. SGLT2i was associated with a 3-fold reduction in the 6-month HF hospitalization rate. These results warrant prospective randomized investigation of the potential benefits of SGLT2i for patients with ACHD., Competing Interests: Funding Support and Author Disclosures Dr Neijenhuis has received support from the Foundation “De Drie Lichten” (Hilversum, the Netherlands), AstraZeneca, and the Leiden University Medical Center research council Cardio-Vascular cluster Themes for Innovation funding. Dr Zemrak has received speaker fees from Abbott Laboratories. Dr Rotmans has received an unrestricted research grant from AstraZeneca. Dr Jongbloed has received support from the Leiden University Medical Center research council Cardio-Vascular cluster Themes for Innovation funding; and has received a personal grant from the NWO/ZonMw (The Hague, the Netherlands), the Bontius Foundation (Leiden, the Netherlands), and the Rembrandt Institute (Leiden, the Netherlands). Dr Egorova has received support from the Leiden University Medical Center research council Cardio-Vascular cluster Themes for Innovation funding; and has received consultancy and speaker fees from Boston Scientific Corporation and Medtronic Inc. The Department of Cardiology of the Leiden University Medical Center has received unrestricted research and educational grants from Boston Scientific Corporation, Medtronic, and Biotronik. The funders were not involved in study design, collection, analysis, interpretation of data, the writing of this paper, or the decision to submit it for publication. No artificial intelligence programs contributed to the compilation of the submitted manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A 78-year-old male was admitted to the hospital with acute renal failure and generalized erythema after starting dapagliflozin 10 mg/day for chronic kidney disease (CKD). A skin biopsy revealed superficial perivascular dermatitis with eosinophils. A renal biopsy revealed lymphocytic and eosinophilic infiltration of the interstitium, and focal tubulitis. The patient was diagnosed with a dapagliflozin-induced drug reaction with eosinophilia and systemic symptoms (DRESS), followed by acute interstitial nephritis (AIN), and prednisolone therapy was therefore initiated. The patient's renal function improved, and erythema disappeared. To our knowledge, this is the first report of DRESS caused by dapagliflozin, and the patient was successfully treated with prednisolone.

Aim: Describe the rationale for and design of Diabetes Remote Intervention to improVe use of Evidence-based medications (DRIVE), a remote medication management program designed to initiate and titrate guideline-directed medical therapy (GDMT) in patients with type 2 diabetes (T2D) at elevated cardiovascular (CV) and/or kidney risk by leveraging non-physician providers., Methods: An electronic health record based algorithm is used to identify patients with T2D and either established atherosclerotic CV disease (ASCVD), high risk for ASCVD, chronic kidney disease, and/or heart failure within our health system. Patients are invited to participate and randomly assigned to either simultaneous education and medication management, or a period of education prior to medication management. Patient navigators (trained, non-licensed staff) are the primary points of contact while a pharmacist or nurse practitioner reviews and authorizes each medication initiation and titration under an institution-approved collaborative drug therapy management protocol with supervision from a cardiologist and/or endocrinologist. Patient engagement is managed through software to support communication, automation, workflow, and standardization., Conclusion: We are testing a remote, navigator-driven, pharmacist-led, and physician-overseen management strategy to optimize GDMT for T2D as a population-level strategy to close the gap between guidelines and clinical practice for patients with T2D at elevated CV and/or kidney risk., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This project was funded by an unrestricted grant from Novo Nordisk to Brigham and Women’s Hospital., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: -3.5 ± 9.4 mL/min/1.73 m 2 /year, post: -0.4 ± 6.3 mL/min/1.73 m 2 /year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: -2.0 ± 10.9 mL/min/1.73 m 2 /year, post: -1.8 ± 5.4 mL/min/1.73 m 2 /year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits-especially annual eGFR decline-of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Muta, Kobayashi, Toyoda, Tone, Suzuki, Tsuriya, Machimura, Shimura, Takeda, Yokomizo, Takeshita, Chin, Kanasaki, Tamura, Miyauchi, Saburi, Morita, Yomota, Kimura, Hatori, Nakajima, Ito, Tsukamoto, Murata, Matsushita, Furuki, Hashimoto, Umezono, Takashi and Kawanami.)

Diabetes, one of the world's top ten diseases, is known for its high mortality and complication rates and low cure rate. Prediabetes precedes the onset of diabetes, during which effective treatment can reduce diabetes risk. Prediabetes risk factors include high-calorie and high-fat diets, sedentary lifestyles, and stress. Consequences may include considerable damage to vital organs, including the retina, liver, and kidneys. Interventions for treating prediabetes include a healthy lifestyle diet and pharmacological treatments. However, while these options are effective in the short term, they may fail due to the difficulty of long-term implementation. Medications may also be used to treat prediabetes. This review examines prediabetic treatments, particularly metformin, glucagon-like peptide-1 receptor agonists, sodium glucose cotransporter 2 inhibitors, vitamin D, and herbal medicines. Given the remarkable impact of prediabetes on the progression of diabetes mellitus, it is crucial to intervene promptly and effectively to regulate prediabetes. However, the current body of research on prediabetes is limited, and there is considerable confusion surrounding clinically relevant medications. This paper aims to provide a comprehensive summary of the pathogenesis of pre-diabetes mellitus and its associated therapeutic drugs. The ultimate goal is to facilitate the clinical utilization of medications and achieve efficient and timely control of diabetes mellitus., Competing Interests: Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)