Effects Of SGLT2 Inhibitors Research Articles

Effects of sodium-glucose cotransporter 2 inhibitors on pulmonary hemodynamics in chronic heart failure patients with a pulmonary artery pressure sensor

Abstract Background Approximately 50% of patients with chronic heart failure (HF), either with preserved or reduced left ventricular ejection fraction (LVEF), have secondary pulmonary hypertension, which results in poorer prognosis. In previous studies, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown a reduction in cardiovascular death, HF hospitalization and pulmonary artery pressure (PAP) in patients with HF, regardless of LVEF, but exact mechanisms remain unclear. Purpose The main objective of this study is to analyse effects of SGLT2i on PAP in patients with chronic HF followed by a PAP sensor (CardioMEMS HF system). The secondary objective is to analyse effects in subgroups of LVEF. Methods We included chronic HF patients (regardless of LVEF) with previously implanted a PAP sensor, from July 2019 to February 2023. SGLT2i had been added in fourth position in patients with reduced LVEF, since they were previously on optimal HF treatment as chronic patients. Changes in PAP, renal function and N-terminal pro B-type natriuretic peptide (NTproBNP) were compared between two periods of time: "30 days before" and "30 days after" SGLT2i initiation. Patients were then classified in two groups: group 1 (LVEF ≤40%) and group 2 (LVEF >40%) and repeated same analyses. Results Overall, 61 patients were screened, and 17 finally were included, mean age 71.7 ± 9.6 years, 64.7% were men, mean LVEF was 49.4 ± 17.5%, 23.5% had ischaemic aetiology and 64.7% were in NYHA class III (Table 1). There were more men in group 1 than in group 2 (p=0.043), without other differences in basal characteristics between groups (Table 1). Dapagliflozin (10mg daily) was initiated in 14 patients (82.4%), 5 from group 1 and 9 from group 2 (p=1.000), and empagliflozin (10mg daily) in 3 patients (17.6%), 1 from group 1 and 2 from group 2 (p=1.000). Before SGLT2i, mean diastolic PAP (dPAP) was 17.3 ± 5.6 mmHg and median NTproBNP was 2841.5 (289-10515) pg/mL. SGLT2i significantly reduced dPAP; average dPAP ("30 days after" period) was 1.5 mmHg lower (95% CI, 0.26-2.74; p=0.021) compared to "30 days before" period (Figure 1). SGLT2i also reduced systolic PAP (-2.2 mmHg), mean PAP (-1.7 mmHg), NTproBNP (-183 pg/mL) and creatinine (-0.2 mg/dL), but not statistically significant. SGLT2i reduced PAP, NTproBNP and creatinine too in group 1 (6 patients), but did not achieve statistical significance. Reductions were as well observed in group 2 (11 patients), and SGLT2i significantly reduced dPAP (-2.04 mmHg) (95% CI, 0.31-3.77; p=0.025). Conclusions In patients with chronic HF and a PAP sensor, SGLT2i, added to previous HF treatment, significantly reduced dPAP. PAP reductions were observed regardless LVEF, but results were more robust in patients with LVEF >40%.Figure 1

Effects of SGLT2i and Pioglitazone on FIB-4 Index in Patients with Metabolic Dysfunction Associated Steatotic Liver Disease—A Real World Retrospective Study from India

Aims: Several studies support type 2 diabetes mellitus (T2DM) as one of the risk factors of metabolic dysfunction associated steatotic liver disease (MASLD). Recently, the use of pioglitazone and sodium-glucose co-transporter 2 inhibitors (SGLT2i) has been on the rise considering its beneficial effects in reducing liver dysfunction. We aim to determine the clinical effectiveness of these drugs in improving MASLD and T2DM. Materials and methods: We conducted a retrospective study of 279 T2DM patients with MASLD who were prescribed pioglitazone and/or SGLT2i from two clinics in India. The primary endpoint was change in fibrosis (FIB-4) index and the aspartate aminotransferase to platelet ratio index (APRI) score at one year follow-up. Appropriate statistical tests were applied to assess the significance of the outcomes. Results: Of the total (276) patients, 46% of patients were at low risk of advanced fibrosis, 11% were at high risk for advanced fibrosis, and the majority (50%) were on SGLT2i treatment. At follow-up, there is a statistically significant reduction in the mean (SD) FIB-4 index (1.92 [1.22] vs. 1.68 [0.99]) and APRI score (0.42 [0.34] vs. 0.33 [0.21]); p < .001. Among treatment groups, there is a significant difference in the mean FIB-4 index both at baseline (F: 4.23; p < .05) and follow-up (F: 3.45; p < .05). These scores were highly significant in the combination treatment with SGLT2i and pioglitazone ( p < .05). Conclusions: Our results indicate a combination therapy with SGLT2i and pioglitazone might be beneficial in managing MASLD, especially in reducing the FIB-4 index and APRI score in Indian T2DM patients with MASLD.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

Sodium-Glucose Cotransporter-2 Inhibitors After Acute Myocardial Infarction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Cardiovascular disease is on the rise globally, with ischemic heart disease being the leading cause of mortality and morbidity. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiovascular outcomes in patients with heart failure, evidence is limited in guiding initiation in post-acute myocardial infarction (post-AMI) patients. Hence, this study aimed to appraise the current literature on the effect of SGLT2i on the clinical outcomes of post-AMI patients. A comprehensive search of PubMed, EMBASE, SCOPUS, and ClinicalTrials.gov was conducted up to 1 May 2024. Only randomized controlled trials studying the use of SGLT2i in post-AMI patients were included. We included adult patients aged 18 years old and older diagnosed with AMI and initiated on SGLT2i in the acute post-AMI setting. SGLT2i studies solely in heart failure settingswere excluded. Eight clinical trials were included in the systematic review, comprising 11,436 patients. Compared with placebo, SGLT2i initiation in post-AMI patients significantly reduced total number of heart failure hospitalizations (risk ratio [RR] 0.74, 95% confidence interval [CI] 0.62-0.90) and was associated with a lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) level (- 26.67 pg/ml, 95% CI - 41.74 to - 11.59). There was no difference in all-cause mortality (RR 1.02, 95% CI 0.81-1.28), cardiovascular mortality (RR 1.03, 95% CI 0.83-1.28), change in left ventricular ejection fraction, and glycated hemoglobin (HbA1c), as compared with placebo. SGLT2i use in patients with AMI was associated with a reduction in heart failure hospitalizations and a decrease in NT-proBNP. There were no significant differences in mortality outcomes. PROSPERO identifier number CRD42024540843.

Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction-associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways.

Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction-associated steatohepatitis (MASH) development in diabetic patients, their combination hasnot been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high-fructose/high-fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high-fructose/high-fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non-alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP-1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF-α), fibrosis (TGF-β1/α-SMA), and apoptosis (TUNEL/Caspase-3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin-dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL-10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose-transporting and lipid-regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co-therapy against diabetes-induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti-inflammatory, anti-oxidative, and anti-fibrotic pathways.

Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan

Background & aimSGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan.MethodsWe conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months.ResultsAfter 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01–0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30–0.84, P = 0.009) compared to DPP4i.ConclusionSGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD.

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

TCT-187 Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

Association of Urinary Epidermal Growth Factor with Kidney Outcomes and Effects of SGLT2 Inhibition: Results from the CANVAS and CREDENCE Trials

Association of Urinary Epidermal Growth Factor with Kidney Outcomes and Effects of SGLT2 Inhibition: Results from the CANVAS and CREDENCE Trials

Assessing the Sympatholytic Effects of SGLT2 Inhibitors in Anuric Haemodialysis Patients Using Microneurography: Study Protocol for a Mechanistic Proof-of-Concept Trial

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug’s ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. Methods: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. Discussion: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673).

Long-term efficacy of SGLT2 inhibitors for elderly patients with acute decompensated heart failure: The OASIS-HF study.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been widely demonstrated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization, regardless of left ventricular ejection fraction (LVEF). However, data on the extent to which rehospitalization is suppressed following HF hospitalization are limited. This study investigated the effects of SGLT2i on rehospitalization and cardiovascular death. The OASIS-HF study, a multicentre, prospective observational cohort study, enrolled 361 patients aged ≥75years hospitalized for acute decompensated HF. The impact on composite events of HF rehospitalization or cardiovascular death and the number of annual rehospitalizations were evaluated between the conventional medical therapy and SGLT2i groups. The change in eGFR slope at the 1-year mark after the initiation of treatment in both groups was also assessed. Over an average follow-up period of 24.9months, composite events occurred in 70 (35.4%) of the conventional therapy group and 36 (22.1%) of the SGLT2i group (log-rank: P=0.016). The average number of rehospitalizations for HF per year was 0.22±0.13 vs. 0.14±0.08, respectively (P=0.019). The change in eGFR over 1year was significantly slower in the SGLT2i group compared with the conventional group (-3.55±8.46 vs. -1.42±7.28mL/min/1.73m2, P=0.025). The SGLT2i are not only associated with the reduction of the composite events of HF rehospitalization or cardiovascular death and protect against worsening renal function but also with a decrease in long-term repeated HF rehospitalizations.

Use of Sodium-glucose cotransporter 2 (SGLT 2) inhibitor is associated with reduced emergency room visits and hospitalizations in patients with Chronic obstructive pulmonary disease (COPD) and type 2 Diabetes Mellitus

BackgroundThe Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) are a class of anti-diabetic medications that confer cardio-renal-metabolic (CRM) benefits. Emerging evidence also suggests that these agents provide better benefits for chronic pulmonary conditions, especially chronic obstructive pulmonary disease (COPD). Research questionWe aimed to assess the association between SGLT2i use and outcomes in patients with COPD and concomitant Type 2 Diabetes Mellitus (T2DM). Study design and methodsWe conducted a retrospective cohort study on adults with T2DM and COPD in a primary care clinic from January 01, 2019 to 01/01//2023. Patients were categorized into two groups based on SGLT2i use. We collected demographic information and outcomes such as emergency room (ER) visits, hospitalizations secondary to COPD exacerbation over the period of four years and time to hospitalization and ER visits. Chi-square analysis was used for categorical variables, whereas an unpaired t-test was used for continuous variables. Cox regression was performed to identify significant prognostic factors of hospitalization and ER visits. A Kaplan-Meir analysis was used to visualize the probability of non-hospitalization and the probability of not visiting the ER. Statistical significance was set at p-value <0.05. ResultsOf the 220 patients screened, 94 met the inclusion criteria, of which 20 patients (21.3 %) had SGLT2i use at admission, and 74 (78.7 %) did not. Baseline demographic information were well-matched between the two groups. SGLT2i use was associated with a significant reduction in ER visits (70 % vs. 97.3 %, p-0.001) and the number of hospitalizations (55 % vs 87.8 %, p-0.001). Further multivariate analysis showed lower hazards of hospitalization (adjusted HR-0.156; CI:0.073 to 0.331) and ER visits (HR)-0.232; CI:0.118 to 0.453) in patients on SGLT2i. InterpretationIn patients with T2DM with COPD, SGLT2i use was associated with reduced ER visits and hospitalizations related to COPD. This protective effect of SGLT2i could be explained by reduced systemic proinflammatory markers and increased anti-inflammatory markers via inhibition of Node like receptor protein 3(NLRP3) inflammasome activation in multiple tissues, including the lungs.

Effect of SGLT2 inhibitors on kidney function of type 2 diabetes patients during Ramadan: A systematic review.

SGLT2 inhibitors are known for their osmotic diuretic effect, and their use by Muslim patients with type 2 diabetes during the fasting month of Ramadan may pose an increased risk of volume depletion, potentially impacting renal function. We conducted a systematic review registered on PROSPERO (registration number CRD42020204582) of studies published between 2013 and January 2023, sourced from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. The study selection criteria included controlled studies that reported the use of SGLT2 inhibitors (SGLT2i) by fasting adult type 2 diabetes patients and provided data on creatinine or estimated glomerular filtration rate (eGFR) as outcomes. Two prospective observational studies, encompassing a total of 359 participants, of which 197 utilized SGLT2 inhibitors, were identified. Our findings indicated that the use of SGLT2 inhibitors during Ramadan did not result in a significant alteration in eGFR. In one study by Hassanein et al., the mean changes in eGFR for the SGLT2i group, as compared to the non-SGLT2i group, were -1.2 ± 19.4 and 3.1 ± 14.8, respectively (p = 0.06). In a study by Shao et al., the least squares mean changes for eGFR in the SGLT2i group, compared to the non-SGLT2i group, were -6.0 ± 1.5 (95% CI, -8.9 to -3.1) and -4.2 ± 1.6 (95% CI, -7.3 to -1.1), respectively (p = 0.39). Despite the limited number of observational studies available, our analysis suggests that the use of SGLT2 inhibitors by type 2 diabetes patients during Ramadan does not appear to significantly impact kidney function.

SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 μmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.

Abstract P300: Modulation of Osmolyte Levels by ACE Inhibitors and SGLT-2 Inhibitors in Normotensive Rats

Hypertension is associated with disturbances in the water-electrolyte balance, leading to changes in osmotic pressure. Osmolytes, such as taurine among other compounds, play a critical role in maintaining cellular integrity under osmotic stress. This study evaluated the effects of ACE inhibitors (ACE-I) and SGLT-2 inhibitors (SGLT2i) on osmolyte homeostasis. Twelve-week-old male Sprague-Dawley (SD, n = 38) rats were divided into five groups: control (water), low and high doses of canagliflozin, and low and high doses of captopril. Metabolic studies were conducted in metabolic cages. Using liquid chromatography coupled with mass spectrometry (LC-MS), we measured osmolyte concentrations in blood, urine, kidney, liver and heart tissues. The obtained results demonstrated significant increases in liver taurine concentrations (13.34 ± 1.39 vs. 10.49 ± 1.45, p=0.029) and urinary taurine excretion (25.08 ± 2.81 vs. 16.54 ± 3.77, p=0.001) in the high-dose canagliflozin group compared to controls. Both treatments enhanced the total urinary excretion of L-alanine, β-alanine, choline, glycine, taurine, and carnitine. Additionally, canagliflozin increased the excretion of betaine and glycerophosphorylcholine (GPC). A reduction in serum β-alanine was noted in the captopril-treated rats. These findings highlight the novel effects of SGLT-2 inhibitors and ACE-I on osmolyte levels in normotensive rats, suggesting potential mechanisms contributing to their cardioprotective effects. Further research is required to elucidate the clinical significance of osmolyte changes in enhancing the protective effects of these drug classes.

Sodium-glucose co-transporter-2 inhibitors in patients with chronic kidney disease with or without type 2 diabetes: systematic review and meta-analysis

ObjectiveTo examine cardiovascular and kidney benefits and harms of sodium-glucose co-transporter-2 (SGLT-2) inhibitors stratified by risk in adults with chronic kidney disease regardless of diabetes status.DesignSystematic review and meta-analysis.Data sourcesOvid...

Inhibition of sodium-glucose cotransporter-2 improves anaemia in mice and humans with sickle cell disease, and reduces infarct size in a murine stroke model.

Sodium-glucose cotransporter-2 (SGLT-2) is expressed in the kidney and may contribute to anaemia and cardiovascular diseases. The effect of SGLT-2 inhibition on anaemia and vascular endpoints in sickle cell disease (SCD) is unknown. A murine model of SCD was studied to determine the effects of the SGLT-2 inhibitor, empagliflozin, on anaemia and stroke size. The University of Michigan's Precision Health Database was used to evaluate the effect of SGLT-2 inhibitors on anaemia in humans with SCD. SCD mice treated with daily empagliflozin for 8 weeks demonstrated increases in haemoglobin, haematocrit, erythrocyte counts, reticulocyte percentage and erythropoietin compared to vehicle-treated mice. Following photochemical-induced thrombosis of the middle cerebral artery, mice treated with empagliflozin demonstrated reduced stroke size compared to vehicle treated mice. In the electronic health records analysis, haemoglobin, haematocrit and erythrocyte counts increased in human SCD subjects treated with an SGLT-2 inhibitor. SGLT-2 inhibitor treatment of humans and mice with SCD is associated with improvement in anaemic parameters. Empagliflozin treatment is also associated with reduced stroke size in SCD mice suggesting SGLT-2 inhibitor treatment may be beneficial with regard to both anaemia and vascular complications in SCD patients.

SGLT2-Inhibition in Patients With Alport syndrome

IntroductionLarge-scale trials showed positive outcomes of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome has not yet been investigated specifically in larger cohorts. MethodsThis observational, multi-center, international study (NCT02378805) assessed 112 patients with Alport syndrome after start of SGLT2i. The study’s primary endpoint was change of albuminuria in albumin/gram creatinine from start of therapy. ResultsCompared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (38±14 years) and had a better estimated glomerular filtration rate, eGFR, (63±35 ml/min/1.73m2; n=98). Maximum follow up was 32 months. Compared to baseline, at the first three follow-up visits (months 1 to 3, 4 to 8 and 9 to 15) after initiation of SGLT2i-therapy, a significant reduction of albuminuria in milligrams albumin/gram creatinine (>30%) was observed. Mean loss of eGFR was 9±12 ml/min/1.73 m2 almost one year after initiation of SGLT2i-therapy (n=35). At a total of 71 patient-years at risk, 0.24 adverse events per patient year on SGLT2i were reported. ConclusionThis study indicates that, additive to RAS-inhibition, SGLT2i have the potential to reduce the amount of albuminuria in patients with Alport syndrome. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with Alport syndrome to assess whether the observed reduction in albuminuria translates to a delay in kidney failure.

Retrospective Longitudinal Observational Study on the Long-Term Effects of Sodium-Glucose Cotransporter-2 Inhibitors on the Development of Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetic Japanese Patients.

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

Comparison of canagliflozin and teneligliptin on energy intake and body weight in Japanese patients with Type 2 diabetes: a subanalysis of the CANTABILE study

BackgroundWhile the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear.MethodsThis was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups.ResultsSeventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased.ConclusionCanagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.

Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomised Controlled Trials.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with or without Type 2 diabetes and heart failure (HF). However, studies have shown conflicting evidence regarding their efficacy in patients following acute myocardial infarction (MI). We conducted a pilot systematic review and meta-analysis to synthesise the available evidence regarding the effectiveness of SGLT2 inhibitors in MI. A systematic literature search was conducted using PubMed/MEDLINE, the Cochrane Library and Embase databases to identify randomised controlled trials (RCTs) that compared clinical outcomes of SGLT2 inhibitors with placebo following MI. We conducted the statistical analysis using RevMan, version 5.4 and pooled risk ratios (RRs) along the corresponding 95% confidence interval (CI) for all outcomes. Five RCTs reporting data for 11,211 patients were included in our study. The mean follow-up duration was 43.8 weeks. Our pooled analysis showed that SGLT2 inhibitors significantly reduced the risk of hospitalisations for heart failure (HHF) (RR = 0.76, 95% CI: 0.61-0.88, p = 0.001) in patients with MI. However, the risk of all-cause mortality (RR = 1.05, 95% CI: 0.78-1.41, p = 0.76), CV mortality (RR = 1.04, 95% CI = 0.84-1.29, p = 0.73) and all-cause hospitalisations (RR = 1.06, 95% CI: 0.96-1.17, p = 0.25) remained comparable across the two groups. SGLT2 inhibitors reduce HHF without affecting all-cause mortality, CV mortality and all-cause hospitalisations. However, further evidence is required to reach a definitive conclusion.