SGLT2 Research Articles

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.

Potential ameliorative effect of Dapagliflozin on systemic inflammation-induced cardiovascular injury via endoplasmic reticulum stress and autophagy pathway.

Dapagliflozin (DPG) is a sodium-glucose cotransporter-2 inhibitor and is used in the treatment of diabetes. In this study, we aimed to investigate the effect of DPG on cardiotoxicity caused by systemic inflammation via endoplasmic reticulum (ER) stress and autophagy. Four groups of thirty-two Wistar Albino rats were created: Control (1ml oral physiological saline for five days and intraperitoneal saline on the 5th day), LPS (1ml oral physiological saline for five days and intraperitoneal 5mg/kg of LPS on the 5th day), LPS + DPG (10mg/kg of DPG orally for five days and 5mg/kg of LPS intraperitoneally on the 5th day), and DPG (10mg/kg of DPG orally for five days and 5mg/kg of SF intraperitoneally on the 5th day). Histopathological and immunohistochemical analyses were performed on heart and aorta tissues. ER stress and autophagy gene markers in heart tissues were evaluated by RT-qPCR. Oxidative stress in heart tissues and serum cardiac enzymes were analyzed by spectrophotometric method. The heart and aortic tissues of the LPS group showed increased expressions of Tumor Necrosis Factor-α (TNF-α) and Caspase-3 (Cas-3), along with mild hyperemia, slight inflammatory cell infiltrations, and myocardial cell damage. The heart tissues also showed genetically increased expressions of include binding immunoglobulin protein (BiP/ GRP78), protein kinase RNA-like ER Kinase (PERK), inositol-requiring enzyme 1 (IRE-1), activating transcription factors 4 (ATF-4), activating transcription factors 4 (ATF6), C/EBP homologous protein (CHOP), and BECLIN 1. Furthermore, Creatine kinase-MB (CK-MB) and Lactate dehydrogenase (LDH) levels in blood tissue significantly increased, according to biochemical analysis. With DPG therapy, all of these findings were reversed. In conclusion, DPG protects against the cardiotoxic effect of systemic inflammation with its antioxidant and anti-inflammatory properties by regulating ER stress and autophagy pathways.

Risk of Urinary Tract Infections in Male Veterans With Diabetes Prescribed Sodium-Glucose Cotransporter-2 Inhibitors Versus Sulfonylureas Across the Veterans Health Administration.

Background: Due to their mechanism of action, sodium-glucose cotransporter-2 inhibitors (SGLT2is) carry a presumed increased risk of urinary tract infection (UTI) which is reflected in current prescribing data. As SGLT2i prescribing trends increase, some retrospective studies confirm an increased risk of UTI while conflicting studies find no increased risk of UTI associated with this therapy. Objectives: This study aims to compare the odds of developing a UTI in male Veterans with type 2 diabetes mellitus (T2DM) on metformin taking a SGLT2i vs a sulfonylurea (SU) within the Veterans Health Administration (VHA). Methods: This retrospective cohort study identified male Veterans with T2DM on metformin with a new fill of SGLT2i or SU between January 1, 2020 to December 31, 2022. Patients were then assessed for UTI diagnosis. An adjusted odds ratio (AOR) was calculated. Results: The SGLT2i cohort had 5.2% of patients diagnosed with outpatient UTI and 1.6% of patients diagnosed with inpatient UTI. The SU cohort had 5.3% of patients diagnosed with outpatient UTI and 1.3% of patients diagnosed with inpatient UTI. A logistic regression analysis resulted in a decreased odds of diagnosis of outpatient UTI in the SGLT2i cohort vs the SU cohort ([AOR] = 0.91, 95% CI [0.86 - 0.96], P-value = < 0.001), and no difference in the diagnosis of inpatient UTI ([AOR] = 1.06, 95% CI [0.96 - 1.18], P-value = 0.234). Conclusion: This retrospective study of national VHA data adds to growing literature which finds no excessive risk of UTI associated with SGLT2i therapies.

Association of initial serum sodium change and clinical outcome in patients with diabetes receiving sodium-glucose cotransporter-2 inhibitor therapy: A multicentre database analysis in Taiwan.

The study aimed to assess the impact of varying degrees of initial serum sodium change among patients with type 2 diabetes (T2D) starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy and their subsequent clinical outcome. We used medical data from a multicentre health care provider in Taiwan and recruited 4400 patients with T2D with baseline normal serum sodium (135-145 mmol/L) and follow-up serum sodium measures available after 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2021. After a median of 2.9 (2.4, 3.4) months of SGLT2i treatment, overall, there was a minimal change in serum sodium levels (from 139.6 ± 2.4 to 139.5 ± 3.7 mmol/L). Most patients (87.8%) maintained normal sodium levels, while 8.6% (n = 378) experienced hyponatraemia (<135 mmol/L) and 3.6% (n = 158) hypernatraemia (>145 mmol/L). Factors independently associated with hyponatraemia included cancer history, chronic lung disease, insulin use, higher glycated haemoglobin, impaired liver function, lower baseline sodium and greater initial decline in kidney function. Conversely, factors linked to hypernatraemia included older age, absence of cancer history, loop diuretic and non-steroidal anti-inflammatory drug use, higher baseline sodium and a lesser initial decline in kidney function. Over a median of 26.0 months of follow-up, hyponatraemia shortly after starting SGLT2i therapy was associated with significantly increased risks of major adverse cardiovascular events [hazard ratio (HR): 2.52; 95% confidence interval (CI): 1.83-3.48], heart failure for hospitalization (HR: 1.66; 95% CI: 1.16-2.37), major adverse renal events (HR: 2.27; 95% CI: 1.73-2.96) and all-cause death (HR: 2.98; 95% CI: 2.17-4.11) after adjusting for clinically relevant factors. Non-linear analysis indicated that a more pronounced initial decline in serum sodium levels correlated steeply with higher risks of these adverse events. While most patients with T2D maintain stable serum sodium homeostasis on SGLT2i therapy, a subset may experience dysnatraemic events with potential worse clinical consequences. Physicians should be vigilant about monitoring sodium levels and considering the associated risks when initiating SGLT2i therapy in patients with risk.

Cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs according to baseline blood pressure in type 2 diabetes: a systematic meta-analysis of cardiovascular outcome trials

Objectives: Using a systematic meta-analysis, we investigated if patients with type 2 diabetes (T2D) and with varying baseline blood pressure (BP) differ in the cardiorenal benefits received from sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Design: Randomized, placebo-controlled, cardiovascular outcome trials (CVOTs) of SGLT-2is and GLP-1RAs were identified from MEDLINE, Embase, and the Cochrane Library up to April 2024. Hazard ratios (HRs) with 95% CIs were pooled. The differential treatment effect by baseline BP category within each trial was estimated as the ratio of the HR (RHR) and pooled. Results: Seventeen publications based on 9 unique CVOTs (4 SGLT-2is and 5 GLP-1RAs) were eligible. In participants with normal baseline BP, comparing SGLT-2is with placebo, the HRs (95% CIs) were 0.88 (0.79-0.97) for major adverse cardiovascular events (MACE), 0.73 (0.59-0.91) for heart failure (HF) hospitalization, 0.78 (0.65-0.94) for composite CVD death/HF hospitalization, and 0.55 (0.41-0.73) for composite renal outcome. The corresponding estimates for participants with higher baseline BP were 0.88 (0.81-0.96), 0.67 (0.57-0.79), 0.73 (0.65-0.82), and 0.61 (0.48-0.77), respectively. In participants with normal baseline BP, GLP-RAs had no strong effect on MACE, stroke and nephropathy, but reduced stroke and nephropathy risk in those with higher baseline BP. Estimated RHRs showed no statistical evidence that baseline BP modified the cardiorenal benefits of SGLT-2is and GLP-1RAs. Conclusions: In patients with T2D, the cardiorenal benefits of treatment with SGLT2-Is and GLP1-RAs were similar in patients with normal baseline BP compared to those with a higher baseline BP.

Rationale and design of Dapagliflozin vErsus SacubiTrIl-valsartaN therapY in Heart Failure with reduced ejection fraction (DESTINY-HF): a pragmatic randomised controlled trial protocol

BackgroundHeart failure affects almost 64 million people, with more than half of it constituting heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter-2 (SGLT2) inhibitors...

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.

Mineralocorticoid receptor antagonists and heart failure with preserved ejection fraction: current understanding and future prospects.

The mineralocorticoid receptor (MR), part of the steroid hormone receptor subfamily within nuclear hormone receptors, is found in the kidney and various non-epithelial tissues, including the heart and blood vessels. When improperly activated, it can contribute to heart failure processes such as cardiac hypertrophy, fibrosis, stiffening of arteries, inflammation, and oxidative stress. MR antagonists (MRAs) have shown clear clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, in cases of heart failure with preserved ejection fraction (HFpEF), there is considerable diversity due to its complex underlying mechanisms, resulting in conflicting findings regarding the effectiveness of MRAs in relevant studies. The concept of phenomapping presents an encouraging avenue for investigating different intervention targets and novel therapies for HFpEF. Post hoc analysis of the TOPCAT trial identified certain HFpEF phenotypes that responded favorably to spironolactone. Growing clinical and preclinical evidence suggests that non-steroidal MRAs, which exhibit greater receptor selectivity, stronger anti-fibrotic and anti-inflammatory properties, and fewer hormone-related side effects, may emerge as another promising treatment option for HFpEF alongside sodium-glucose co-transporter 2 (SGLT2) inhibitors. This review aims to outline the structural and functional characteristics of MR, discuss the physiological effects of its activation and inhibition, and delve into the potential for personalized MRA therapy based on the concept of HFpEF phenotype.

Targeting Sodium in Heart Failure.

A dominant event determining the course of heart failure (HF) includes the disruption of the delicate sodium (Na+) and water balance leading to (Na+) and water retention and edema formation. Although incomplete decongestion adversely affects outcomes, it is unknown whether interventions directly targeting (Na+), such as strict dietary (Na+) restriction, intravenous hypertonic saline, and diuretics, reverse this effect. As a result, it is imperative to implement (Na+)-targeting interventions in selected HF patients with established congestion on top of quadruple therapy with angiotensin receptor neprilysin inhibitor, β-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor, which dramatically improves outcomes. The limited effectiveness of (Na+)-targeting treatments may be partly due to the fact that the current metrics of HF severity have a limited capacity of foreseeing and averting episodes of congestion and guiding (Na+)-targeting treatments, which often leads to dysnatremias, adversely affecting outcomes. Recent evidence suggests that spot urinary sodium measurements may be used as a guide to monitor (Na+)-targeting interventions both in chronic and acute HF. Further, the classical (2)-compartment model of (Na+) storage has been displaced by the (3)-compartment model emphasizing the non-osmotic accumulation of (Na+), chiefly in the skin. 23(Na+) magnetic resonance imaging (MRI) enables the accurate and reliable quantification of tissue (Na+). Another promising approach enabling tissue (Na+) monitoring is based on wearable devices employing ion-selective electrodes for electrolyte detection, including (Na+) and (Cl-). Undoubtably, further studies using 23(Na+)-MRI technology and wearable sensors are required to learn more about the clinical significance of tissue (Na+) storage and (Na+)-related mechanisms of morbidity and mortality in HF.

Safety and Efficacy of Sodium-Glucose Transport Protein 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Diabetic Kidney Transplant Recipients: Synthesis of Evidence.

Background: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of novel antidiabetics, namely, sodium-glucose transport protein 2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), in diabetic kidney transplant recipients. Methods: Medline, Scopus, Web of Science, CENTRAL, and Clinicaltrials.gov were systematically searched from inception until 25 August 2024. Pooled estimates were obtained by applying random-effects models. Results: Overall, 18 studies (17 observational studies and one randomized controlled trial) were included. GLP1-RA were administered to 270 and SGLT2-i to 1003 patients. After GLP1-RA therapy, patients presented significantly lower glycated hemoglobin [mean difference (MD): -0.61%; 95% confidence interval (CI): -0.99; -0.23] and body weight (MD: -3.32 kg; 95% CI: -5.04; -1.59) but a similar estimated glomerular filtration rate (eGFR) and systolic blood pressure. After SGLT2-i therapy, patients had significantly lower glycated hemoglobin (MD: -0.40%, 95% CI: -0.57; -0.23) and body weight (MD: -2.21 kg, 95% CI: -2.74; -1.67), while no difference was noted in eGFR or systolic blood pressure. Preliminary data have shown an association between SGLT2-i use and a reduced risk of cardiovascular events, graft loss, and mortality. Evidence regarding the association between GLP1-RA and SGLT2-i and proteinuria was mixed. No significant effects on calcineurin inhibitor levels were observed. The risk of urinary tract infections was similar among patients treated with SGLT2-i or placebo (odds ratio: 0.84, 95% CI: 0.43; 1.64). Conclusions: Observational data suggest that GLP1-RA and SGLT2-i administration in diabetic kidney transplant recipients may be associated with better glycemic control and reduced body weight, presenting an acceptable safety profile.

Current management of chronic kidney disease in type-2 diabetes-A tiered approach: An overview of the joint Association of British Clinical Diabetologists and UK Kidney association (ABCD-UKKA) guidelines.

A growing and significant number of people with diabetes develop chronic kidney disease (CKD). Diabetes-related CKD is a leading cause of end-stage kidney disease (ESKD) and people with diabetes and CKD have high morbidity and mortality, predominantly related to cardiovascular disease (CVD). Despite advances in care over the recent decades, most people with CKD and type 2 diabetes are likely to die of CVD before developing ESKD. Hyperglycaemia and hypertension are modifiable risk factors to prevent onset and progression of CKD and related CVD. People with type 2 diabetes often have dyslipidaemia and CKD per se is an independent risk factor for CVD, therefore people with CKD and type 2 diabetes require intensive lipid lowering to reduce burden of CVD. Recent clinical trials of people with type 2 diabetes and CKD have demonstrated a reduction in composite kidney end point events (significant decline in kidney function, need for kidney replacement therapy and kidney death) with sodium-glucose co-transporter-2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonist finerenone and glucagon-like peptide 1 receptor agonists. The Association of British Clinical Diabetologists (ABCD) and UK Kidney Association (UKKA) Diabetic Kidney Disease Clinical Speciality Group have previously undertaken a narrative review and critical appraisal of the available evidence to inform clinical practice guidelines for the management of hyperglycaemia, hyperlipidaemia and hypertension in adults with type 2 diabetes and CKD. This 2024 abbreviatedupdated guidance summarises the recommendations and the implications for clinical practice for healthcare professionals who treat people with diabetes and CKD in primary, community and secondary care settings.

Non-alcoholic fatty liver disease risk with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes: a nationwide nested case–control study

BackgroundNon-alcoholic fatty liver diseases (NAFLDs)/non-alcoholic steatohepatitis (NASH) are the most common liver disorders among patients with type 2 diabetes. Newer classes of glucose-lowering agents (GLAs), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), have been shown to improve liver-related biomarkers. However, their effects on the development of NAFLD/NASH remain inconclusive.MethodsA nested case–control study was conducted using Taiwan’s National Health Insurance Research Database for 2011–2018. Patients aged ≥ 40 years, diagnosed with type 2 diabetes, having stable non-insulin GLA use, and without NAFLD/NASH history were included. Patients with incident NAFLD/NASH were matched up to 10 randomly sampled controls based on individual’s age, gender, cohort entry date, type 2 diabetes diagnosis date, and disease risk score. Conditional logistic regression analyses were employed to estimate the association between liver risk and treatment exposure. Dose-response analysis was also performed.ResultsThere were 621,438 study patients included for analysis. During 1.8 years of median follow-up, the incidence of NAFLD/NASH was 2.7 per 1000 person-years. After matching, 5,730 incident NAFLD cases (mean age: 57.6 years, male: 53.2%) and 45,070 controls (57.7 years, 52.7%) were identified. Using GLP-1RAs or SGLT2is was associated with an insignificantly lower NAFLD/NASH risk (i.e., odds ratios [95% CIs]: 0.84 [0.46–1.52] and 0.85 [0.63–1.14], respectively) and increased cumulative SGLT2i doses were significantly associated with a reduced NAFLD/NASH risk (0.61 [0.38–0.97]).ConclusionGLP-1RA and SGLT2i therapies in type 2 diabetes patients might prevent NAFLD/NASH development, with a significantly lower risk related to greater treatment exposure.

Efficacy and Safety of SGLT-2 Inhibitors in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis.

Since there is no specific recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in acute myocardial infarction (MI), this systematic review and meta-analysis was performed to address this lack of evidence. Scopus, Embase, PubMed, Web of Sciences, and Cochrane Library were searched from inception until May 30, 2024. We used both random and fixed-effects models for data analyses. Odds ratio (OR) and standard means difference (SMD) were performed for binary and continuous variables, respectively. Nine studies including five randomized clinical trials (RCTs) and four observational studies including 15,595 individuals with acute MI were entered. Overall, SGLT-2 inhibitors are significantly associated with a reduction of hospitalization for heart failure (OR, 0.78; 95% CI, 0.63 to 0.97; P = .02; I2 = 0%) and all-cause mortality (OR, 0.55; 95% CI, 0.38 to 0.81; P = .002; I2 = 0%) based on the RCTs and observational studies, respectively. SGLT-2 inhibitors also significantly improved the left ventricular ejection fraction (SMD, 0.36; 95% CI, 0.02 to 0.70; P = .04; I2 = 62%) among RCTs. Further evaluation of these drugs also revealed an acceptable safety profile without any major adverse events. In conclusion, although SGLT-2 inhibitors may have some clinical benefits among acute MI individuals, further RCTs are still needed to provide robust evidence regarding the use of SGLT-2 inhibitors in this setting.

Possible mechanism of effect of the empagliflozin on cardiovascular mortality

Introduction. The development of heart failure is closely associated with the appearance of life threatening arrhythmias, which are often a terminal event for these patients. An analysis of randomized clinical trials of inhibitors of sodium-glucose cotransporter type 2 indicates the clinically significant potential of these drugs as agents with antiarrhythmic properties. However, at the moment the full mechanism by which this effect can be realized is still not fully understood.Aim. To evaluate the effect of empagliflozin on the transmembrane calcium currents and the intracellular calcium transients on isolated ventricular cardiomyocytes of mice under conditions of normoglycemia.Materials and methods. In the experiment, ventricular cardiomyocytes were isolated from 12 outbred male mice. 2 groups were formed: group № 1 – control ventricular cardiomyocytes; group № 2 – ventricular cardiomyocytes after two hours incubation with 5 µmol/L empagliflozin solution. Transmembrane calcium currents were recorded and intracellular calcium transients were assessed.Results and discussion. Incubation of ventricular cardiomyocytes with empagliflozin significantly increased ICa current density and accelerated Ca2+ temporal dynamics. The amplitude of the Ca2+ wave and the rate of rise and decay were increased and the duration of the Ca2+ wave was shortened.Conclusion. The result of the experiment indicates that empagliflozin is able to modulate Ca2+-dependent mechanism of the excitation-contraction-coupling, enhancing and accelerating Ca2+ release into cytoplasm and reuptake. This presumably can optimize, namely reduce the time of systole and enhance it, which may be one of the important elements in the manifestation of empagliflozin antiarrhythmic properties.

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

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

Chronic kidney disease in Kuwait: a multicenter study of two cohorts with different levels of access to public healthcare

IntroductionKuwait has a large expatriate community who experience both restricted access to public health services and lower income than Kuwaiti citizens. Given these conditions, we examined differences in characteristics and management of chronic kidney disease (CKD) between Kuwaitis and expatriates.MethodsClinical and laboratory data for adult CKD Stages 3–5 not on dialysis (CKD 3–5 ND) patients with native kidneys attending nephrology clinics in all Ministry of Health hospitals collected from January 1, 2022, to December 31, 2022. Cohort was then divided into Kuwaiti patients and expatriates patients for comparison.ResultsWe collected data from 2,610 patients (eGFR: 30.8 ml/min/1.73m2; age: 62.6 years; males: 56.7%; Kuwaitis: 62.1%). Kuwaitis were older (63.94 vs. 60.3 years, p < 0.001), with lower mean eGFR (30.4 vs. 31.5 ml/min/1.73m2, p = 0.052) than non-Kuwaitis, however, Kuwaitis had lower mean blood pressure (137.2/76.5 vs. 139.1/78.9 mmHg, p = 0.006), lower HbA1c in diabetics (7.59 vs. 7.82%, p = 0.010), and better lipid profile despite higher body mass indexes (29.6 vs. 28.9 kg/m2, p = 0.002). Both groups had high diabetes mellitus and hypertension rates. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were used in only 22.6% and renin-angiotensin-aldosterone system inhibitors (RAASi) in only 46.2%.ConclusionCKD 3–5 ND is caused by diabetes mellitus in 56.6% of cases, and the majority have hypertension. In our study, non-Kuwaitis had higher eGFR; however, restricted public healthcare access and lower income can lead to an unhealthy diet and suboptimal care, which may cause higher blood pressure, higher HbA1c, and a higher dyslipidemia rate. RAASi and SGLT2i utilization must increase to combat CKD, and antihypertensive selection must improve.

Efficacy and Safety of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor Use during Ramadan Fasting: A Systematic Review.

Abstract Background Religious intermittent fasting for 30 days during Ramadan may increase the risk of dehydration, hypovolemia, and hypoglycemia. These events may also be encountered when using sodium-glucose cotransporter 2 inhibitors (SGLT2is). Objectives This article evaluates the safety of the SGLT2 inhibitors in people with type 2 diabetes during Ramadan. Search Methods We searched PubMed CENTRAL, MEDLINE, and Google Scholar on July 25, 2023 without language restrictions. Selection Criteria All trials assessing the safety of SGLT2 inhibitors during Ramadan were assessed and summarized into preset points. Data Extraction Two authors independently extracted and reviewed the retrieved studies. A third author reviewed the merged summary of the two authors and modified the article when necessary. Results Diabetic ketoacidosis, hospitalization due to diabetes-related problems, and thrombosis were either not significantly related to SGLT2i use or not studied. Estimated glomerular filtration rate (eGFR) dropped significantly in one study; otherwise, it was either not statistically significant or not studied. Hypovolemia and dehydration were significantly increased in one study only. Conclusion From the available evidence, the use of SGLT2 inhibitors in people with diabetes during Ramadan seems to be safe and well tolerated. Hypovolemia and a drop in eGFR were reported in a few studies, with no reported clinical significance.

Physio-Friendly Remission-Facilitating Pharmacotherapy (PRP) in Type 2 Diabetes

This brief communication describes the concept of physiofriendlypharmacotherapy for type 2 diabetes mellitus.Physio-friendly therapy is defined as that which restoresmetabolic, including glycaemic and weight homoeostasis,to near normal levels. Drugs such as glucagon likepeptide 1 receptor agonists (GLP1RA), sodium glucose cotransporter-2 inhibitors (SGLT2i), and alfa glucosidaseinhibitors, along with metformin, work in a physio-friendlymanner and may facilitate remission. Thus, they can also betermed as remission-facilitating drugs.Keywords: Diabetes, relapse, remission, person centredcare, type 2 diabetes

Dysregulated renal tubular handling of filtered glucose in patients with type 2 diabetes mellitus: a descriptive study

Objective: To determine the frequency of suspected dysregulated renal tubular handling of filtered glucose, and its association with blood glucose levels in type 2 diabetes mellitus. Method: The analytical, cross-sectional study was conducted from November 2022 to June 2023 at the Department of Medicine along with the Department of Pathology and Biochemistry, Pakistan Railway Hospital, Islamic International Medical College, Rawalpindi, Pakistan, and comprised diabetics aged 19-80 years. Blood and urinary glucose were assessed at the point of contact. Blood glucose 80-180mg/dl was considered glucose in range and &gt;180mg/dl glucose above range. Hyper-function of sodium glucose transport receptors was suspected if urinary glucose was &lt;++ and the function of these receptors was considered normal if urinary sugar was ++ or more. Association of suspected receptors and their association with blood glucose levels was determined. Data was analysed using SPSS 26. Results: Of the 159 diabetics, 91(57%) were females and 68(43%) were males. The overall mean age was 57±11 years (range: 46-68 years). Of the total, 43(27%) patients had glucose in range and 116(73%) had glucose above range. Of the diabetics with glucose above range, 54(47%) patients had hyper-functioning sodium glucose transport receptors, and 62(53%) had normal functioning sodium glucose transport receptors. Of the patients with glucose in range, 11(26%) had hyper-functioning sodium glucose transport receptors, and 32(74%) had normal functioning sodium glucose transport receptors. There was a significant association between sodium glucose transport receptors’ function and blood glucose levels (p&lt;0.001). Conclusion: Dysfunction of sodium glucose transport receptors affected the secretion of glucose in the urine, resulting in impaired glucose regulation in type 2 diabetes mellitus cases. Key Words: Blood glucose, Diabetes, Glycosuria, Sodium-glucose transporter 2.

In-hospital initiation of sodium-glucose co-transporter-2 inhibitors in patients with acute heart failure.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular and kidney benefits to patients with heart failure (HF) and/or chronic kidney disease (CKD), regardless of diabetes status and left ventricular ejection fraction (LVEF). Despite robust data demonstrating the efficacy of SGLT-2 inhibitors in both ambulatory and hospital settings, real-world evidence suggests slow and varied adoption of SGLT2 inhibitors among patients hospitalized for HF. Barriers to implementation of SGLT2i may include clinicians' concerns regarding potential adverse events such as diabetic ketoacidosis (DKA), volume depletion, and symptomatic hypoglycemia; or concerns regarding physiologically expected reductions in eGFR. Guidelines lack specific, practical safety data and definitive recommendations regarding in-hospital initiation and continuation of SGLT2i in patients hospitalized with HF. In this review, we discuss the safety of in-hospital SGLT2 inhibitor initiation based on recent trials and highlight the clinical implications of their early use in patients hospitalized for HF.