Sodium-glucose Cotransporter 2 Inhibitor Therapy Research Articles

WCN25-3864 A Rare Case of Emphysematous Cystitis Linked to Early SGLT-2 Inhibitor Therapy in Diabetes

WCN25-3864 A Rare Case of Emphysematous Cystitis Linked to Early SGLT-2 Inhibitor Therapy in Diabetes

Effects of SGLT2i on right ventricule function in HFpEF: an echocardiographic study

Abstract Background several studies have demonstrated the cardioprotective effects of Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) in patients with heart failure (HF), irrespective of the presence of diabetes. These findings have culminated in new recommendations for SGLT2i in the treatment of HF, either with reduced or preserved ejection fraction (EF). Purpose the purpose of this study was to analyze the effect of Gliflozin on right ventricular function, in patients with HFpEF, using speckle tracking echocardiography and new echocardiographic surrogates of right ventricular-pulmonary artery (RV-PA) coupling. Methods we enrolled 105 symptomatic HF patients (aged 71,143 ± 9,913 years) with EF > 40% (47,9 ± 7,26) into a multicentric prospective observational study; main anamnestic information, NT-proBNP values and complete echocardiographic data were collected in an ambulatory setting, at time of enrolment and after 6 months of therapy with SGLT-2i. The echocardiographic analysis included conventional, tissue-derived imaging, and myocardial deformation speckle tracking echocardiography of left and right sections. TAPSE/PASP (tricuspid annular plane systolic excursion/pulmonary artery systolic pressure) and RVFWLS/PASP (Right ventricle free wall longitudinal strain) were also collected as surrogates of RV-PA coupling such as Results after 6 months of SGLT-2i therapy echocardiographic evaluation revealed improvement of LVEF (47,909 ± 7,260; 49,562 ± 8,784; p value 0.003) LVGLS (-13,312 ± 3,555; -14,894 ± 3,970; p value < 0.001), RVFWLS (-18,324 ± 6,430; -20,705 ± 6,469; p value 0.002). Echocardiographic parameters of diastolic function such as E/E’m (11,270 ± 6,282; 9,782 ± 6,622; p value 0.003) and PASP (36,580 ± 14,879; 31,757 ± 10,740; p value 0.036) were also ameliorated. Both TAPSE/PASP (0,567 ± 0,267; 0,762±0,536; p value 0.036) and RV FWLS/PASP (-0,588 ± 0,299; -0,785 ± 0,663 p value 0.003) showed higher values. Conclusions our study has demonstrated a significant impact of SGLT-2i on echocardiographic parameters of LV diastolic function and on both left and right ventricle systolic function in patients with HFpEF in a 6 months follow up. Moreover, our findings of RV-PA coupling echocardiographic surrogates improvement, after SGLT-2I use, could underscore the potential of SGLT-2i in managing RV dysfunction in HFpEF.

Antiarrhythmic Effects of SGLT2 Inhibitors on Supraventricular Tachyarrhythmias in Patients with HFrEF

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.

The Impact of Sodium-Glucose Co-Transporter-2 Inhibition on Insulin Resistance and Inflammation in Patients with Type 2 Diabetes: A Retrospective Study

Background and Objectives: Insulin resistance (IR) is a key factor involved in the development of type 2 diabetes (T2D). Besides its role in the pathogenesis of T2D, insulin resistance is associated with impairment of glycemic control, reduced achievement of glycemic targets, and increases in cardiovascular risk and diabetes complications, being thus a negative prognosis factor. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are therapies for T2D which demonstrated, besides glycemic control, improvements of biomarkers traditionally associated with IR and inflammation. This study aimed to evaluate the impact of SGLT2i treatment on IR and inflammation biomarkers in patients with T2D. Materials and Methods: In a retrospective study, 246 patients with T2D treated with SGLT2i for a median of 5 years were evaluated regarding IR (estimated glucose disposal rate—eGDR, triglyceride/glucose index, triglyceride/HDLc index) and inflammation biomarkers (neutrophils to lymphocyte ratio, platelets to lymphocytes ratio and C-reactive protein) before and after intervention with SGLT2i. Results: After a median 5 years of SGLT2i treatment, patients with T2D had a higher eGDR (6.07 vs. 5.24 mg/kg/min; p < 0.001), lower triglyceride/HDLc ratio (3.34 vs. 3.52, p < 0.001) and lower triglyceride/glucose index (9.23 vs. 9.58; p < 0.001). The inflammation biomarkers decreased after SGLT2i therapy: C-reactive protein (3.07 mg/L vs. 4.37 mg/L), NLR (0.68 vs. 0.72; p < 0.001), and PLR (115 vs. 122; p < 0.001). Intervention with SGLT2i also improved the biomarkers associated with diabetes complications and cardiovascular risk: HbA1c (7.1% vs. 8.4%; p < 0.001), body mass index (30.0 vs. 31.5 kg/m2; p < 0.001) and urinary albumin to creatinine ratio (4.75 vs. 11.00 mg/g; p < 0.001). Conclusions: Treatment with SGLT2i in patients with T2D leads to decreases in IR and inflammation. These mechanisms may partially explain the additional cardiovascular and renal risk reductions associated with SGLT2i therapy, alongside the improvements in glycemic control, in patients with T2D.

Real-world effectiveness and safety of sodium-glucose co-transporter 2 inhibitors in chronic kidney disease

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.

Impact of Sodium-Glucose Co-Transporter 2 Inhibitors on Atrial Fibrillation Recurrence Post-Catheter Ablation Among Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Atrial fibrillation (AF) is the most common cause of arrhythmia-induced cardiomyopathy. Effective management strategies include medical therapy for rate and rhythm control, catheter ablation (CA), and goal-directed medical therapy. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), a novel class of antidiabetic drugs, have shown a promising impact in reducing cardiovascular events in diabetic and nondiabetic heart failure (HF) patients. It is unclear what impact SGLT2i use may have on AF recurrence following CA. To evaluate the effects of SGLT2i on preventing AF recurrence following CA and its impact on other cardiovascular outcomes. We performed a comprehensive literature search through multiple search engines (PubMed, Scopus, Web of Science, and Cochrane) to include eligible studies using the appropriate keywords until 10 April 2024. Our search yielded nine eligible studies with 16 857 patients. Our analysis reveals a significant reduction in AF recurrence after CA among patients receiving SGLT2i compared to non-SGLT2i medications (RR = 0.72, 95% CI [0.67-0.78], p < 0.00001). Additionally, SGLT2i therapy was associated with decreased all-cause hospitalizations and reduced risk of ischemic stroke. However, no significant difference in all-cause mortality was observed between SGLT2i and non-SGLT2i groups. Our study found that SGLT2 inhibitors significantly reduced AF recurrence post-CA in diabetic patients. Moreover, SGLT2i use was associated with lowered hospitalization and ischemic stroke risk. Though no significant difference in mortality was noted, the decrease in hospitalization suggests a possible favorable effect on cardiovascular events.

Type 2 diabetes disease and management patterns across a large, diverse healthcare system: Issues and opportunities for guideline-directed therapies.

The prevalence, chronicity and clinical impact of type 2 diabetes (T2D) defines this disease state as a critical determinant in morbidity and mortality, as encountered by individuals, health care systems, and public health in general. The need to understand and optimize T2D identification and management is now further heightened by the advent of medications with established cardiovascular (CV) and kidney benefits in such patients, namely sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA). Prescription rates for these agents have remained low despite guidelines incorporating and emphasizing their use. Better understanding T2D disease and management patterns, including percentage of patients meeting guideline indications, is necessary to address undertreatment, improve patient management, and enable better strategies. We evaluated such issues, including eligibility for and utilization of SGLT2i and GLP-1 RA, in a large health system caring for over 1.5 million patients annually. The electronic health record (EHR) at a large health network in the Northeastern United States was queried to identify patients 18 years of age or older with T2D and at least 1 hemoglobin A1c (HbA1c) between January 1, 2020 and January 1, 2023, examining those with T2D and 1) atherosclerotic CV disease (ASCVD), 2) an estimated 10-year ASCVD risk score ≥ 10% without known ASCVD, 3) heart failure (HF), and/or 4) chronic kidney disease (CKD) based on EHR listed comorbidities. Demographics, medications, comorbidities, and indications for SGLT2i and/or GLP-1 RA therapy were assessed by 1 or more of the 4 indications above as outlined in society guidelines. Of the 147,338 patients who met inclusion criteria, 47% were female, 28% were non-white, and 14% with a non-English language preference. Of those, 121,508 (83%) had an indication for either SGLT2i or GLP-1 RA based on guideline recommendations: 17% were prescribed an SGLT2i, 22% were prescribed GLP-1 RA, and 6% of patients were prescribed both medications. Only 33% of all eligible patients were prescribed therapy. Of patients eligible for either an SGLT2i or GLP-1 RA therapy not currently receiving either therapy, 49% had 10-year ASCVD risk ≥ 10% without known ASCVD, 42% had ASCVD, 52% had CKD, and 14% had HF. More than 4 out of 5 patients with T2D had a CV or kidney indication for either SGLT2i or GLP-1 RA. However, uptake of SGLT2i/GLP-1 RA in these high-risk populations remains low (just 32%) across this health network. Future studies are needed to identify better strategies to overcome provider, patient, and system-level barriers to the uptake and dissemination of guideline-concordant T2D therapies.

Reducing hyperuricemic events with SGLT2 inhibitors: An updated systematic review with meta-regression.

Although sodium-glucose cotransporter-2 inhibitors (SGLT2i) were shown to lower hyperuricemic events in patients with type 2 diabetes mellitus (T2DM), the extent of this effect in the general population is yet to be elucidated. We performed an updated systematic review and meta-analysis on a large sample of patients with and without T2DM to evaluate the influence of SGLT2i therapy on clinically relevant hyperuricemic events, defined as the composite of acute gout flare episodes, acute anti-gout management or urate-lowering therapy initiation. Furthermore, we conducted a multivariate meta-regression to assess the relationship between different covariates and the pooled effect size. We systematically searched all reported outcomes of interest in patients on SGLT2i (PROSPERO: CRD42023442077) across PubMed, Scopus and Cochrane databases looking for randomized controlled trials, observational studies and post-hoc analyses since inception until August 2023. Data from seven randomized controlled trials and seven observational studies were included for a total of 464,009 patients, 13,370 of whom did not have T2DM. A total of 50% of the patients included were on SGLT2i. The pooled analysis demonstrated that SGLT2i reduce clinically relevant hyperuricemic events by 33% (HR, 0.67; 95% CI, 0.59-0.77; I2=83%) regardless of the concomitant diagnosis of T2DM. The multivariate meta-regression on chronic kidney disease (CKD) showed a positive correlation on the pooled effect size. SGLT2i reduce the risk of developing hyperuricemic events regardless of the concomitant diagnosis of T2DM. The multivariate meta-regression on CKD showed a significant impact on the main outcome. Further studies are essential to investigate more conclusively the extent of these beneficial effects.

Impact of SGLT2 inhibitors on cardiovascular outcomes and metabolic events in Chinese han patients with chronic heart failure

ObjectiveThis study aimed to evaluate the real-world impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the efficacy, safety, and metabolic profiles of patients with chronic heart failure (CHF), both with and without type 2 diabetes mellitus (T2DM).MethodsA cohort of 1,130 patients with reduced ejection fraction chronic heart failure (HFrEF) was recruited from Zhongnan Hospital of Wuhan University, spanning January 2021 to August 2023. Among these, 154 patients received SGLT2i therapy, while 131 patients were assigned to a non-SGLT2i group, following specified inclusion and exclusion criteria. The association between SGLT2i therapy and the risk of primary and secondary endpoints was analyzed, alongside the effect of guideline-recommended heart failure medications at varying dosages on Major Adverse Cardiovascular Events (MACE).ResultsSGLT2i treatment led to reductions in blood pressure, uric acid, NT-proBNP, and pulmonary artery pressure, while increasing body mass index (BMI) and left ventricular ejection fraction (LVEF) in CHF patients. Multivariate Cox regression analysis revealed that SGLT2i therapy reduced the primary endpoint risk by 40.3% (HR 0.597, 95% CI 0.356–0.973, p = 0.047). Univariate Cox regression indicated that SGLT2i might also reduce the incidence of new diagnoses of atrial fibrillation, non-fatal acute myocardial infarction, and MACE in CHF patients. Moreover, the use of a four-drug combination for heart failure management was associated with a lower risk of MACE compared to monotherapy.ConclusionSGLT2i therapy not only enhances LVEF but also significantly reduces ambulatory blood pressure, uric acid, fasting blood glucose, pulmonary artery pressure, and NT-proBNP levels in CHF patients. Additionally, SGLT2i improves prognosis by lowering the risk of both primary and secondary endpoints. Compared to monotherapy, a four-drug regimen for CHF substantially reduces the risk of MACE, supporting the effectiveness of comprehensive treatment strategies.

Clinical Profile and Treatment Adherence in Patients with Type 2 Diabetes and Chronic Kidney Disease Who Initiate an SGLT2 Inhibitor: A Multi-cohort Study.

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). 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 (TheNetherlands), 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. 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 (stage4) was uncommon (1.6-6.7%). The median duration of SGLT2i therapy ranged from 7.5months in PHARMO to 17.0months in VID. At least 50% of patients were currently receiving SGLT2i treatment at 1year after initiation. 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.

Incidence of ketoacidosis in diabetic patients treated with sodium–glucose cotransporter-2 inhibitors: A prospective cohort study

Introduction: Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have gained significant attention for their benefits in managing type 2 diabetes mellitus (T2DM), particularly in patients with chronic kidney disease (CKD) and heart failure. However, the potential for SGLT2is to increase the risk of ketoacidosis, particularly euglycemic diabetic ketoacidosis (EDKA), warrants further investigation. This prospective cohort study assesses the incidence of ketoacidosis among T2DM patients treated with SGLT2is and examines related risk factors. Methods: This is a prospective study included 575 patients with T2DM. Patients over 18 years undergoing SGLT2i therapy were followed for six months. Baseline demographics, clinical history, glucose management practices, and medication use, with an emphasis on SGLT2is, were recorded. Blood gas analysis (BGA) and urine ketones were measured monthly. Ketoacidosis was defined by urine ketone positivity with pH &lt;7.30, bicarbonate (HCO3) ≤18 mEq/L, and an elevated anion gap. Results: Out of 575 patients, 35.6% (205) had positive urine ketones at least once during the study, with 11 patients (0.7%) meeting ketoacidosis criteria. Patients with ketoacidosis had a mean hospital stay of 8.2 days compared to 5.4 days in non-ketoacidosis patients (p = 0.02). No in-hospital mortality occurred among ketoacidosis patients. Conclusion: Ketoacidosis was rare but clinically relevant in T2DM patients on SGLT2is. The incidence of euglycemic ketoacidosis highlights the need for monitoring and identifying high-risk individuals early during SGLT2i treatment initiation.

Trends in prescribing sodium-glucose cotransporter 2 inhibitors for individuals with type 2 diabetes with and without cardiovascular-renal disease in South Korea, 2015-2021.

This study evaluates shifts in oral glucose-lowering drug prescription patterns and the adoption of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in South Korea. A cross-sectional and retrospective cohort analysis of the Korean National Health Insurance database (2015-2021) assessed the prescription patterns of oral glucose-lowering drugs by therapy level, SGLT2i prescriptions by cardiovascular-renal disease (CVRD) status, and the mean duration for SGLT2i therapy initiation and intensification. From 2015 to 2021, the number of individuals prescribed oral glucose-lowering drugs across all regimen levels increased. However, the proportion of individuals receiving monotherapy or dual combination therapy decreased by 9.2 percentage points, whereas the proportion prescribed triple or more combination therapy increased. SGLT2i prescriptions increased from 2.5% in 2015 to 13.9% in 2021, marking an 11.4 percentage point growth. This trend was consistent among individuals with and without CVRD, with the most significant increase observed in individuals with heart failure-from 2.2% in 2015 to 16.6%. The mean time to SGLT2i initiation post-diagnosis was shortened from 249 days in 2015 to 158 days in 2019. The adoption of SGLT2i therapy was on the rise, especially among individuals with heart failure, accompanied by a notable decrease in time to treatment initiation. Despite these positive trends, the overall use of SGLT2i among individuals with CVRD remained limited.

Enhanced renoprotective effects of combined glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: Real-world evidence.

Developing a more effective treatment for the global impact of diabetic kidney disease is crucial. This study examined the renoprotective effects of combining glucagon-like peptide-1 receptor agonists (GLP-1 RA) with sodium-glucose cotransporter 2 inhibitors (SGLT2i) compared to SGLT2is alone in type 2 diabetes (DM). This retrospective cohort study used data from the TriNetX Global Collaborative Network. Type 2 DM patients with estimated glomerular filtration rates ≥60 mL/min/1.73 m2 who used GLP-1 RA or SGLT2i between January 1, 2013, and December 31, 2023. Propensity score matching balanced baseline characteristics, resulting in 71,186 patients in each group (combined GLP-1 RA and SGLT2i therapy vs SGLT2i alone). Cox regression model was adopted to compare outcomes over a 5-year period, including major adverse kidney events (MAKE), acute kidney injury (AKI), end-stage kidney disease (ESKD), and all-cause mortality. After matching, the average age was 57.1 ± 10.8 years for the GLP-1 RA plus SGLT2i group and 57.2 ± 11.7 years for the SGLT2i-only group. The GLP-1 RA plus SGLT2i group had significantly lower risk of MAKE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.69-0.77), AKI (HR: 0.82, 95% C0I: 0.77-0.87), ESKD (HR: 0.61, 95% CI: 0.47-0.78), and all-cause mortality (HR: 0.54, 95% CI: 0.50-0.58) compared to the SGLT2i-only group. Moreover, subgroup analyses showed consistent benefits across different subgroups. Dual therapy with GLP-1 RA and SGLT2i is supported to enhance renal outcomes and address the growing burden of diabetic kidney disease.

Fournier's Gangrene and Sodium-Glucose Cotransporter 2 Inhibitor Use: A Report of Two Cases.

Necrotizing fasciitis is a serious infection that requires prompt surgical excision and broad spectrum antibiotics. Fournier's gangrene (FG) is a type of necrotizing fasciitis that specifically affects the perineal, scrotal, and genital region. FG is a known adverse outcome of the class of medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. This class of drugs is most commonly use to treat diabetes, but recently it's use has expanded to include those with heart failure, regardless of whether they have diabetes. With the increased use of SGLT2 inhibitors, the incidence of FG may increase as well. We present 2 case reports of patients who experienced FG while on SGLT2 inhibitor therapy.

SGLT2 inhibitors increase low serum magnesium levels in patients with chronic kidney disease immediately after treatment.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment. Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6months after treatment and the factors associated with these changes. Median eGFR and mean serum Mg2+ at baseline were 33.5mL/min/1.73m2 and 2.03mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1month after treatment compared with those at baseline and persisted over 6months, with an overall mean change of 0.13mg/dL from baseline to 6months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid-base status, were independently associated with these changes. SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis.

Abstract 4122290: Association between SGLT2 inhibitors and risk of Dementia and Parkinson’s Disease: A Meta-analysis of 12 Randomized Controlled Trials.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated to reduce the risk of hospitalizations from heart failure and cardiovascular mortality. However, SGLT2i therapy’s potential effects on the risks of dementia and Parkinson’s disease are not well established, with conflicting results based on observational studies. Objective: We sought to evaluate the association between SGLT2i and the risk of dementia and Parkinson’s disease in patients with type 2 diabetes mellitus (T2DM), heart failure, or chronic kidney disease. Methods: We performed a systematic literature search on PubMed, Scopus, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until March 2024 without any language restrictions. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model. Results: A total of 12 RCTs with 74, 442 patients (40784 in the SGLT2i group and 33658 in the control group) were included in the analysis. The mean age of patients in SGLT2i and control was 65.3 and 65.2 years respectively. The mean follow-up duration was 2.9 years. Pooled analysis showed that there is no significant association between SGLT2i and the risk of dementia (OR, 1.37 (95%CI: 0.70-2.69), P= 0.36, I2=0%), dementia Alzheimer’s type (OR, 2.62 (95%CI: 0.47-14.49), P= 0.27, I2=0), vascular dementia (OR, O.52 (95%CI: 0.09-2.98), P= 0.46, I2=0%), and Parkinson’s disease (OR, 0.75 (95%CI: 0.25-2.25), P= 0.61, I2=0%) was comparable between SGLT2i and control groups. Conclusion: Our study suggest that there is no significant association between SGLT2i and the risk of dementia, its subtypes, and Parkinson’s disease. Further large-power randomized trials are needed to strengthen the understanding of neuropsychiatric beneficial effects of SGLT2i.

Sodium-glucose cotransporter 2 inhibition in patients with liver cirrhosis and diabetes: a possible role in ascites control?

The aim of this brief report is to evaluate sodium-glucose cotransporter 2 inhibitors (SGLT2-I) effects on patients with both refractory ascites and type 2 diabetes mellitus (T2D). We consecutively recruited all the diabetic patients with refractory ascites due to decompensated liver cirrhosis admitted between February and May 2023 at the Internal Medicine Unit of the University Hospital of Palermo. Clinical and laboratory data were collected after starting SGLT2-I therapy. SGLT2-I use was associated with a reduction/resolution of ascites and with an improvement in serum albumin and sodium levels and estimated glomerular filtration rate. SGLT2-I might represent a valid therapeutic option in the treatment of patients with refractory ascites and T2D, as already hypothesized by other research groups.

Abstract 4116177: Metabolic and Pharmacokinetic Profiling of Ketone Ester by Background SGLT2 Inhibitor Therapy in Heart Failure with Reduced Ejection: A Phase I Clinical Trial

Background: Growing evidence supports a therapeutic role for ketones in HFrEF. However, no pharmacokinetic (PK) studies are available to guide further investigation, and uncertainty exists regarding use with the ketogenic SGLT2i and dose-dependent effects. Methods: We conducted a phase I trial of two doses of ketone ester (KE, 250 mg/kg and 500 mg/kg) in 20 HFrEF participants, stratified by SGLT2i use. Non-compartmental analysis assessed PK parameters of ketones. Paired t-tests and generalized linear mixed models assessed changes in mass-spectrometry based targeted metabolites, blood gas, and vital sign assessments up to 4 hours after dosing. Results: The mean age was 66.0±14.8 years, 45% were women, 30% were non-White, and average EF was 33±13%. The median (25 th –75 th percentile) T max , C max , and T 1/2 for total ketones with 250 and 500 mg/kg doses were 1.01 (0.64-1.24) and 1.58 (1.06-1.99) hours, 2317 (2165-2491) and 3354 (3291-3538) µM, and 0.85 (0.66-1.24) and 2.04 (1.36-3.47) hours, respectively ( Figure 1A ). One hour after KE consumption, insulin levels robustly increased, while non-esterified fatty acids, branched-chain amino acids, and acylcarnitines decreased except for C2/C4-OH acylcarnitines, which increased (FDR-adjusted p-value&lt;0.05). Increases in ketones and C2/C4-OH acylcarnitines were dose-dependent, while background SGLT2i was associated with blunting of the decrease across acylcarnitines. One hour post KE, heart rate initially rose by 4 (95%CI 2-6) beats/min, while systolic blood pressure (-7, 95%CI -12, -2 mmHg), pH (-0.07, 95%CI -0.08, 0.05), and bicarbonate (-3, 95%CI -4, -2 mEq/L) decreased, with dose-dependent acid-based effects ( Figures 1B-C ). These values returned close to baseline by 4 hours. Adverse events were infrequent and mild. Conclusions: Acute KE ingestion is associated with rapid changes in several key metabolic pathways, with differential effects imparted by background SGLT2i (fatty acid metabolism) and dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose/SGLT2i, while acidotic effects were heightened with increasing dose. These data support the safety of combined KE and SGLT2i in HFrEF and provide grounding data for further trials.

Sodium-Glucose Cotransporter 2 Inhibitors Improve Body Composition by Increasing the Skeletal Muscle Mass/Fat Mass Ratio in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated. This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters. Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US). Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: -2.9 ± 0.6 kg at T6; -2.8 ± 0.6 kg at T12; VAT: -0.3 ± 0.1 L at T6; -0.4 ± 0.1 L at T12; all p < 0.01). Changes in SMM were less pronounced (-0.4 ± 0.3 kg at T6, ns; -0.7 ± 0.4 kg at T12, p < 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p < 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study. In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.

Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF

Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF