Sodium-glucose Cotransporter 2 Inhibitor Therapy Research Articles

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 <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<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.

Cardiovascular Risks With SGLT2 Inhibitors in Clinical Practice Among Patients With Type 2 Diabetes

Cardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain. To analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice. This retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified. The primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023. Overall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history). In this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.

Prognostic impact of SGLT2-inhibitor therapy on survival in patients with transthyretin amyloid cardiomyopathy

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) significantly improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction. Recently published data indicates the safety and tolerability of SGLT2i therapy in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, there is a lack of evidence regarding the impact of SGLT2i therapy on clinical outcomes in those patients. Purpose This study aims to investigate the association between SGLT2i therapy and clinical outcomes in patients with ATTR-CM. Methods This is an analysis of a prospective registry conducted at an expert center for hypertrophic cardiomyopathies. We included all participants with a confirmed diagnosis of ATTR-CM, who were enrolled until December 2022. Prior and concomitant SGLT2i treatment was systemically assessed according to the patient interview and medical records. Patients’ outcomes were retrieved from local medical and health insurance records. Results We enrolled 116 patients, of whom 7 patients (6%) were treated with SGLT2i at inclusion and 44 patients (38%) were started on SGLT2i therapy during the observational period while 65 patients (56%) were SGLT2i-naïve. There were no significant differences in baseline characteristics between groups, as shown in the table. Median (interquartile range) age was 80 (76-82) years with 15% females. Median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 2844 (1519-5033) pg/ml, median estimated glomerular filtration rate (eGFR) 58 (46-69) ml/min/1,73m2, and median troponin T 56 (34-83) pg/ml. During a median follow-up of 2.6 (1.8-3.7) years, 28 patients (24%) died, of whom 6 patients (5%) were in the treatment group and 22 patients (19%) in the control group. In univariate Cox-regression analysis, SGLT2i treatment was significantly associated with a lower mortality (HR 0.325, 95%CI 0.132-0.802, p=0.015). This association persisted after adjusting for age and sex (HR 0.347, 95%CI 0.139-0.867, p=0.023). However, when treatment initiation time was considered, the benefit did not remain statistically significant. No significant associations between SGLT2i treatment and worsening heart failure hospitalizations or cardiovascular death were observed. Conclusion In a prospective registry-based cohort of patients with ATTR-CM, SGLT2i therapy was associated with significantly better survival, with a potential treatment initiation time bias. These results suggest that SGLT2i may exert beneficial effects in patients with ATTR-CM and warrant a randomized controlled trial.

Quality of life in patients with heart failure and improved ejection fraction: one-year follow-up with ARNI and SGLT2i

Abstract Introduction A baseline Heart Failure (HF) with reduced Ejection fraction (HFrEF) &amp;lt;=40% that improved for &amp;gt;=10 points and a second measured left ventricle ejection fraction (LVEF) &amp;gt;40%, can be considered as HF with improved ejection fraction (HFimpEF). The novel therapy for HFrEF and HFimpEF are sacubitril/valsartan (ARNI- angiotensin receptor/neprilysin inhibitor) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i). Purpose Our study aimed to evaluate ARNI and SGLT2i therapy on the health status of HFrEF patients, as well as the prognostic impact of HFimpEF in terms of quality of life and outcomes (mortality and rehospitalization due to HF) during a one-year follow-up. Methods In this prospective study, we included 376 hospitalized HFrEF patients, in whom ARNI and SGLT2i were initiated into regular therapy. A 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) was performed at discharge and after one year. The primary prognostic endpoints were all-cause mortality and HF rehospitalization. Results Initially, about two-thirds of the study population were men (71%), mean age of 61.0±11.5 years, mean LVEF 27.5±5.2 % and mean KCCQ overall summary (KCCQ-OS) score of 48.5±12.5, while quality of life KCCQ-QoL 37.4±10.2. After one year LVEF was increased by 35.6±7.1 %. The total number of 143 patients (38%) met the criteria for HFimpEF, with the improvement of mean LVEF (45.2±8.6 %., p&amp;lt;0.001). Overall, HFimpEF patients experienced an average 5.3 ± 18.6-point improvement in the KCCQ-OS compared with 2.5 ± 17.4 points for non-HFimpEF group (differences in mean changes of 2.9 [95% CI: 1.4 to 4.7). This is largely due to improvements in the domain of KCCQ-QoL (5.8 ± 29.7 points vs. 2.9 ± 22.2 points, respectively). During one year of follow-up, combined SGLT2i + ARNI therapy was represented statistically significantly more in HFimpEF compared to the non-HFimpEF group (86% vs. 34%, p&amp;lt;0.0005), where 45% took only one medicine and 21% none. The HFimpEF group had a significantly better outcome in terms of all-cause mortality (2.8% vs. 18.9%, p&amp;lt;0.005) and HF rehospitalization (3.5% vs. 40%, p&amp;lt;0.0001). The one-year KCCQ-12 was independently associated with outcomes; the hazard ratio for the integrated endpoints (mortality and HF rehospitalization) was 1.08 (95% CI: 1.05–1.11, p = 0.005). Conclusions In routine clinical practice, initiation of the ARNI and SGLT2i therapy was associated with significant improvements in the health status of HFrEF patients, but also change to HFimpEF. The one-year quality of life in patients with heart failure and improved ejection fraction was superior to baseline and compared to the non-HFimpEF group. HFimpEF was associated with a better outcome. All HF patients should undergo KCCQ-12 because it is an independent predictor of outcome.

Unravel novel therapeutic targets in heart failure and associated pulmonary hypertension

Abstract Background Heart Failure (HF) is a complex clinical syndrome with poor prognosis. Pulmonary hypertension (PH) often complicates HF but can hardly be addressed therapeutically. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with HF. Whether SGLT2i positively impact on HF-associated PH is poorly understood. Omics offer great promise in the discovery of novel biomarkers and therapeutic targets for HF and PH. Aims We investigated novel markers associated with HF and PH, as well as how these biomarkers vary in response to HF-modyfing therapies, including SGLT2i. We also explored the impact of SGLT2i, compared with conventional anti-HF therapy, on HF-associated PH and right ventricular function. Methods Seventy-four patients with HF and reduced ejection fraction (HFrEF) with/without diabetes were divided into a gliflozin (G)-group receiving 10 mg/day empagliflozin or dapagliflozin, and a control (C)-group receiving conventional anti-HF therapy. Resting echocardiography, analyses on senescence markers [leucocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)], as well as measurement of two microRNAs (miRNA-21 and miRNA-92, recently implicated in response to treatment in HFpEF patients), were performed. Shotgun proteomic analyses were conducted on peripheral blood mononuclear cells. Results Compared to group C, group G had a significantly higher ejection fraction (EF, 42±13 vs 33±8, p=0.001), reduced left ventricular filling pressures (11±3 vs 15±5, p=0.001), reduced pulmonary artery systolic pressure (PAPs, 31±11 vs 46±15, p=0.001), better right ventricular-pulmonary artery coupling index (0.64±0.31 vs 0.44±0.22, p=0.002), increased LTL (Figure 1 A), higher mtDNAcn (Figure 1 B), reduced miRNA-21 levels (Figure 1 C) and no significant changes of miRNA-92 (Figure 1 D). Functional proteomic analysis showed that, compared with the C-group, the protein cargo from the G-group was able to trigger several biological pathways, showing a significant activation of T lymphocytes immune response (p-value=9.67x10-06, z-score=2.21) chemotaxis of monocytes (p-value=9.39x10-07, z-score=2.0), leukocytes (p-value=9.67x10-10, z-score=2.0)and phagocytes (p-value)=3.10x10-10, z-score=2.03) (Figure 2). Compared with the C-group, the G-group showed a downregulation of activin signaling pathway (z-score=-2.12), which is a novel therapeutic target in pulmonary arterial hypertension (PAH). Conclusions In HF patients, SGLT2i therapy is associated with improved left ventricular function and improved pulmonary hemodynamics. Activin is overactive in HF patients and its serum levels may be reduced by SGLT2i. SGLT2i may preserve LTL and mtDNA-cn as well as modulate the expression of specific miRNA implied in the regulation of endothelial function. SGLT2i may represent an additional therapeutic tool in patients with HF-associated PH, an area with no approved treatment options beyond traditional HF therapy.Figure 1:genomic analysesFigure 2:proteomic analyses

Machine learning identifies individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death who have unrealised opportunities to reduce future cardiovascular risk

Abstract Background Machine learning may be able to identify individuals at risk of cardio-renal-metabolic events using routinely-collected data, and these individuals may be suitable for targeted preventative strategies.(1, 2) Purpose To train and test a machine learning algorithm to identify individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death, and then establish if there are opportunities to reduce their future cardiovascular risk. Methods We trained a random classifier (OPTIMISE) in UK primary care EHR data from 2 081 139 individuals aged ≥30 years (Jan 2, 1998, Nov 30, 2018), randomly divided into training (80%) and testing (20%) datasets. We calculated the cumulative incidence rate for ten cardio-renal-metabolic diseases and death. Fine and Gray’s models with competing risk of death were fit for each outcome between higher and lower predicted risk. In a multi-centre pilot interventional single arm study consenting individuals aged ≥30 years at higher predicted risk received cardio-renal-metabolic phenotyping and assessment for guideline target attainment. Results In the testing dataset (n = 416 228), individuals at higher predicted risk had higher long-term risk of heart failure (HR 12.54), aortic stenosis (HR 9.98), AF (HR 8·75), stroke/TIA (HR 8.07), CKD (HR 6.85), PVD (HR 6.62), valvular heart disease (HR 6.49), MI (HR 5.02), diabetes (HR 2.05) and COPD (HR 2.02) (Figure 1). This cohort were also at higher risk of death (HR 10.45), accounting for 74% of cardiovascular deaths (8 582 of 11 676) during 10-year follow up. Of 82 higher risk patients in the pilot study (mean age 71.6 years (SD 7.5), 50% women), the prevalence of cardio-renal-metabolic disease was high (Table 1), and there were opportunities to reduce future cardiovascular risk. Of higher risk patients with hypertension, 58.5% (31/53) of those aged &amp;lt;80 years had a systolic blood pressure (SBP)&amp;gt;140mmHg, and 54.5% (6/11) of those aged ≥80 years had a SBP &amp;gt;150mmHg. Of those with type 2 diabetes and co-existent ASCVD, only 23.1% (3/13) were on SGLT2 inhibitor therapy. Of higher risk patients on statin therapy, 37.0% (20/54) had LDL-cholesterol &amp;gt;1.8 mmol/L, and 52.0% (12/25) of patients with previous ASCVD had an LDL-cholesterol &amp;gt;1.4mmol/L. Furthermore, 19.5% (16/82) of the higher risk cohort had undiagnosed moderate or high risk CKD; who were infrequently prescribed a statin (41.7%; 5/12), ACE-i/ARB therapy with co-existent hypertension (61.5%. 8/13), or SGLT2 inhibitor with co-existent diabetes (83.3% (5/6)). Obesity was present in 49%, and 17% (14/82) were eligible for GLP-1 RA therapy. Conclusions The machine learning OPTIMISE algorithm can identify people at higher risk of cardio-renal-metabolic diseases and death using routinely collected data. On prospective evaluation higher risk individuals have unrecorded and undertreated cardio-renal-metabolic diseases, which are actionable targets for preventative care.Figure 1

Association of sodium-glucose cotransporter-2 inhibitor with regression of coronary plaque burden

Abstract Background Sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a novel oral hypoglycemic therapy of type 2 diabetes mellitus (T2DM), has been proved to benefit cardiac function. However, it remains unknown whether SGLT2i has an impact on coronary plaque characteristics. Purpose The aim of this study was to investigate whether SGLT2i was able to improve coronary plaque composition, burden and inflammation [i.e., fat attenuation index (FAI)] using series coronary computed tomography angiography (CCTA) images among T2DM patients with angina pectoris. Methods T2DM patients presenting with angina pectoris admitted at our center were screened. Eligible patients were those underwent first CCTA within 3 months prior to initiating SGLT2i therapy, and repeated CCTA beyond 6 months after the first CCTA. Those patients not treated with SGLT2i underwent likewise longitudinal CCTA tests were propensity score matching in a 1:1 ratio using age, sex and CCTA time interval. Routine CCTA images were assessed for coronary plaque characteristics using dedicated softwares. Paired or unpaired Student’s t test or Mann–Whitney U test were used for comparing coronary plaque characteristics between series CCTA and patients with or without SGLT2i. The relationships between SGLT2i and changes of plaque characteristics was examined using logistic regression analysis. Results After propensity score matching, a total of 196 T2DM patients with angina pectoris were included (mean age, 60.4±9.2 years; male, 69.9%; SGLT2i treatment, 50%). Time interval between baseline and the last CCTA examinations was 400 (343,496) days. In the SGLT2i group, the non-calcified plaque burden [(39.86±14.30)% vs. (36.84±13.86)%, p=0.002)] and low attenuation non-calcified plaque burden (6.62 [4.11,10.13]% vs. 5.78 [3.40,9.28]%, p=0.042) were significantly decreased between two CCTA images. Whereas, in the non-SGLT2i group, there was no difference with regard to non-calcified and low attenuation non-calcified plaque burden between two CCTA images (all p&amp;gt;0.05). Moreover, changes of total plaque burden and non-calcified plaque burden were higher in the SGLT2i group than the non-SGLT2i group (all p&amp;lt;0.05). Importantly, SGLT2i was associated with total plaque volume (odd ratio=0.594, p=0.024) and non-calcified plaque volume regression (odd ratio=0.619, p=0.042) after adjusting for confounding factors. Conclusion SGLT2i significantly regresses coronary plaque burden, in particularly non-calcified plaque. These findings might explain the observed cardio-protective effect of SGLT2i in large trials.

Risk of Incident colorectal carcinoma in patients with type 2 diabetes on SGLT-2 inhibitor users: a population-based cohort study

Abstract Background Patients with type 2 diabetes (T2D) are at substantially higher risk for developing colorectal carcinoma (CC) than the general population. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use on the development of incident CC in patients with T2D, but the findings are inconsistent. Purpose This study aimed to examine the association between SGLT-2i use and incident CC risk in patients with T2D. Methods We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database (2015–2021). The primary outcome was the risk of incident CC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Therefore, multiple Cox regression modeling was conducted to analyze the association between SGLT-2i use and incident CC risk in patients with T2D. Results 268,495 propensity score-matched pairs of patients with T2D using SGLT-2i and non-using SGLT-2i, 1557 and 1264 incident CCs were recorded, respectively. There was a decreased risk of incident CC for SGLT-2i users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.79, 95% CI 0.74–0.84) compared with non-SGLT-2i users. The sensitivity test for the propensity score 1:2-matched analyses showed similar result (adjusted HR 0.79, 95% CI 0.74–0.85). Conclusions This population-based cohort study found that SLGT2i user was associated with a lower risk of CC by 21% compared to non-SGLT-2i users in T2D patients. More studies are needed to credibly evaluate the effects of SGLT-2i therapy on CC prevention in patients with T2D.

Exploring the Cardiorenal Benefits of SGLT2i: A Comprehensive Review

The history of sodium-glucose cotransporter 2 inhibitors (SGLT2i) is so long and started in 1835 when Petersen extracted a compound called phlorizin from apple tree bark. About fifty years later, von Mering discovered its glucosuric properties. In the 1980s, it was discovered that the glucosuria resulted from inhibition by phlorizin of glucose reabsorption by the renal tubules, which lowered blood glucose levels in diabetic rats. Nowadays, beyond their glucose-lowering effects, growing evidence suggests significant cardiorenal benefits associated with SGLT2i therapy. Indeed, several clinical trials, including landmark studies such as EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58, have demonstrated robust reductions in cardiovascular events, particularly heart failure hospitalizations and cardiovascular mortality, among patients treated with SGLT2i. However, subsequent trials showed that SGLT2i benefits extend beyond the diabetic population, encompassing individuals with and without diabetes. Additionally, SGLT2i exhibit nephroprotective effects, manifesting as a slowing of the progression of chronic kidney disease and a reduction in the risk of end-stage kidney disease. The mechanisms underlying the cardiorenal benefits of SGLT2i are multifactorial and include improvements in glycemic control, reduction in arterial stiffness, modulation of inflammation and oxidative stress, reduction of intraglomerular pression and promotion of natriuresis and diuresis through inhibition of SGLT2 in the luminal brush border of the first segments of the proximal kidney tubule. This narrative review aims to explore the cardiorenal outcomes of SGLT2i, encompassing their mechanisms of action, clinical evidence, safety profile, and implications for clinical practice.

Effect of Dapagliflozin on Measured vs. Panel-Estimated Glomerular Filtration Rate.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m2, P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.

Impact of SGLT2-Inhibitor Therapy on Survival in Patients with Transthyretin Amyloid Cardiomyopathy: Analysis of a Prospective Registry Study.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7-3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227-0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235-0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141-0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524-2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted.

8243 Euglycemic Diabetic Ketoacidosis Unveiled: Delayed Presentation and Complications of SGLT-2 Inhibitor Therapy in a Multimorbid Patient - A Case Report

Abstract Disclosure: T. Amin: None. A.K. Bala: None. M.A. Jones: None. M.S. Akula: None. K. Chalasani: None. M. Patel: None. J. Cheng: None. Introduction: Normal serum glucose levels (&amp;lt;200 mg/dL) in euglycemic diabetic ketoacidosis (EDKA) can complicate the typical clinical presentation of diabetic ketoacidosis (DKA), posing a diagnostic challenge. SGLT-2 inhibitors, a class of antihyperglycemic drugs, have been rarely but significantly associated with EDKA. These inhibitors enhance renal glucose clearance by preventing glucose reabsorption via sodium-glucose cotransport. The increased renal clearance may contribute to the euglycemic picture, potentially leading to an underestimation of required insulin dosage, thereby precipitating ketoacidosis in EDKA. Although the mechanisms of EDKA are not fully understood, the association with SGLT-2 inhibitors is becoming increasingly evident. Case A 53-year-old male with a medical history of type 2 Diabetes Mellitus, coronary artery disease, chronic kidney disease, hyperlipidemia, was admitted to the trauma bay after a fall. Medications included empagliflozin, metformin, aspirin, amlodipine, spironolactone, and carvedilol. Upon presentation, he had a brief loss of consciousness, complained of headache and chest pain, and was found to have an epidural hematoma with regional brain compression on the CT head. Admission labs showed a blood glucose level of 172, an unremarkable anion gap, and normal renal and liver function tests. Due to traumatic brain injury, he was admitted to the ICU for neurological monitoring. Despite remaining neurologically stable, he developed hypoxia, necessitating intubation. After successful extubation, he exhibited worsening metabolic acidosis on the fourth day, with an elevated anion gap of 22 and a blood glucose level of 174. Arterial blood gas analysis revealed a pH of 7.3 (and elevated beta-hydroxybutyrate (&amp;gt;4), while lactic acid levels remained normal. Urine analysis showed elevated blood glucose (&amp;gt;1000) and ketones (&amp;gt;40). Home medications, metformin, and empagliflozin were appropriately withheld, but euglycemic DKA attributed to empagliflozin was diagnosed. Treatment included intravenous fluid resuscitation and insulin infusion, leading to resolution of acidosis and improved mentation within 24 hours. Conclusion: EDKA is a diagnosis of exclusion often overlooked in ICU patients due to diverse causes of high-anion gap metabolic acidosis. Typical cases occur while the patient is using the drug, often associated with triggers like illness, alcohol use, surgery, or starvation. SGLT2 inhibitors, such as empagliflozin, with a half-life of 12.4 hours, are expected to clear the bloodstream in about 48 hours, yet this case suggests an association with EDKA both during use and after drug cessation. This delayed presentation highlights additional risk considerations associated with SGLT2 inhibitors, guiding future clinical diagnoses of EDKA even several days post discontinuation. Presentation: 6/3/2024