Safety Of Sodium-glucose Co-transporter 2 Inhibitors Research Articles

SGLT2i impact on HCC incidence in patients with fatty liver disease and diabetes: a nation-wide cohort study in South Korea.

This study evaluated the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cancer development, particularly in hepatocellular carcinoma (HCC), in individuals with concomitant fatty liver disease (FLD) and type 2 diabetes mellitus (T2DM). Using data from Korea's Health Insurance Review and Assessment Service, we performed Kaplan-Meier and Cox regression analyses in patients with non-alcoholic fatty liver disease (NAFLD) and T2DM (NAFLD-T2DM cohort) and those with chronic viral hepatitis (CVH) alongside FLD and T2DM (FLD-T2DM-CVH cohort). In the propensity score (PS) matched NAFLD-T2DM cohort (N = 107,972), SGLT2i use was not associated with the occurrence of overall cancer, including HCC. However, old age, male sex, liver cirrhosis, and hypothyroidism were identified as independent risk factors for HCC occurrence, whereas statin and fibrate usage were associated with reduced HCC risk in this cohort in multivariate Cox analysis. In the PS-matched FLD-T2DM-CVH cohort (N = 2798), a significant decrease in HCC occurrence was observed among SGLT2i users (P = 0.03). This finding remained consistent in the multivariate Cox regression analysis (Hazard ratio = 2.21, 95% confidence interval = 1.01-4.85, P = 0.048). In conclusion, SGLT2i may be a beneficial option for diabetes management in patients with concomitant T2DM, FLD, and CVH while affirming the overall safety of SGLT2i in other types of cancer.

SGLT2 inhibitors in diabetic and non-diabetic kidney transplant recipients: current knowledge and expectations.

The beneficial effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown recently in numerous randomized controlled trials (RCT) and systematic reviews. According to KDIGO guidelines, SGLT2i currently represent a first choice for diabetic patients with chronic kidney disease (CKD). In addition, a recent meta-analysis of 13 large led by the 'SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium' (SMART-C) provided solid evidence of SGLT2i beneficial effects in CKD or in patients with heart failure, with and without diabetes. Collectively, the patients treated with SGLT2i had a decreased risk of CKD progression, acute kidney injury (AKI), end-stage kidney disease (ESKD) or death from heart failure. Whether these cardio-renal benefits should be extrapolated to kidney transplant recipients (KTR) needs to be assessed in further studies. In this article, we report recent data accumulated so far in the literature, looking at the efficacy and safety of SGLT2i in diabetic and non-diabetic KTR. We found encouraging data regarding the use of SGLT2i in KTR with diabetes. These agents appeared to be safe, and they reduced body weight and blood pressure in this group of patients. Potential effects on kidney graft function and survival are yet to be investigated.

Sodium-glucose cotransporter 2 inhibitors for transthyretin amyloid cardiomyopathy: Analyses of short-term efficacy and safety.

Despite their potential, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been well-studied in transthyretin amyloid cardiomyopathy (ATTR-CM) as randomized trials have excluded patients with this morbid disease. We performed a retrospective study assessing the short-term efficacy and safety of SGLT2i in ATTR-CM. We screened consecutive patients seen at a tertiary care centre and identified 87 ATTR-CM patients treated with SGLT2i and 95 untreated control patients. Endpoints included changes in weight, loop diuretic dose, and cardiac/renal biomarkers. The median age of the overall population was 79 (interquartile range [IQR] 11) years. Nearly 90% of patients were male, and 93% were on a transthyretin stabilizer. Control patients demonstrated generally less severe disease at baseline compared to SGLT2i-treated patients, with lower median Columbia risk score (p < 0.001). Median follow-up time was 5.6 (IQR 5.2) and 8.4 (IQR 2.1) months in the SGLT2i and control cohorts, respectively. Compared with controls, SGLT2i treatment was associated with significantly greater reductions from baseline in weight, loop diuretic dose, and uric acid during follow-up (p < 0.001). While no significant between-group differences were observed on cardiac biomarkers, estimated glomerular filtration rate was significantly reduced versus controls 1 month after SGLT2i initiation (p = 0.002), but no significant differences were observed at later timepoints. Results were similar in a propensity score-matched analysis (n = 42 per cohort). A total of 10 (11.5%) patients discontinued SGLT2i, most commonly due to genitourinary symptoms. Sodium-glucose cotransporter 2 inhibitors were well tolerated by most patients with ATTR-CM and appeared to improve volume status and combat diuretic resistance. Randomized studies are needed to confirm these findings.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.

Current Place of SGLT2i in the Management of Heart Failure: An Expert Opinion from India.

Heart failure (HF) is a global health concern that is prevalent in India as well. HF is reported at a younger age in Indian patients with comorbidity of type 2 diabetes (T2DM) in approximately 50% of patients. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), originally approved for T2DM, are new guideline-recommended and approved treatment strategies for HF. Extensive evidence highlights that SGLT2i exhibits profound cardiovascular (CV) benefits beyond glycemic control. SGLT2i, in conjunction with other guideline-directed medical therapies (GMDT), has additive effects in improving heart function and reducing adverse HF outcomes. The benefits of SGLT2i are across a spectrum of patients, with and without diabetes, suggesting their potential place in broader HF populations irrespective of ejection fraction (EF). This consensus builds on the updated evidence of the efficacy and safety of SGLT2i in HF and recommends its place in therapy with a focus on Indian patients with HF.

Expanding the possibilities of using sodium-glucose cotransporter 2 inhibitors in patients with heart failure.

Aim: To study the potential mechanisms of the beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, the possibilities of improving the treatment and prognosis of patients with acute heart failure (HF) during their use. Materials and Methods: The data analysis of literary sources has been conducted regarding the results of existing studies evaluating the clinical benefit and safety of SGLT-2 inhibitors in patients with acute heart failure. Conclusions: The peculiarities of the pharmacological action of SGLT-2 inhibitors and the obtained research results expand the possibilities of using this group of drugs, demonstrating encouraging prospects in improving the prognosis of patients hospitalized with acute heart failure.

Effectiveness and Safety of Sodium-Glucose Cotransporter2 Inhibitors Added to Dual or Triple Treatment in Patients with Type2 Diabetes Mellitus.

We evaluated the effectiveness and safety of sodium-glucose cotransporter2 inhibitor (SGLT2i) add-on treatment in patients with type2 diabetes mellitus (T2DM) in the real-world setting. This single-center retrospective study used the clinical database of Seoul National University Hospital in South Korea. Patients who received metformin monotherapy or combination therapy with ≥ 1 other oral hypoglycemic medication and had a baseline glycosylated hemoglobin (HbA1c) between 7.0% and 10.5% were included. Propensity score matching was applied between patients treated with and without SGLT2 inhibitors (SGLT2i and non-SGLT2i groups, respectively). Changes in HbA1c from baseline to week26 were compared between the SGLT2i and non-SGLT2i groups, and risk of adverse events (AE) were also assessed. A total of 1106 patients were included. At week26, HbA1c was significantly more reduced by 0.35 percentage points in the SGLT2i group than in the non-SGLT2i group (95%CI 0.30-0.41, P < 0.001). Likewise, the proportion of patients achieving HbA1c < 7% was also significantly higher (51.9% vs. 37.6%, P < 0.05) in the SGLT2i group than in the non-SGLT2i group. The risk of adverse events in the SGLT2i group was mostly comparable with those in the non-SGLT2i group except for diseases of the liver, pain, hypertensive diseases, and metabolic disorders, which showed significantly higher odds in the SGLT2i group. SGLT2i add-on treatment is an effective and safe therapeutic option for patients with T2DM in the real-world practice setting.

Cardiovascular outcomes and safety of SGLT2 inhibitors in chronic kidney disease patients.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors provide cardiovascular protection for patients with heart failure (HF) and type 2 diabetes mellitus (T2DM). However, there is little evidence of their application in patients with chronic kidney disease (CKD). Furthermore, there are inconsistent results from studies on their uses. Therefore, to explore the cardiovascular protective effect of SGLT2 inhibitors in the CKD patient population, we conducted a systematic review and meta-analysis to evaluate the cardiovascular effectiveness and safety of SGLT2 inhibitors in this patient population. We searched the PubMed® (National Library of Medicine, Bethesda, MD, USA) and Web of Science™ (Clarivate™, Philadelphia, PA, USA) databases for randomized controlled trials (RCTs) of SGLT2 inhibitors in CKD patients and built the database starting in January 2023. In accordance with our inclusion and exclusion criteria, the literature was screened, the quality of the literature was evaluated, and the data were extracted. RevMan 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata® 17.0 (StataCorp LP, College Station, TX, USA) were used for the statistical analyses. Hazard ratios (HRs), odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were used for the analysis of the outcome indicators. Thirteen RCTs were included. In CKD patients, SGLT2 inhibitors reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HHF) by 28%, CVD by 16%. and HHF by 35%. They also reduced the risk of all-cause death by 14% without increasing the risk of serious adverse effects (SAEs) and urinary tract infections (UTIs). However, they increased the risk of reproductive tract infections (RTIs). SGLT2 inhibitors have a cardiovascular protective effect on patients with CKD, which in turn can significantly reduce the risk of CVD, HHF, and all-cause death without increasing the risk of SAEs and UTIs but increasing the risk of RTIs.

Abstract 17053: Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Mortality in Hypertrophic Cardiomyopathy: A Retrospective Study

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to improve outcomes in congestive heart failure (HF). However, their effect in hypertrophic cardiomyopathy (HCM) is unknown. Research Question: Can SGLT2i improve clinical outcomes in HCM patients? Methods: Using TriNetX Global Research Network from March 2013 to February 2021, patients diagnosed with HCM (ICD-10 codes I42.1, I42.2) were identified and categorized into 2 groups: those on SGLT2i vs. those who are not. To avoid inclusion of other causes of left ventricular hypertrophy, patients with aortic stenosis or systemic hypertension were excluded. Propensity score matching (PSM) was used to limit confounders. Primary outcome was all-cause mortality and secondary outcomes were HF exacerbation, all-cause hospitalization, and documented cardiovascular symptoms (chest pain, dyspnea, palpitations, or leg edema) over a 2-year follow-up period. Results: A total of 27,561 HCM patients were identified; 408 (1.5%) on SGLT2i and 27,153 (98.5%) were not. Patients on SGLT2i were older (55 ± 15 vs. 48 ± 19, p&lt;0.01) and had more comorbidities, including a nearly 6-fold higher prevalence of diabetes mellitus (44% vs. 7%, p&lt;0.01) and congestive HF (65% vs. 10%, p&lt;0.01). After PSM, each group consisted of 355 patients. HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.22 [95% CI: 0.12, 0.39]; p&lt;0.01), hospitalizations (OR 0.72 [95% CI: 0.53, 0.98]; p=0.04), and cardiovascular symptoms (OR 0.71 [95% CI: 0.52, 0.97]; p=0.029) when compared to patients not on SGLT2i. There was no statistical difference in the rate of HF exacerbation (OR 0.82 [95% CI: 0.54, 1.24]; p=0.3). Conclusion: In this large dataset, SGLT2i use in a select subset of HCM patients was associated with improved survival, less hospitalizations, and fewer cardiovascular symptoms. These data support future randomized trials to evaluate the efficacy and safety of SGLT2i in more diverse HCM patient populations.

The effect of sodium-glucose cotransporter 2 inhibitors as an adjunct to insulin in patients with type 1 diabetes assessed by continuous glucose monitoring: A systematic review and meta-analysis

AimsPatients undergoing insulin-based therapy for type 1 diabetes often experience poor glycemic control characterized by significant fluctuations. This study was undertaken to analyze the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2Is), as an adjunct to insulin, on time in range (TIR) and glycemic variability in patients with type 1 diabetes, using continuous glucose monitoring (CGM). In addition, we examined which type of SGLT2I yielded a superior effect compared to others. MethodsWe conducted a comprehensive search of PubMed, EMBASE, the Cochrane Library, Web of Science, and clinical trial registry websites, retrieving all eligible randomized clinical trials (RCTs) published up until February 2023. We analyzed the mean TIR, mean amplitude of glucose excursions (MAGE), mean daily glucose (MDG), diabetic ketoacidosis (DKA), standard deviation (SD), total insulin dose, and severe hypoglycemia to evaluate the efficacy and safety of SGLT2Is. A random-effects model was also employed. ResultsThis study encompassed 15 RCTs. The meta-analysis revealed that the use of SGLT2Is as an adjuvant therapy to insulin led to a significant increase in TIR (MD = 10.78, 95%CI = 9.33–12.23, I2 = 42 %, P < 0.00001) and a decrease in SD (MD = −0.38, 95%CI = −0.50 to −0.26, I2 = 0 %, P < 0.00001), MAGE (MD = −0.92, 95%CI = −1.17 to −0.67, I2 = 19 %, P < 0.00001), MDG(MD = −1.01, 95%CI = −1.32 to −0.70, I2 = 48 %, P < 0.00001), and total insulin dose (MD = −5.81, 95%CI = −7.81 to −3.82, I2 = 32 %, P < 0.00001). No significant increase was observed in the rate of severe hypoglycemia (RR = 1.04, 95 % CI = 0.76–1.43, P = 0.80). However, SGLT2I therapy was associated with increased DKA occurrence (RR = 2.79, 95 % CI = 1.42–5.48; P = 0.003, I2 = 16 %). In addition, the subgroup analyses based on the type of SGLT2Is revealed that dapagliflozin might exhibit greater efficacy compared to other SGLT2Is across most outcomes. ConclusionsSGLT2Is exhibited a positive effect on improving blood glucose level fluctuations. Subgroup analysis showed that dapagliflozin appeared to have more advantages. However, giving due consideration to preventing adverse effects, particularly DKA, is paramount. RegistrationProspero CRD42023408276.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors for heart failure with mildly reduced or preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials.

We sought to conduct a meta-analysis to evaluate the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and HF with mildly reduced ejection fraction (HFmrEF). We searched the Cochrane Library, MEDLINE (via PubMed), Embase, and ClinicalTrials.gov till March 2023 to retrieve all randomized controlled trials of SGLT2i in patients with HFpEF or HFmrEF. Risk ratios (RRs) and standardized mean differences (SMDs) with their 95% confidence intervals (95% CIs) were pooled using a random-effects model. We included data from 14 RCTs. SGLT2i reduced the risk of the primary composite endpoint of first HF hospitalization or cardiovascular death (RR 0.81, 95% CI: 0.76, 0.87; I2 = 0%); these results were consistent across the cohorts of HFmrEF and HFpEF patients. There was no significant decrease in the risk of cardiovascular death (RR 0.96, 95% CI: 0.82, 1.13; I2 = 36%) and all-cause mortality (RR 0.97, 95% CI: 0.89, 1.05; I2 = 0%). There was a significant improvement in the quality of life in the SGLT2i group (SMD 0.13, 95% CI: 0.06, 0.20; I2 = 51%). The use of SGLT2i is associated with a lower risk of the primary composite outcome and a higher quality of life among HFpEF/HFmrEF patients. However, further research involving more extended follow-up periods is required to draw a comprehensive conclusion. PROSPERO (CRD42022364223).

THU298 Effect Of SGLT2 Inhibition On Metabolic, Cardiac And Renal Outcomes In Heart Transplant Recipients (EMPA-HTx study): Protocol And Study Design

Abstract Disclosure: L.M. Raven: None. C.A. Muir: None. C. Kessler Iglesias: None. E. Kotlyar: None. K. Muthiah: None. N.K. Bart: Advisory Board Member; Self; Bristol-Myers Squibb. Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Pfizer, Inc. P.S. Macdonald: Speaker; Self; Boehringer Ingelheim, AstraZeneca. C.S. Hayward: None. A. Jabbour: None. J.R. Greenfield: Speaker; Self; Boehringer Ingelheim, AstraZeneca. Background: Heart transplantation (HTx) is standard of care for treatment of end-stage heart failure. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant post-transplant complications include metabolic (diabetes, weight gain), renal impairment and cardiac disease, such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 inhibitors (SGLT2i) may have positive effects on all of these post-transplant complications. SGLT2i have been observed to improve metabolic parameters in patients with type 2 diabetes following cardiac and renal transplantation, but their benefit and safety in HTx has not been evaluated in randomised prospective studies. Aims: The overall aim of this project is to study the safety and efficacy of empagliflozin in HTx recipients. The primary end point will be improvement in glycaemic control assessed by change in glycosylated hemoglobin (HbA1c) and/or fructosamine, with secondary endpoints of cardiac fibrosis assessed by cardiac magnetic resonance, and renal function assessed by serum creatinine. Methods: Randomised, placebo-controlled trial of empagliflozin 10 mg daily versus placebo in recent HTx recipients. One hundred participants will be randomised 1:1. They will commence the study medication within 6-8 weeks of transplantation. Follow up will be 12 months after transplantation. Results from routine pre-HTx assessment will be reviewed to assess for pre-HTx diagnosis of diabetes. Routine laboratory tests, including full blood count, biochemistry, glucose, lipids and liver function as well as HbA1c, fructosamine, beta-hydroxybutyrate and urine albumin creatinine ratio, will be measured at baseline prior to receipt of study drug or placebo. Patients will be reviewed monthly during the study until 12 months post-HTx and data will be collected for each patient at each study visit. Cardiovascular magnetic resonance will be measured at baseline and 12 months after HTx. This study has been approved by St Vincent’s Hospital Human Research Ethics Committee (2021/ETH12184). Trial registration: ACTRN12622000978763. Discussion: This study will, for the first time, determine the efficacy and safety of SGLT2i in HTx recipients. Presentation: Thursday, June 15, 2023

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney disease: a systematic review and meta-analysis.

Owing to the pharmacological mechanism, sodium-glucose cotransporter 2 inhibitors (SGLT2is) may be less effective in patients with reduced renal functions, but no systematic review or meta-analysis addressed chronic kidney disease (CKD) patients specifically. We aimed to assess the efficacy and safety of SGLT2is in CKD patients. We conducted a systematic review and meta-analysis of randomized controlled trials. Mean difference (MD) were pooled for the decline of glomerular filtration rate (eGFR) and change in urine albumin-to-creatinine ratio (uACR). Hazard ratio (HR) and rate ratio (RR) were pooled for composite of renal outcomes and adverse effects. Thirty articles were identified. Overall MD in rate of eGFR decline was 0.02 (P = 0.05), with a borderline significant difference favoring SGLT2is, while the change in uACR from baseline was - 141.34mg/g and hazard ratio of composite renal outcomes was 0.64 significantly favoring SGLT2is. Subgroup analyses showed that the long-term renal function, participants with baseline macroalbuminuria, and stage 4 CKD patients had significantly slower eGFR decline rate in SGLT2is compared to the placebo group. Risks of genital mycotic infection and ketoacidosis were significantly higher among the SGLT2is group than placebo. For CKD patients, no matter diabetic or non-diabetic, our study showed potential renoprotective effects favoring SGLT2is in overall and long-term phase, and in patients with macroalbuminuria or stage 4 CKD. However, only slight increased risk of adverse effects among the SGLT2is group is observed. Therefore, we concluded that in CKD patients, prescribing SGLT2is was safe and had renal benefits.

Racial, ethnic and regional differences in the effect of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes: a systematic review and meta-analysis of cardiovascular outcome trials.

The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs. Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled. In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high. There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation.PROSPERO Registration: CRD42023401734.

Role and mechanisms of SGLT-2 inhibitors in the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD) is a chronic inflammatory condition that affects approximately 20-40% of individuals with diabetes. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, emerging as novel hypoglycemic agents, have demonstrated significant cardiorenal protective effects in patients with DKD. Initially, it was believed that the efficacy of SGLT-2 inhibitors declined as the estimated glomerular filtration rate (eGFR) decreased, which led to their preferential use in DKD patients at G1-G3 stages. However, recent findings from the DAPA-CKD and EMPA-KIDNEY studies have revealed equally beneficial cardiorenal effects of SGLT-2 inhibitors in individuals at stage G4 DKD, although the underlying mechanism behind this phenomenon remains unclear. In this comprehensive analysis, we provide a systematic review of the mechanisms and functioning of SGLT-2 inhibitors, potential renal protection mechanisms, and the therapeutic efficacy and safety of SGLT-2 inhibitors in kidney diseases, with a particular focus on stage G4 DKD. Gaining a deeper understanding of the renal protective effect of SGLT-2 inhibitors and their underlying mechanisms is highly significance for the successful utilization of these inhibitors in the treatment of diverse kidney disorders.

Evaluating the Safety of Sodium-Glucose Cotransporter-2 Inhibitors in a Nationwide Veterans Health Administration Observational Cohort Study

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are indicated in patients with or without type 2 diabetes mellitus atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. Postmarket surveillance data have identified many safety signals which warrants further investigation. We aimed to compare the safety of SGLT-2i and glucagon-like peptide-1 receptor agonists (GLP-1RA). Using the Veterans Health Administration nationwide database, patients with type 2 diabetes mellitus who were newly initiated on a SGLT-2i or GLP-1RA between April 1, 2013 and September 1, 2020 were identified. The primary outcome was the incidence of any amputation, below-knee amputation (BKA), all clinical fractures, hip fracture, Fournier gangrene, acute pancreatitis, diabetic ketoacidosis (DKA), serious urinary tract infections (UTIs), and venous thromboembolism (VTE). All outcomes were compared between the treatment groups. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) for the comparative analysis. A total of 70,694 propensity-matched new users of SGLT-2i and GLP-1RA were identified. The use of SGLT-2 inhibitors, compared with GLP-1RA, was not associated with an increased rate of any amputation (aHR 1.02, 95% confidence interval [CI] 0.82 to 1.27), BKA (aHR 1.05, 95% CI 0.84 to 1.32), all clinical fractures (aHR 0.94, 95% CI 0.86 to 1.03), hip fractures (aHR 0.82, 95% CI 0.50 to 1.32), DKA (aHR 1.66, 95% CI 0.97 to 2.85), VTE (aHR 1.02, 95% CI 0.80 to 1.30), acute pancreatitis (aHR 1.02, 95% CI 0.80 to 1.30), and Fournier gangrene (aHR 0.92 95% CI 0.61 to 1.38). Lower rates of serious UTIs were observed in the SGLT-2i group than in the GLP-1RA group (aHR 0.74, 95% CI 0.64 to 0.84). This real-world study found that SGLT-2i use compared with GLP-1RA did not increase the rate of amputation, BKA, clinical fractures, hip fracture, Fournier gangrene, acute pancreatitis, DKA, serious UTIs, and VTE in veteran patients.

#6674 SAFETY AND EFFICACY OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS IN KIDNEY TRANSPLANT PATIENTS WITH TYPE 2 OR POST-TRANSPLANT DIABETES

Abstract Background and Aims Diabetes mellitus (DM) is a complication in kidney transplant (KT) patients, leading to a higher cardiovascular mortality and graft loss. Therapies such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown a cardioprotective and nephroprotective effect and may offer benefits in KT. The aim of our study is to describe the effectiveness and safety of SGLT2i in KT patients. Method Retrospective cohort study of KT with DM who started SGLT2i in three Spanish hospitals (Puerta del Mar University Hospital, Jerez de la Frontera University Hospital and Puerto Real University Hospital) between May 2018 and December 2022. Clinical and demographic variables were analyzed. We collected SGLT2i type and dose. Glomerular filtration rate (eGFR), proteinuria, and weight were collected at the start of treatment and after 6 and 12 months. We analyze glycemic control, blood pressure, lipid profile and magnesium, uric acid and hemoglobin levels. We document adverse effects. Parametric and non-parametric tests were performed according to the normality of the sample. Results In this period, 57 KT with DM were treated with SGLT2i, of which thirty-five (61%) patients had developed post-transplant diabetes mellitus (PTDM). Fifty-one patients completed a minimum follow-up of 6 months and thirty-six patients 1 year. At the start of the treatment the mean age was 62 years and 65% were men. Mean baseline estimated glomerular filtration rate (eGFR) was 54.5 ml/min/1.73 m2 and the time post-KT was 44 months. The median proteinuria measured by the albumin-creatinine ratio in isolated urine was 83.2 mg/g. The mean weight was 91 kg. The SGLT2i mostly prescribed was empagliflozin (58%). The maintenance immunosuppressive therapy included steroids (94%), tacrolimus (96%), mycophenolate (84%), everolimus (19%) and cyclosporine (2%). Glomerular filtration rate and proteinuria remained unchanged during all the follow-up. In our cohort, body weight significantly reduced (−2.6 Kg at 6 months, p = .007 and −2.1 Kg at 12 months, p = .073). Furthermore, HbA1c (−1.2 mmol/L at 6 months) and faster blood sugar levels (−21.7 mg/dl at 6 months, p = .006 and 14.3 mg/dl at 12 months) decreased. On the other hand, we observed a reduction in LDL-cholesterol (−6 mg/dl at 6 months, p = 0.033 and −11.5 mg/dl at 12 months, p = 0.012). Finally, we observe a reduction in uric acid levels (−0.4 mg/dl at 6 months, p = 0.081) and an improvement in magnesium (+0.07 mg/dl at 6 months, p = 0.021) and haemoglobin levels (+0.3 g/dl at 6 months, p = 0.001). We found no differences in antihypertensive, diuretics, antidiabetic, lipid-lowering drugs and doses of epoetin alfa during the follow-up. Regarding adverse effects, 8 patients suffered urinary tract infections (UTIs) after starting the drug and one of them required hospital admission. Three patients had to discontinue the drug due to impaired renal function. Conclusion SGLT2i may be an option for the management of DM in KT patients, improving glycemic control and cardiovascular risk factors. An adequate selection, hygienic recommendations and surveillance of urinary infections are important.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction: an overview of 36 systematic reviews.

The recently published randomized trials (RCTs) evaluating the effect of Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) led researchers to perform a plethora of systematic reviews (SRs), often providing contradictory conclusions. This overview of reviews was aimed at summarizing the evidence of these SRs, quantifying the overlap, re-analyzing the evidence in case new studies that were identified, and mapping knowledge gaps. Literature search was conducted through Medline, Scopus, and Cochrane until March 22, 2023. Overall, 36 SRs synthesizing results from 18 RCTs were identified. A substantial overlap was identified among the SRs synthesizing large heart failure or cardiovascular outcome trials (CVOTs). Regarding the composite outcome of cardiovascular (CV) mortality or hospitalization for heart failure (HHF), all authors reported a significant favorable effect. A beneficial effect was also noted for CV and all-cause mortality, albeit not significant. Our meta-analysis demonstrated a significant improvement in health-related quality-of-life (HRQoL) as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS, MD = 1.97, p < 0.001), Total Symptom Score (KCCQ-TSS, MD = 2.29, p < 0.001), Clinical Summary Score (KCCQ-CSS, MD = 1.59, p < 0.001), and the 6-min walking distance (MD = 10.78m, p = 0.032). Regarding safety, SGLT2i were associated with a significantly lower risk of serious adverse events compared to placebo (RR = 0.94, p = 0.002). The use of SGLT2i in HFpEF is both efficient and safe. Further research is required to clarify the impact of SGTL2i on different subphenotypes of HFpEF and the cardiorespiratory capacity of these patients.

Sodium-glucose cotransporter 2 inhibitors and the risk of venous thromboembolism: A population-based cohort study.

The cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) result from their complex impact on coronary and arterial vessels. However, their effect on veins and the risk of venous thromboembolism (VTE) remains unclear. Meta-analysis of trials has suggested no significant change in risk, but observational studies on the topic are scarce. Our objective was to determine if the use of SGLT2Is, compared to the use of dipeptidyl peptidase 4 inhibitors (DPP-4Is), is associated with the risk of VTE among patients with type 2 diabetes. Using the Clinical Practice Research Datalink linked to hospitalization and vital statistics databases, we conducted a retrospective cohort study using a prevalent new-user design. SGLT2Is were matched to DPP-4I users on calendar time, diabetes treatment intensity, duration of previous DPP-4I use and time-conditional high-dimensional propensity score. Cox proportional hazard models estimated the hazard ratio (HR) for VTE with SGLT2Is versus DPP-4Is. SGLT2I use was not associated with an increased risk of VTE (HR 0.65, 95% confidence interval [CI] 0.34 to 1.25). This finding was consistent among prevalent (HR 0.47, 95% CI 0.16 to 1.42) and incident (HR 0.75, 95% CI 0.33 to 1.72) new users. We found that SGLT2Is were not associated with an increased risk of VTE compared to DPP-4Is. Although we observed a numerically decreased risk of VTE with SGLT2Is, estimates were accompanied by wide 95% CIs. Nonetheless, given the morbidity associated with VTE, our results provide some reassurance regarding the safety of SGLT2Is with respect to VTE.

Renal protection and safety of sodium-glucose cotransporter-2 inhibitors in chronic kidney disease.

Chronic kidney disease (CKD) has a clinical characteristic of progressive loss of kidney function and becomes a serious health and social concern. SGLT2i (sodium-glucose cotransporter 2 inhibitors), a class of anti-diabetic medications, is shown to reduce cardiovascular and renal events. This systematic review and meta-analysis aimed to assess whether SGLT2i could become a new treatment strategy for CKD for its renal protection and safety. Based on predetermined criteria, a bibliographical search was performed on May 31, 2022, by searching the following databases: ISI Web of Science, Embase, PubMed, and the Cochrane Library. Statistical analysis was conducted to assess renal protection and safety of SGLT2i by using Cochrane Review Manager Version 5.3. Thirty randomised controlled trials fulfilled the inclusion criteria and were eligible for this meta-analysis. Our study found that the SGLT2i can sustainably reduce the urine albumin/creatinine ratio (UACR) at different time points and prevent the progression to macroalbuminuria. Before 24 weeks, SGLT2i can decrease the estimated glomerular filtration rate (eGFR) compared to the control group. Interestingly, after 24 weeks, SGLT2i can continuously maintain the increase in eGFR when compared with the control group. Furthermore, SGLT2i can reduce the event rates of incident or worsening nephropathy, a decline in estimated eGFR of ≥ 50%, doubling of serum creatinine level, acute renal failure and renal failure. Interestingly, the renoprotective effects of SGLT2i are independent of its glycemic effects. SGLT2i can reduce the morbidity rate of any related adverse events, any related severe adverse events and SGLT2i have not increased the event rates of urinary tract infection, bone fractures, amputation, and acute pancreatitis when compared with the control group. SGLT2i can protect renal function and are safe drug for CKD. SGLT2i are promising therapeutic agents for CKD patients.