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Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a promising therapy for diabetes and CKD patients. However, the pros and cons of SGLT2i in Type2 diabetes patients with CKD stage 5 remained largely unexplored. By using Taiwan's national health insurance research database (NHIRD), this observational cohort study enrolled T2DM patients with newly identified as having CKD5, and the index date defined as the date of CKD5 identification. The enrollees were divided into 2 groups depending on whether SGLT2 inhibitors were used for more than 3 months or not following the index date. A 1:4 propensity score matching was performed to balance characteristics between two groups. The SGLT2-inhibitor group exhibited significantly lower risks of new-onset ESRD (35.9% vs. 58.2%, hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.59–0.74). For the risks of MACCEs (16.72% vs. 17.66%, HR 0.84, 95% CI: 0.62–1.15), infections related hospitalization (2.4% vs. 2.61%, HR:1.02, 95% CI:0.80–1.31), Infection-associated mortality (3.45% vs. 4.18% HR:0.80, 95% CI:0.41–1.56) and all-cause mortality (13.79% vs. 13.83%, HR:0.95, 95% CI:0.68–1.32), no significant differences were observed between two groups. In conclusion, we provide evidence suggesting that SGLT2 inhibitors may offer renal protection and did not increase infection risks for CKD5 patients with type2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed. Methods: A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses. Results: A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74–0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64–0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65–0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65–0.99; P = 0.04). Conclusion: SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD. Systematic review registration: PROSPERO (CRD42024601914) Highlights: 1. Redefine outcomes of ventricular arrhythmias (VAs) and sudden cardiac death (SCD) for SGLT2 inhibitor medication in heart failure patients. 2. SGLT2 inhibitors lower the risks of VAs and SCD in patients at various stages of HF, excluding advanced HF. 3. Longer therapeutic effects were associated with a significant reduction in the incidence of VAs and SCD. [ABSTRACT FROM AUTHOR]

Introduction: The clinical landscape for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) is rapidly evolving. As part of the FOUNTAIN platform (NCT05526157; EUPAS48148), we described and compared cohorts of adult patients with CKD and T2D initiating a sodium-glucose cotransporter 2 inhibitor (SGLT2i) before the launch of finerenone in Europe, Japan, and the United States (US). Methods: This was a multinational, multi-cohort study of patients with T2D in five data sources: the Danish National Health Registers (DNHR) (Denmark), PHARMO Data Network (The Netherlands), Valencia Health System Integrated Database (VID) (Spain), Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex) (Japan), and Optum's de-identified Clinformatics® Data Mart Database (CDM) (US). Eligible patients had CKD (based on either diagnosis codes, eGFR values, and/or urine ACR) and initiated an SGLT2i between 2012 and 2021. Baseline demographic, lifestyle, and clinical characteristics were analyzed, and drug utilization patterns were described. Results: The final cohorts included 21,739 patients in DNHR, 381 in PHARMO, 31,785 in VID, 1157 in J-CKD-DB-Ex, and 56,219 in CDM. Across data sources, approximately 41–70% had CKD stage 1 or 2 at baseline; severe CKD (stage 4) was uncommon (1.6–6.7%). The median duration of SGLT2i therapy ranged from 7.5 months in PHARMO to 17.0 months in VID. At least 50% of patients were currently receiving SGLT2i treatment at 1 year after initiation. Conclusions: At a 1-year follow-up, at least half of the patients with CKD and T2D were receiving SGLT2i treatment across the data sources. In patients initiating SGLT2i, treatment options for T2D and CKD were heterogeneous and dynamic within and among data sources. [ABSTRACT FROM AUTHOR]

Background: In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated significant cardiovascular and renal benefits in patients with heart failure (HF), in addition to their established antidiabetic effects. However, their role in arrhythmia prevention remains unclear. This study aimed to assess the effect of SGLT2 inhibitors on the incidence of supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in patients with HF with reduced ejection fraction (HFrEF) during an extended follow-up period. Methods: This retrospective cohort study was conducted between January 2019 and November 2024 at the Ulm University Heart Center. All patients exhibited severely reduced left ventricular function and underwent primary prophylactic implantable cardioverter-defibrillator (ICD) implantation. Half of the cohort initiated SGLT2 inhibitor therapy alongside optimal medical HF treatment (the SGLT2 group). Patients were followed for approximately three years (846.2 ± 520.0 days) and the incidence of SVT and VT was analyzed using intracardiac Holter records of the ICD. Results: The study population consisted of 78 patients with a mean age of 66.6 ± 12.9 years. Over the follow-up period, a significant prolongation in the time to first occurrence of SVT was observed in the SGLT2 group (Log-Rank p = 0.03), suggesting a potential protective effect of SGLT2 inhibitors. However, regarding VT, additional SGLT2 inhibitor therapy did not show an additional benefit to optimal medical HF treatment. Conclusions: This study suggests that SGLT2 inhibitors may play a beneficial role in reducing the incidence of SVT in patients with HFrEF. These results highlight the importance of further investigating the antiarrhythmic potential of SGLT2 inhibitors through large-scale, prospective studies to better understand their clinical implications and mechanisms of action. [ABSTRACT FROM AUTHOR]

Simple Summary: SGLT2 inhibitors, first introduced in the clinical practice for diabetes, have been suggested to be effective against different types of cancer. Here, we review the literature on the re-purposing of SGLT2 inhibitors for cancer, focusing on the data that are most relevant for human cancer. Cancer cells utilize larger amounts of glucose than their normal counterparts, and the expression of GLUT transporters is a known diagnostic target and a prognostic factor for many cancers. Recent evidence has shown that sodium-glucose transporters are also expressed in different types of cancer, and SGLT2 has raised particular interest because of the current availability of anti-diabetic drugs that block SGLT2 in the kidney, which could be readily re-purposed for the treatment of cancer. The aim of this article is to perform a narrative review of the existing literature and a critical appraisal of the evidence for a role of SGLT2 inhibitors for the treatment and prevention of cancer. SGLT2 inhibitors block Na-dependent glucose uptake in the proximal kidney tubules, leading to glycosuria and the improvement of blood glucose levels and insulin sensitivity in diabetic patients. They also have a series of systemic effects, including reduced blood pressure, weight loss, and reduced inflammation, which also make them effective for heart failure and kidney disease. Epidemiological evidence in diabetic patients suggests that individuals treated with SGLT2 inhibitors may have a lower incidence and better outcomes of cancer. These studies are confirmed by pre-clinical evidence of an effect of SGLT2 inhibitors against cancer in xenograft and genetically engineered models, as well as by in vitro mechanistic studies. The action of SGLT2 inhibitors in cancer can be mediated by the direct inhibition of glucose uptake in cancer cells, as well as by systemic effects. In conclusion, there is evidence suggesting a potential role of SGLT2 inhibitors against different types of cancer. The most convincing evidence exists for lung and breast adenocarcinomas, hepatocellular carcinoma, and pancreatic cancer. Several ongoing clinical trials will provide more information on the efficacy of SGLT2 inhibitors against cancer. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of sodium‐glucose co‐transporter 2 inhibitor [SGLT‐2i] therapy on renal haemodynamics in T2D patients with glomerular hyperfiltration. Materials and Methods: Sixty T2D patients with elevated [HYPER] and normal [NORMO] GFR were randomized to dapagliflozin 10 mg/day [DAPA/HYPER, n = 15; DAPA/NORMO, n = 15] or to metformin/glipizide [CONTROL/HYPER, n = 15; CONTROL/NORMO, n = 15] to reach similar glycaemic control after 4 months. GFR was measured with Iohexol and hyperfiltration was empirically defined as >125 mL/min/1.73 m2. GFR, renal plasma flow [RPF], mean arterial pressure [MAP], filtration fraction [FF], and renal vascular resistance [RVR] were determined before/after therapy. Results: HbA1c decreased similarly in all 4 groups. GFR declined by ~18% in DAPA/HYPER and by ~7% in DAPA/NORMO and did not change in CONTROLS (p < 0.05 vs. DAPA). RPF remained unchanged in all four groups. Thus, FF (%) declined from 0.23 ± 0.01 to 0.18 ± 0.01 in DAPA/HYPER and from 0.17 ± 0.01 to 0.15 ± 0.01 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). MAP (mmHg) decreased from 95.4 ± 1.4 to 88.1 ± 1.3 in DAPA/HYPER and from 95.6 ± 1.3 to 91.8 ± 0.8 in DAPA/NORMO and remained unchanged in CONTROLS (p < 0.05 vs. DAPA). RVR [mmHg/L/min] declined in DAPA/HYPER (92.7 ± 7.8 to 80.4 ± 6.1) and DAPA/NORMO (90.1 ± 3.0 to 81.4 ± 2.1) but not in CONTROLS (p < 0.05 vs. DAPA). Conclusions: Despite comparable glycaemic control, dapagliflozin treatment, but not metformin and /or glipizide, reduced glomerular hyperfiltration in T2D patients and decreased both filtration fraction and renal vascular resistance. These findings suggest that a post‐glomerular vasodilatory action of SGLT2 inhibitors contributes to their renal protective effect in T2D. [ABSTRACT FROM AUTHOR]

Aim: Over recent years, therapy options and strategies for type 2 diabetes mellitus (T2DM) have developed substantially. This study investigated glucose‐lowering treatment in patients with high cardiovascular risk over three decades. Materials and Methods: A total of 2158 patients undergoing elective coronary angiography at a tertiary care hospital in Europe were included in three sequential observational studies (OS): OS1 (1999–2000; n = 672), OS2 (2005–2008; n = 1005) and OS3 (2022–2023; n = 481). Sociodemographic data, patient‐reported medication, medical histories and blood samples were analysed. Results: A clear trend towards more complex glucose‐lowering therapies was found. A wider array of glucose‐lowering drugs was used over time (OS1: 11; OS2: 21; OS3: 25) and the number of different drugs used in combination therapy in a single patient increased to a maximum of five in OS3. Furthermore, substantial differences in applied medication regimens were observed: Sodium‐glucose cotransporter‐2 inhibitors were the most frequently reported substance class (34.0% of total reported glucose‐lowering drugs) in OS3, whilst metformin remained a key component (OS1: 33.9%; OS2: 41.8%; OS3: 32.0%). Other drug classes like sulfonylureas were largely replaced. A total of 69.2% of patients in OS3 achieved an HbA1c level of < 7% (vs. OS1: 51.9%, OS2: 54.7%; ptrend < 0.001). Over 25% of patients with T2DM were newly diagnosed at admission (OS1: 43.8%, OS2: 29.7%, OS3: 27.2%; ptrend < 0.001) and had therefore no diabetes‐related medication. Conclusion: These real‐world data emphasize a marked shift in T2DM treatment towards novel substance classes. However, the use of incretin mimetics remained low. Significantly more patients reached HbA1c targets in the most recent cohort. [ABSTRACT FROM AUTHOR]

The article discusses the discontinuation of SGLT2 inhibitors (SGLT2i) in people with type 2 diabetes following hospitalization for heart failure. A study conducted in New South Wales, Australia, found that nearly 30% of SGLT2i users discontinued therapy within 90 days of discharge, with one in five remaining off treatment at 365 days. Factors such as age, hospitalization duration, number of prior hospitalizations, and chronic kidney disease were associated with higher discontinuation rates. The study highlights the importance of minimizing SGLT2i discontinuation to reduce mortality and readmission risks in this population. [Extracted from the article]

Enavogliflozin, a sodium–glucose cotransporter 2 inhibitor, was approved in 2022 by the Korean Ministry of Food and Drug Safety as a therapeutic agent for type 2 diabetes mellitus and has been investigated for expanded therapeutic efficacy in diabetic retinopathy and cardioprotection. In this study, we developed and validated an analytical method to precisely detect enavogliflozin in mouse plasma, employing liquid–liquid extraction combined with liquid chromatography–tandem mass spectrometry. Overall, the analytical method, covering a range of 5–3000 ng/mL, is reliable for investigating the time-concentration profiles of enavogliflozin, demonstrating acceptable accuracy, precision, extraction recovery, and minimal matrix effects without stability concerns as evidenced by assessments of post-treatment stability, freeze–thaw stability, and short-term stability of enavogliflozin. Pharmacokinetic profiles and all pharmacokinetic parameters of enavogliflozin in mice did not differ between fed and fasted states after oral administration of enavogliflozin (1 mg/kg). Additionally, no differences in the pharmacokinetic profiles of enavogliflozin were observed among single, 7-day repeated, and 14-day repeated oral administrations at 1 mg/kg. In the tissue distribution study, enavogliflozin showed the highest distribution in the kidneys, followed by the large intestine, stomach, small intestine, liver, heart, lungs, spleen, and testes after oral administration at both 1 and 3 mg/kg doses. Dose proportionality in tissue distribution was observed except for the kidneys. In conclusion, enavogliflozin can be administered without concern for pharmacokinetic changes, regardless of single or multiple dosing and whether in fed or fasted states. Furthermore, the tissue distribution profile may offer valuable insights into the therapeutic potential of this drug. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in clinical trials for slowing chronic kidney disease (CKD) progression, but real-world data in diverse populations are limited. This retrospective study evaluated the effectiveness and safety of SGLT2i versus renin-angiotensin-aldosterone system (RAAS) blockade in CKD patients. Data from Ramathibodi Hospital (2010–2022) were analyzed, including 6,946 adults with CKD stages 2–4, with and without diabetes, who received SGLT2i (n = 1,405) or RAAS blockade (n = 5,541) for at least three months. Patients were matched 1:4 by CKD stage and treatment initiation date. A weighted Cox proportional hazards model with inverse probability weighting assessed the effect on composite major adverse kidney events (MAKEs), including eGFR decline ≥ 40%, progression to CKD stage 5, dialysis initiation, and cardiovascular or kidney death. SGLT2i therapy was associated with a lower risk of composite MAKEs (HR: 0.59; 95% CI: 0.36–0.98; P = 0.041) and less frequent progression to CKD stage 5 (HR: 0.52; 95% CI: 0.34–0.80; P < 0.003). Adverse event rates were similar between groups, with lower urinary tract infection incidence in the SGLT2i group. These findings suggest SGLT2i therapy might reduce adverse kidney outcomes in CKD patients, regardless of diabetic status, with a favorable safety profile. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is classically characterized as an autoimmune disease wherein the immune system erroneously attacks insulin‐producing pancreatic β‐cells, causing insulin insufficiency and severe metabolic dysregulation. However, intensive investigation and numerous clinical trials with immunotherapies have been largely unable to significantly alter the course of disease. Currently, there is no effective way to prevent or cure T1D, and insulin remains the cornerstone of T1D treatment. In recent years, a growing body of research suggests that β‐cells actively contribute to the immune response and to disease development. Factors including glucotoxicity, lipotoxicity, inflammation, endoplasmic reticulum (ER) and oxidative stress can induce β‐cell apoptosis and senescence, further promoting insulitis. Recent studies highlight the importance of targeting metabolic control for T1D management and treatment. Metabolic interventions, through their direct and indirect impacts on β‐cells, have shown promise in preserving β‐cell function. These interventions can reduce glucose toxicity, alleviate oxidative stress and inflammation, enhance insulin sensitivity, and indirectly mitigate the autoimmune responses. By preserving β‐cell function, individuals with T1D attain better glycaemic control, reduced complication risks and exhibit improved overall metabolic health. Here, we provide an overview of insights from clinical studies, systematic reviews and meta‐analyses that collectively demonstrate that adjunctive metabolic interventions can enhance glycaemic control, reduce insulin requirements and mitigate adverse effects associated with insulin monotherapy. They also show potential for halting disease progression, preserving residual β‐cell function and improving long‐term outcomes for newly diagnosed individuals. Future research should focus on optimizing these treatment strategies and establishing their long‐term efficacy and safety. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. To better understand their molecular effects, RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection. Male adult DBA wild-type (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10 mg/kg diet) for 2 wk, and other Akita mice received GLP1R agonist semaglutide [sema; 3 nmol/(kg body wt·day), sc]. Dapa (254 ± 11 mg/dL) and Sglt1-KO (367 ± 11 mg/dL) but not sema (407 ± 44 mg/dL) significantly reduced hyperglycemia in Akita mice (480 ± 33 mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (∼1%) differentially expressed genes versus WT (DEGs; adjusted P ≤ 0.1), including downregulation of anionic transport, unsaturated fatty acid, and carboxylic acid metabolism. Dapa changed only two genes in WT but restored 43% of DEGs in Akita, including upregulation of the lipid metabolic pathway, carboxylic acid metabolism, and organic anion transport. In Akita, sema restored ∼10% of DEGs, and Sglt1-KO and dapa were synergistic (restored ∼61%), possibly involving additive blood glucose effects (193 ± 15 mg/dL). Targeted analysis of transporters and channels (t test, P < 0.05) revealed that ∼10% of 526 detectable transporters and channels were downregulated by Akita, with ∼60% restored by dapa. Dapa, dapa + Sglt1-KO, and sema also altered Akita-insensitive genes. Among DEGs in Akita, ∼30% were unresponsive to any treatment, indicating potential new targets. In conclusion, SGLT2i restored transcription for multiple metabolic pathways and transporters in SGLT2-positive proximal tubule segments in diabetic mice, with a smaller effect also observed for GLP1R agonism. NEW & NOTEWORTHY: SGLT2 inhibitors and GLP1 receptor agonists have kidney protective effects. By combining immunostaining-guided laser capture microdissection and RNA sequencing, the study established how the gene expression profile changes in SGLT2-positive proximal tubule cells in response to type 1 Akita diabetes and to pharmacological intervention by SGLT2 inhibition or GLP1R agonism and genetic deletion of SGLT1. The data also indicate genes unresponsive to those treatments that may include new therapeutical candidates. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Sodium‐glucose co‐transporter 2 inhibitors are a novel class of antihyperglycaemic drugs used in the management of type 2 diabetes, that improve glycaemic control, cardiovascular outcomes and promote weight loss. They are also approved for the treatment of heart failure and chronic kidney disease in patients with or without diabetes. This narrative review discusses the peri‐operative effects and implications of sodium‐glucose co‐transporter 2 inhibitors and gives an overview of current evidence and existing peri‐operative guidelines. Methods: We conducted a literature review to identify peer‐reviewed English language articles published since 2000, with further articles identified by reviewing the references of key papers. Results: Peri‐operative sodium‐glucose cotransporter 2 inhibitor use carries a risk of euglycaemic ketoacidosis. Although clinically significant diabetic ketoacidosis remains a rare event, sodium‐glucose co‐transporter 2 inhibitors inhibitor‐associated diabetic ketoacidosis has been observed across almost all surgical specialities. Ketoacidosis may present with any blood glucose level. Existing guidelines are inconsistent and may be a source of clinical confusion. Discussion: Based on the half‐life of sodium‐glucose cotransporter 2 inhibitors, we recommend withholding treatment for 72 h before elective surgery (5 half‐lives), with additional multidisciplinary input for specific procedures with dietary alterations and in patients with poorly controlled diabetes of cardiac/renal disease. In the event of emergency surgery or any surgery within 72 h of sodium‐glucose cotransporter 2 inhibitor administration, we recommend pre‐, intra‐ and postoperative blood ketone monitoring (6 hourly for 24 h post‐surgery and until full oral diet is resumed). Sodium‐glucose cotransporter 2 inhibitor treatment should only be resumed after resumption of full oral diet in the absence of ketosis. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of add‐on dapagliflozin in patients with type 2 diabetes mellitus (T2D) who had inadequate glycaemic control with metformin and linagliptin. Materials and Methods: A total of 235 patients with inadequate response to metformin (≥1000 mg/day) plus linagliptin (5 mg/day) were randomized to receive either dapagliflozin/linagliptin fixed‐dose combination (FDC [AJU‐A51]) 10/5 mg/day (n = 117) or linagliptin 5 mg plus placebo (n = 118) for 24 weeks. After the main treatment period, patients who received linagliptin plus placebo were treated with AJU‐A51 for an additional 28 weeks. Change in glycated haemoglobin (HbA1c) from baseline to Week 24 was the primary endpoint. Results: AJU‐A51 significantly reduced HbA1c levels (from 7.93% ± 0.82% to 7.11% ± 0.61%) compared with linagliptin plus placebo (from 7.80% ± 0.71% to 7.87% ± 0.94%), with a least squares mean difference of −0.88% (95% confidence interval −1.07 to −0.68; p < 0.0001) at 24 weeks. The AJU‐A51 group had a significantly higher proportion of patients who achieved HbA1c <7.0% at Week 24 than the control group (44.8% vs. 18.6%; p < 0.001). The AJU‐A51 group maintained glycaemic efficacy up to 52 weeks, whereas the control group showed a substantial reduction in HbA1c after switching to AJU‐A51 in the extension study period. Both groups had similar incidence of treatment‐emergent and serious adverse events, and no cases of symptomatic hypoglycaemia were reported. Conclusions: Dapagliflozin and linagliptin FDC (AJU‐A51) showed potent glucose‐lowering effects, with good tolerability, in patients with T2D who had poor glycaemic control on metformin and linagliptin (ClinicalTrials.gov [NCT06329674]). [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While glucokinase (GCK)-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY, such as hepatocyte nuclear factor-1-alpha (HNF1A)-MODY (formerly MODY-3) and HNF4A (formerly MODY-1), usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to investigate racial and ethnic disparities in the use of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor antagonists (GLP-1RAs) among older adults with type 2 diabetes and cardiorenal conditions. Methods: Using Medicare fee-for-service data (2013–2019), this retrospective cohort study identified older adults (≥65 years) with type 2 diabetes initiating second-line therapies (SGLT2is, GLP1-RAs, dipeptidyl peptidase-4 inhibitors [DPP4is] and sulfonylureas [SUs]) with (1) heart failure (HF), (2) atherosclerotic cardiovascular disease (ASCVD), (3) chronic kidney disease (CKD) and (4) no recorded cardiorenal conditions. Participants were classified as non-Hispanic White, non-Hispanic Black and Hispanic. Multinomial regressions, adjusting for sociodemographic, clinical and county-level characteristics, were used to model the odds of initiating SGLT2is or GLP-1RAs within each cohort. Results: Black participants with HF, ASCVD, CKD or no recorded cardiorenal conditions had 35% (adjusted OR 0.65 [95% CI 0.61, 0.68]), 33% (0.67 [0.64, 0.69]), 32% (0.68 [0.64, 0.72]) and 24% (0.76 [0.74, 0.79]) lower odds of initiating SGLT2is, respectively, than White participants. Disparities ameliorated from 50–60% lower odds in 2013 to 17–18% in 2019. Similar patterns were observed for GLP-1RA uptake among Black participants. By contrast, Hispanic participants had similar odds of SGLT2i initiation in the HF and CKD cohorts as White participants, but 6% (0.94 [0.91, 0.98]) lower odds in the ASCVD cohort. Notable disparities for Hispanic participants compared with White participants were observed for GLP-1RA uptake in the HF, ASCVD, CKD and no cardiorenal conditions cohorts: 11% (0.89 [0.84, 0.94]), 16% (0.84 [0.81, 0.87]), 16% (0.84 [0.80, 0.89]) and 25% (0.75 [0.72, 0.78]) lower odds, respectively. Participants had greater odds than White participants of initiating DPP4is, which confer no cardiorenal benefits, across all cohorts (HF 1.25 [1.19, 1.31]; ASCVD 1.36 [1.32, 1.40]; CKD 1.32 [1.26, 1.38). Adjustment for social determinants of health did not meaningfully change the study findings. Conclusions/interpretation: Compared with White participants, disparities in the uptake of SGLT2is were evident for Black participants, and in the uptake of GLP-1RAs for both Black and Hispanic participants. This study highlights how type 2 diabetes management is evolving, while underscoring historical imbalances that have shown signs of abatement. [ABSTRACT FROM AUTHOR]

Cardiomyocytes undergo a variety of cell death events during myocardial ischemia‒reperfusion injury (MIRI). Understanding the causes of cardiomyocyte mortality is critical for the prevention and treatment of MIRI. Among the various types of cell death, autosis is a recently identified type of autophagic cell death with distinct morphological and chemical characteristics. Autosis can be attenuated by autophagy inhibitors but not reversed by apoptosis or necrosis inhibitors. In recent years, it has been shown that during the late phase of reperfusion, autosis is activated, which exacerbates myocardial injury. This article describes the characteristics of autosis, autophagic cell death, and the relationship between autophagic cell death and autosis; reviews the mechanism of autosis in MIRI; and discusses its clinical significance. [ABSTRACT FROM AUTHOR]

Background Diabetic ketoacidosis (DKA) is a common hyperglycemic emergency characterized by hyperglycemia, metabolic acidosis, and ketonemia. DKA is a rare but serious complication of sodium-glucose cotransporter-2 (SGLT2) inhibitors that requires careful monitoring. Case Report We present two cases of acute ischemic stroke in patients who developed DKA during the administration of SGLT2 inhibitors. Case 1 was a 70-year-old woman with a right middle cerebral artery (MCA) infarction who developed severe metabolic acidosis and ketonemia on hospital day 5, which resolved after insulin and fluid therapy. Case 2 was a 52-year-old woman with a right MCA infarction and carotid stenosis who developed DKA on hospital day 3. Despite initial resolution, DKA recurred after SGLT2 inhibitor re-administration and permanent discontinuation was necessary. Conclusion These cases highlight the risk of DKA in the acute phase of ischemic stroke in patients treated with SGLT2 inhibitors.

ABSTRACT Aim Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear. Materials and Methods This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure. Results At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time. Conclusions The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes.

Abstract Background SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i’s produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function. Methods Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data. Results Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels. Conclusions Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling. Graphical Abstract

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes. Methods We assessed MAMs formation in podocytes from DKD patients’ renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes. Results MAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect. Conclusions Inhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.

ABSTRACT Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) have demonstrated a blood pressure (BP) reduction benefit despite other indications for use. We evaluated BP changes and antihypertensive medication use pre‐ and post‐SGLT2i initiation among 12 960 patients with treated hypertension and among subgroups with apparent treatment‐resistant hypertension (aTRH) and/or proteinuria. Post‐SGLT2i initiation, the mean (SD) systolic blood pressure (SBP) was reduced from 133.9 (16.4) to 128.6 (15.5) mmHg and the mean diastolic blood pressure (DBP) was reduced from 70.8 (11.8) to 68.3 (11.3) mmHg among all patients. The mean SBP/DBP reduction was 5.3/2.5, 6.2/2.8, and 6.1/2.9 mmHg among all patients, patients with aTRH, and patients with proteinuria, respectively. Achieved BP < 130/80 mmHg increased by 12.5%, 16.9%, and 11.1% for all patients, patients with aTRH, and patients with proteinuria, respectively. Discontinuation of ≥ 1 antihypertensive medication within 12 months of SGLT2i initiation occurred in 33.4% overall, 47.6% of patients with aTRH, and 38.7% of patients with proteinuria.

Abstract 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 (Emax) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher Emax 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.

Aim Materials and Methods Results Conclusions To comprehensively evaluate the benefits and risks of glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium‐glucose cotransporter 2 inhibitors (SGLT2i).A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP‐1RAs, or SGLT2i to placebo. Twenty‐one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population‐averaged odds ratios (ORs) with 95% CIs.Twenty‐six trials enrolling 198 177 participants were included. GLP‐1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP‐1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns.Given the distinct benefit–risk profiles, the selection of glucose‐lowering drugs should be individualized based on patient characteristics and risk factors. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Skin disorders occur more frequently with sodium‐dependent glucose cotransporter type 2 (SGLT2) inhibitors than with other antidiabetic drugs. We conducted basic research using ipragliflozin, with the aim of identifying new measures to prevent skin disorders caused by SGLT2 inhibitors.db/db type 2 diabetes model mice were orally administered ipragliflozin (10 mg/kg or 30 mg/kg) once a day for 28 days and skin function genes were analysed by real‐time RT‐PCR or Western blotting.No difference in the expression level of collagen (Col1a1 and Col1a2) in the skin was detected between the ipragliflozin treatment group and the control group. On the other hand, the expression levels of enzymes involved in the synthesis and decomposition of hyaluronic acid (Has2 and Hayl1) and enzymes involved in the synthesis and decomposition of ceramide (Sptlc1, Sptlc2, Asah1, and Acer1) were significantly decreased by the administration of ipragliflozin. Furthermore, the expression levels of filaggrin (Flg), loricrin (Lor), elastin (Eln), and aquaporin‐3 (Aqp3) in the skin were lower in the ipragliflozin treatment group than in the control group.It was revealed that ipragliflozin reduces the expression of genes involved in skin barrier and moisturizing functions, which this may be one of the mechanisms through which this drug causes skin disorders. [ABSTRACT FROM AUTHOR]

Background: Systemic autoimmune rheumatic disease (SARD) patients have been excluded from sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials given putative risks, but this risk magnitude is unknown. We aimed to quantify SGLT2i adverse event risks among patients with vs. without SARD. Methods: In a retrospective cohort study, patients with SARD at Mass General Brigham, a multihospital system in Boston, Massachusetts, prescribed SGLT2i were age-, self-reported race-, and sex-matched to patients prescribed the same SGLT2i between 1/1/2016 and 12/10/2021. Cumulative incidence and Cox models, overall and sex-stratified, estimated patient-reported adverse event risks from prescription date, censoring for discontinuation, death, or study end (12/12/2022). Results: Four hundred sixty-eight SARD and 420 matched non-SARD patients were compared: mean age 64 years (SD 11.3), 61% female, and 70% White. SARD patients had shorter SGLT2i use duration (8.4 vs. 12.7 months; p < 0.0001) and time to adverse event (0.59 vs. 0.85 years; p 0.04). Yeast infections (9.8% vs. 6.2%; p 0.047) and muscular symptoms (3.4% vs. 1.0%, p 0.01) were more prevalent among those with SARD. Adjusting for baseline demographics, adverse event risk was higher (MV HR 1.68; 95% CI 1.28, 2.21), in patients with vs. without SARD. Risk was higher in women than men overall and in women with SARD vs. without (adjusted HR 1.86; 95% CI 1.36, 2.54). Conclusion: Patients with vs. without SARD had 68% higher adverse event risk with SGLT2i use. Women with vs. without SARD had > 85% higher adverse event risks, although most were not serious. Trials of safety and efficacy of SGLT2i among SARD patients are warranted. Key Points •To our knowledge, this is the first study to compare adverse events associated with SGLT2i utilization in patients with vs. without SARD, despite RCT exclusion and documented SGLT2i use in the population. •In our comparison of 468 patients with SARD and 420 patients without, we identified a greater than 65% increase in risk of adverse event outcomes among patients with SARD. •Furthermore, we found that this risk disproportionately affected female patients, with a 4.4-fold increased risk among women with SARD compared to men without. [ABSTRACT FROM AUTHOR]

Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways. [ABSTRACT FROM AUTHOR]

The article "Representation of women in randomized controlled trials of novel antidiabetic drugs: A cohort study" published in Diabetes, Obesity & Metabolism highlights the underrepresentation of women in clinical trials for diabetes drugs, impacting the precision of medical interventions. The study focused on trials with primary outcomes related to cardiac and renal events, revealing a significant lack of female participants. Despite efforts to reduce gender disparities in clinical research, women were notably underrepresented, affecting the accuracy of treatment practices. The study recommends future research prioritize recruiting women in proportions reflective of their representation in the population to enhance the relevance of medical interventions. [Extracted from the article]

Aim: To assess the cost‐effectiveness of diabetic nephropathy treatment with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors in Japanese clinical practice, considering diabetes‐related complications. Materials and Methods: A population‐based Monte Carlo simulation was used to estimate the cost‐effectiveness for people with diabetic nephropathy who initiated pharmacotherapy with an SGLT2 inhibitor plus conventional treatment or conventional treatment alone, based on quality‐adjusted life‐years (QALYs) and healthcare costs. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) and the Japanese Society for Dialysis Research statistical survey were the primary sources of probability and mortality, while Japanese Health Insurance Claims Data were the cost source. The state transition model included diabetic nephropathy, hospitalization due to cardiovascular disease, dialysis, and death. One‐way and probabilistic sensitivity analyses were used to explore model uncertainty. Results: Using the threshold of JPY 5 000 000 per QALY, SGLT2 inhibitor plus conventional treatment was more cost‐effective than conventional treatment alone, with an incremental cost‐effectiveness ratio of JPY 654 309 per QALY. Treating 100 000 people, SGLT2 inhibitor plus conventional treatment prevented 2234 deaths and reduced 5793 fewer heart failure cases, 3967 fewer myocardial infarctions and stroke events. Sensitivity analysis affirmed the robustness of these results for patients aged under 70 years. Conclusions: The SGLT2 inhibitor treatment appeared to be cost‐effective for the overall population of our study and particularly for younger patients (<70 years old). For older patients (≥70 years old), the cost‐effectiveness was less clear and may require further evaluation. Decision‐makers should consider this age‐based heterogeneity when making recommendations about SGLT2 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) presents a significant clinical and economic burden to healthcare systems worldwide, which increases considerably with progression towards kidney failure. The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial demonstrated that patients with or without type 2 diabetes who were treated with dapagliflozin experienced slower progression of CKD versus those receiving placebo. Understanding the effect of long-term treatment with dapagliflozin on the timing of kidney failure beyond trial follow-up can assist informed decision-making by healthcare providers and patients. The study objective was therefore to extrapolate the outcome-based clinical benefits of treatment with dapagliflozin in patients with CKD via a time-to-event analysis using trial data. Methods Patient-level data from the DAPA-CKD trial were used to parameterize a closed cohort-level partitioned survival model that predicted time-to-event for key trial endpoints (kidney failure, all-cause mortality, sustained decline in kidney function and hospitalization for heart failure). Data were pooled with a subpopulation of the Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial to create a combined CKD population spanning a range of CKD stages; a parallel survival analysis was conducted in this population. Results In the DAPA-CKD and pooled CKD populations, treatment with dapagliflozin delayed time to first event for kidney failure, all-cause mortality, sustained decline in kidney function and hospitalization for heart failure. Attenuation of CKD progression was predicted to slow the time to kidney failure by 6.6 years [dapagliflozin: 25.2, 95% confidence interval (CI) 19.0–31.5; standard therapy: 18.5, 95% CI 14.7–23.4] in the DAPA-CKD population. A similar result was observed in the pooled CKD population with an estimated delay of 6.3 years (dapagliflozin: 36.0, 95% CI 31.9–38.3; standard therapy: 29.6, 95% CI 25.5–34.7). Conclusion Treatment with dapagliflozin over a lifetime time horizon may considerably delay the mean time to adverse clinical outcomes for patients who would go on to experience them, including those at modest risk of progression. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated benefit in patients with heart failure, but minimal data exist concerning the use of these medications in amyloid light-chain cardiomyopathy (AL-CM). We performed a retrospective study to assess the safety and efficacy of SGLT2is in AL-CM. We queried our institutional registry and identified 27 patients with AL-CM who received SGLT2is. The safety analysis included all 27 patients and assessed SGLT2i-associated adverse events, hospitalizations and deaths. To decrease confounding, the efficacy analysis included only a subset of patients with stable disease (on stable anti-plasma cell therapy for ≥ 2 months prior to baseline and had achieved at least a hematologic Very Good Partial Response) and compared disease-marker changes in these patients (n = 17) with those of a contemporaneous untreated control cohort from our registry (n = 21). The mean age of the overall population was 68.6 (standard deviation 9.4) years. Of the patients, 7 (14.6%) had diabetes, and 19 (39.6%) had chronic kidney disease. In the safety analysis, the median follow-up time was 10.9 (interquartile range 7.2) months. Two (7.4%) patients discontinued SGLT2is due to hypovolemia and genital irritation, and 6 (22.2%) additional patients temporarily held SGLT2is due to an adverse event that is commonly related to volume depletion. There were 13 hospitalizations, all considered unrelated to SGLT2i use, and no deaths occurred. In the efficacy analysis, SGLT2i-treated patients had more severe disease at baseline than controls, demonstrating significantly higher median troponin-T and loop diuretic dosage (P < 0.05). Compared with controls, SGLT2i treatment was associated with significantly greater reductions in loop diuretic dosage (P < 0.001) and NTproBNP levels (P = 0.033) across 3-, 6- and 12-month follow-up timepoints. SGLT2i treatment was also associated with a significantly greater reduction in mean arterial pressure at 12 months (P = 0.031) but not at other timepoints. No significant differences were observed in changes in weight, eGFR, troponin-T, proteinuria, or albumin levels. In this small-scale retrospective study, we demonstrate that SGLT2is are well tolerated by most patients with AL-CM, but volume depletion symptoms may limit continuous use. SGLT2is may aid management of congestion in AL-CM, as evidenced by reduced diuretic dosage and NTproBNP levels without adverse renal effects. Larger long-term studies are needed to build on our findings. [ABSTRACT FROM AUTHOR]

This study is aimed at evaluating the effect of empagliflozin in preventing atrial fibrillation after coronary artery bypass grafting (CABG). Eighty-two patients who fulfilled the inclusion criteria were allocated to the empagliflozin group (n = 43) or placebo group (n = 39). In two groups, patients received empagliflozin or placebo tablets 3 days before surgery and on the first three postoperative days (for 6 days) in addition to the standard regimen during hospitalization. During the first 3 days after surgery, types of arrhythmias after cardiac surgery, including supraventricular arrhythmias, especially postoperative atrial fibrillation (POAF), ventricular arrhythmias, and heart blocks, were assessed by electrocardiogram monitoring. C-reactive protein (CRP) levels were evaluated pre-operatively and postoperative on the third day. The incidence of POAF in the treatment group was lower compared to the control group; however, this reduction was statistically non-significant (p = 0.09). The frequency of ventricular tachycardia was reduced significantly in the treatment group versus patients in the control (p = 0.02). Also, a significant reduction in the frequency of premature ventricular contractions (PVCs) was seen in the treatment group in comparison with the control group (p = 0.001). After the intervention, CRP levels were significantly less in the empagliflozin group compared to the control group in the third postoperative day (p = 0.04). The prophylactic use of empagliflozin effectively reduced the incidence of ventricular arrhythmia in patients undergoing CABG surgery. [ABSTRACT FROM AUTHOR]

Sodium-glucose transporter 2 (SGLT2) inhibitors such as empagliflozin are one of the main treatments for type 2 diabetes mellitus (DM2) and heart failure (HF). They have also demonstrated anti-arrhythmic effects in some preclinical and clinical studies. The purpose of this study was to assess the effects of empagliflozin on ventricular arrhythmias in HF patients with an implantable cardioverter-defibrillator (ICD). In a prospective double-blinded, randomized controlled trial of Iran County, Mashhad (72 patients 1:1), we compared the frequency and proportion of ventricular arrhythmias and ICD therapies during the 24 weeks to the prior 24 weeks. Results revealed that empagliflozin significantly reduced the frequency and proportion of ventricular tachycardia (VT)/fibrillation (VF) episodes (P = 0.019 and 0.039, respectively). Moreover, it tended to reduce the frequency and proportion of ICD therapies, including anti-tachycardia pacing (ATP) and shock. Subgroup analysis of patients with or without any antiarrhythmic drugs (digoxin, mexiletine, amiodarone, or sotalol) revealed that only patients who were previously on the antiarrhythmic drugs benefit from empagliflozin antiarrhythmic effects. In conclusion, empagliflozin exhibits anti-arrhythmic effects in HF patients with an ICD. Larger and long-term clinical studies are still needed to investigate and confirm all positive effects of SGLT2 inhibitors in this regard. Trial registration number: IRCT20120520009801N7 (Approval date: June 11, 2022). [ABSTRACT FROM AUTHOR]

Clinical studies have investigated the effects of using sodium-glucose co-transporter-2 (SGLT2) inhibitors on the development of new-onset stroke (NOS) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD), but the findings are inconsistent. This study aimed to examine the association between the use of SGLT2 inhibitors and NOS risk in patients with T2D and CKD. We conducted a nationwide retrospective cohort study using data from the Taiwan Health Insurance Review and Assessment Service database for the years 2004 to 2019. The primary outcome was the risk of incident stroke, which was estimated using hazard ratios (HRs) and 95% confidence intervals (CIs). We used multiple Cox regression modeling to analyze the association between SGLT2 inhibitor use and the risk of stroke in patients with T2D and CKD. In a cohort of 113,710 patients with T2D and CKD who were using SGLT2 inhibitors and 227,420 patients with T2D and CKD who were not using SGLT2 inhibitors, after applying a 1:2 sex- and age-matching strategy, 2,842 and 7,169 NOS events were recorded, respectively. The event rate per 10,000 person-months was 10.60 (95% CI 10.21 to 11.03) for SGLT2 inhibitor users and 13.71 (13.39–14.03) for non-SGLT2 inhibitor users. After adjusting for the index year, sex, age, comorbidities, and concurrent medication, there was a decreased risk of NOS for SGLT2 inhibitor users (adjusted HR 0.80; 95% CI 0.77–0.84) compared with non-SGLT2 inhibitor users. The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.80; 95% CI 0.76–0.84). The type of SGLT2 inhibitor subgroup analysis for incident stroke showed consistent results. We concluded that the use of SGLT2 inhibitors in patients with T2D and CKD was associated with significantly low rates of NOS. The significantly low rates of NOS in patients with T2D and CKD were greater among females and less than 50 years patients. [ABSTRACT FROM AUTHOR]

Aim: Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear. Materials and Methods: This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure. Results: At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time. Conclusions: The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Trial registration The objective of this study was to examine the effects of empagliflozin on endothelium‐dependent and endothelium‐independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).In this double‐blind, placebo‐controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2‐week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium‐dependent and endothelium‐independent vasodilatory function, respectively. Total peripheral resistance, 24‐h blood pressure (BP) and biochemical markers of NO activity were measured as well.Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24‐h systolic BP by 5 mmHg (95% CI: −9; −1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: −5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: −94; −1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.Empagliflozin improves endothelium‐independent vasodilation, reduces vascular resistance and lowers 24‐h BP in patients with T2DM, whereas no change in endothelial‐dependent vasodilation was observed.EU Clinical Trials Register number: 2019‐004303‐12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK). [ABSTRACT FROM AUTHOR]

Background: SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function. Methods: Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data. Results: Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels. Conclusions: Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling. [ABSTRACT FROM AUTHOR]