Sodium-glucose Cotransporter Type Research Articles

From Emergency Department to clinic center: management of patients with Heart Failure with Reduced Ejection Fraction

Aims: primary outcomes - cardiovascular and all-cause mortality evaluation within 1 year in elderly patients enrolled with Angiotensin Receptor Inhibitor (ARNI) and/or Sodium Glucose Co-Transporter Type 2 Inhibitors (SGLT2-i) in an Internal Medicine Department; recurrent hospitalization assessment for acute Heart Failure with Reduced Ejection Fraction (HFrEF); length of hospitalization analysis compared to not-enrolled patients. Secondary endpoints - to identify any parameters predicting the length of hospitalization; safety assessment through the incidence of complications and treatment interruption. Materials and Methods: prospective observational real-life cohort study that analyzes the recruitment during hospitalization and follow-up 3-6-12 months after discharge. Several clinical parameters were recorded for each patient of any ethnicity, considering a diagnosis of acute HFrEF with NT-proBNP and chest x-ray. Results: the enrolled group (34 patients) showed a hospitalization period lower than the not-enrolled one. The rehospitalizations percentage was inferior to Randomized Clinical Trials (RCTs) for ARNI. Cardiovascular-cause mortality, symptomatic hypotension, and Urinary Tract Infections (UTI) were lower than RCTs data. Age, eGFR, NT-proBNP, Cumulative Illness Rating Scale (CIRS), and severe comorbidities, except for EF, predicted the lengthening of hospitalization. Hypoglycemia wasn’t recorded. Conclusions: ARNI/SGLT2-i are effective and safe in elderly patients. Comorbidities and bio-humoral features influence HFrEF and quality of life. The future aim is to confirm the results obtained so far.

Dapagliflozin added to metformin reduces perirenal fat layer in type 2 diabetic patients with obesity

Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria-induced net caloric output and secondary volumetric reduction, but its maintenance could be due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue (“eco-obesity”) is a recently described methodology used to measure 5 consecutive layers of abdominal fat, not assessable by DEXA or CT scan: superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK). PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6.5–9%) and Obesity (IMC > 30 kg/m2) in an open-label, randomized, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was −5.5 ± 5.2 kg (5.7% from initial weight) in cohort A and −8.4 ± 4.4 kg (8.6%) in cohort B. Abdominal circumference showed a −2.7 ± 3.1 cm and −5.4 ± 2.5 cm reduction, respectively (p = 0.011). Both Metformin alone (−19.4 ± 20.1 mm; −21.7%) or combined with Dapaglifozin (−20.5 ± 19.4 mm; −21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort’s B reached Om thickness below the cut-off for MS criteria. RK fat loss was significantly greater in cohort B group compared to cohort A, at both kidneys. Only in the Met + Dapa group, we observed correlations between Om fat with leptin/CRP/MAL and RK fat with HOMA-IR. US is a useful clinical tool to assess ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS but combined treatment is particularly effective in perirenal fat layer reduction. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.

Metabolic and renal benefits of using sodium-glucose cotransporter type 2 inhibitors in patients with type 1 diabetes mellitus and continuous subcutaneous insulin infusion

Metabolic and renal benefits of using sodium-glucose cotransporter type 2 inhibitors in patients with type 1 diabetes mellitus and continuous subcutaneous insulin infusion

Long-term uroseptic and metabolic effects of a herbal medicinal preparation in women with type 2 diabetes taken gliflosins

Background. The problem of urinary tract infections, including recurrent cystitis, and the choice of effective and safe means of treatment and prevention, taking into account the increasing burden of antibiotic resistance, are extremely relevant. Aim. To evaluate the effectiveness and safety of the herbal medicine Canephron® N for the prevention of exacerbations of recurrent cystitis and its effect on metabolic parameters in patients with type 2 diabetes mellitus taking sodium glucose cotransporter type 2 inhibitors. Material and methods. A prospective, randomized, open-label, parallel group study of 60 women without exacerbation of recurrent cystitis. The main group took the drug Canephron® N for 3 months, 2 tablets 3 times a day, and for the next 3 months they were monitored without taking the drug. The main evaluation parameters were: frequency of cystitis relapses, albumin/creatinine ratio in the morning urine, glomerular filtration rate, plasma lipid profile, glycemia and malondialdehyde in low-density lipoproteins. Results. 3 months after the end of taking the drug Canephron® N, patients in the main group maintained a positive effect in reducing exacerbations of cystitis – 3.3 times less relapses of the disease (3 and 10%, respectively; p=0.038). The urine albumin/creatinine ratio, lipid profile, glycemia and malondialdehyde in low-density lipoproteins after a 3-month treatment period had positive dynamics, but in the long-term period they corresponded to the values at the inclusion stage, both in the main and control groups. Conclusion. Prophylactic use of the herbal drug Canephron® N for 3 months is safe and reduces the frequency of relapses of cystitis in women with chronic cystitis against the background of diabetes mellitus taking sodium glucose cotransporter type 2 inhibitors, this effect persists for 3 months after discontinuation of the drug. Positive metabolic effects are associated with taking Canephron® N and are gradually leveled out when it is discontinued.

Effects of SGLT2 inhibitors on right ventricular function in heart failure patients: Updated meta-analysis of the current literature.

There is some discrepancy in current studies concerning the effect of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) on right ventricular (RV) functions in heart failure (HF) patients. Hence, this meta-analysis was focused on determining the impact of SGLT2i on RV functions in such individuals. Two independent investigators searched PubMed, Google Scholar, and the Cochrane Library for articles of interest. To analyze heterogeneity, Higgins' I2 as well as prediction intervals and Egger's test were used to assess heterogeneity. The Newcastle-Ottawa standard ratings approach was used to assess the quality of observational studies. The ROBINS-I risk of bias algorithm was used to assess bias risks of randomized studies. This meta-analysis evaluated 8 studies in total. Over the follow-up time frame, patients who used SGLT2i had substantially lower systolic pulmonary artery pressure and higher tricuspid annular plane systolic excursion values (mean difference [MD] = -5.23 [-7.81; -2.66] and, MD = 1.47 [1.01; 1.93]; P <0.01, respectively). There was no significant difference in RVS' values between follow-up and baseline (MD = 1.54 [-0.19; 3.26]; P = 0.08). However, as compared to the baseline period, fractional area contraction values were substantially larger at the end of the follow-up (MD = 5.52 [4.23; 6.82]; P <0.01). To the best of our knowledge, this is the first meta-analysis assessing the impact of SGLT2i on RV function in HF patients. Our findings suggest that SGLT2i may improve RV performance in HF patients.

Effect of SGLT2-Inhibitors on Polygraphic Parameters in Elderly Patients Affected by Heart Failure, Type 2 Diabetes Mellitus, and Sleep Apnea

Obstructive sleep apneas (OSAs) and central sleep apneas (CSAs) are the most common comorbidities in Heart Failure (HF) that are strongly associated with all-cause mortality. Several therapeutic approaches have been used to treat CSA and OSA, but none have been shown to significantly improve HF prognosis. Our study evaluated the effects of a 3-months treatment with sodium-glucose cotransporter type 2 inhibitor (SGLT2i) on polygraphic parameters in patients with sleep apnea (SA) and HF, across the spectrum of ejection fraction, not treated with continuous positive air pressure (CPAP). A group of 514 consecutive elderly outpatients with HF, type 2 diabetes mellitus (T2DM) and SA, eligible for treatment with SGLT2i, were included in the investigation before starting any CPAP therapy. The two groups were compared with the t-test and Mann–Whitney test for unpaired data when appropriate. Then, a simple logistic regression model was built using 50% reduction in AHI as the dependent variable and other variables as covariates. A multivariate stepwise logistic regression model was constructed using the variables that linked with the dependent variable to calculate the odds ratio (OR) for the independent predictors associated with the reduction of 50% in AHI. The treated group experienced significant improvements in polygraphic parameters between baseline values and follow-up with reduction in AHI (28.4 ± 12.9 e/h vs. 15.2 ± 6.5 e/h; p &lt; 0.0001), ODI (15.4 ± 3.3 e/h vs. 11.1 ± 2.6 e/h; p &lt; 0.0001), and TC90 (14.1 ± 4.2% vs. 8.2 ± 2.0%; p &lt; 0.0001), while mean SpO2 improved (91. 3 ± 2.3 vs. 93.8 ± 2.5); p &lt; 0.0001. These benefits were not seen in the untreated population. The use of SGLT2i in patients suffering from HF and mixed-type SA not on CPAP therapy significantly contributes to improving polygraphic parameters.

Metabolic control in type 2 diabetic patients treated with empagliflozin: A case series.

Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.

Time trends and regional variation in utilization of antidiabetic medicines in China, 2015-2022.

To assess the use of non-insulin antidiabetic medicines in China. We analysed the national procurement data for 29 non-insulin antidiabetic medicines from nine subgroups in China from 2015 to 2022. We estimated the number of defined daily doses (DDDs) procured per year in seven regions of China for nine subgroups and adjusted the data by the number of patients with diabetes. For each subgroup, the regional ratio was calculated by comparing the procurement per patient in each region with the procurement nationwide. The regional disparity was the difference between the highest and lowest regional ratios. We compared the medication patterns across regions. Nationally, between 2015 and 2022, the number of DDDs per patient increased from 14.45 to 47.37. The two most commonly used categories were sulphonylurea and biguanides, which increased from 7.04 to 15.39 (119%) and 3.28 to 11.11 (239%) DDDs per patient, respectively. The procurement of new drugs (dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors and glucagon-like peptide-1 receptor agonists) increased quickly and had >5000% relative changes. Particularly for sodium-glucose cotransporter type 2 inhibitors, it increased from 0.08 to 5.03 DDDs (6662%). The southwest region had the highest relative change (319%), while the southern region had the lowest (118%). Biguanide and thiazolidinediones had the lowest (1.19) and highest level (2.21) of regional disparity in 2022, respectively. The procurement of non-insulin antidiabetic medicines in China has increased a lot from 2015 to 2022. In terms of DDDs per patient, sulphonylurea ranked first, followed by metformin. The procurement of new drugs increased greatly. A large regional disparity existed in medicine usage and patterns.

Sodium-Glucose Cotransporter-2 Inhibitors vs Sulfonylureas for Gout Prevention Among Patients With Type 2 Diabetes Receiving Metformin

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits. To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy. This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022. Initiation of SGLT2i vs sulfonylurea. The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023. Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting. In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

In-hospital results of therapy with the NGLT-2 inhibitor dapagliflozin in patients with acute decompensation of heart failure: prospective randomized study

BACKGROUND: This study focuses on the development of new approaches to the management of patients with acute decompensation of heart failure (ADHF) using sodium-glucose cotransporter type 2 (iHLT-2) inhibitors, particularly dapagliflozin, and its role in early treatment initiation.&#x0D; AIM: Our aim was to determine the predictors of severe ADHF outcomes in patients with low left ventricular ejection fraction (LVEF) and the role of early initiation of iGLT-2 therapy (within the first 24 h).&#x0D; MATERIALS AND METHODS: This prospective randomized study included a total of 140 patients hospitalized with ADHF between January 1 to September 1, 2023. The patients were randomized into two groups: in group 1, iGLT-2 therapy was started within 24 h from the moment of admission (n=70), and in group 2, standard therapy was implemented (n=70). Hospital data were analyzed. The endpoint was the persistence of congestion in one or both circulatory circuits with New York Heart Association Functional Classes III–IV, indicating severe ADHF.&#x0D; RESULTS: The initial demographic and clinical characteristics of both groups were comparable. In both groups 47% patients did not receive optimal drug therapy (excluding iGLT-2) for chronic heart failure, and no differences were found in this indicator (p=0.081). iGLT-2 therapy did not demonstrate a significant effect on the likelihood of an adverse ADHF outcome (odds ratio [OR]=0.88; 95% confidence interval [CI] 0.43–1.78, p=0.719). Multivariate analysis showed an increase in the probability of this outcome for every 1000 pg/mL increase in N-terminal propeptide of brain natriuretic hormone (NT-proBNP) (OR=1.72, 95% CI 1.37–2.17; p 0.001), blood urea per 1 mmol/L (OR=1.54, 95% CI 1.21–1.97; p=0.001), pulmonary hypertension (OR=7.08, 95% CI 2.15–23.34; p=0.001), and a decrease in the probability of outcome with a 1% increase in LVEF (OR=0.91, 95% CI 0.84–0.99; p=0.031). The sensitivity and specificity of the adverse outcome model were 91.3 and 85.1%, respectively.&#x0D; CONCLUSION: The leading predictors of an unfavorable ADHF outcome include increased levels of NT-proBNP and blood urea, pulmonary hypertension, and decreased LVEF.

Serum urate change among gout patients treated with sodium-glucose cotransporter type 2 inhibitors vs. sulfonylurea: A comparative effectiveness analysis

ObjectiveTo investigate the serum urate (SU) change among gout patients initiating SGLT2i, and to compare with sulfonylurea, the second-most widely used glucose-lowering medication after metformin. MethodsWe conducted a cohort study of patients with gout and baseline SU >6 mg/dL who had SU measured within 90 days before and after SGLT2i or sulfonylurea initiation. Using multivariable linear regression, we compared SU change among SGLT2i initiators between those with and without diabetes and then compared SU change between SGLT2i and sulfonylurea. ResultsWe identified 28 patients with gout initiating SGLT2i (including 16 with diabetes) and 28 patients initiating sulfonylurea (all with diabetes). Among SGLT2i initiators, the mean within-group SU change was -1.8 (95 % CI, -2.4 to -1.1) mg/dL, including -1.2 (-1.8 to -0.6) mg/dL and -2.5 (-3.6 to -1.3) mg/dL among patients with and without diabetes, respectively, with an adjusted difference between those with and without diabetes of -1.4 (-2.4 to -0.5) mg/dL. The SU did not change after initiating sulfonylurea (+0.3 [-0.3 to 1.0] mg/dL). The adjusted SU change difference between SGLT2i vs. sulfonylurea initiation was -1.8 (-2.7 to -0.9) mg/dL in all patients. The SU reduction persisted regardless of urate-lowering therapy or diuretic use and the presence of diabetes, chronic kidney disease, or heart failure. ConclusionAmong patients with gout, SGLT2i was associated with a notable reduction in SU compared with sulfonylurea, with a larger reduction among patients without diabetes. With their proven cardiovascular-kidney-metabolic benefits, adding SGLT2i to current gout management could provide streamlined benefits for gout and its comorbidities.

Novel cardioprotective and nephroprotective combination in patients with type 2 diabetes and chronic kidney disease: perspectives of use

Chronic kidney disease (CKD) is a common complication of diabetes mellitus. It increases significantly cardiovascular risk and decreases the quality of life. CKD requires treatment, and the treatment paradigm for type 2 diabetes has shifted from a glucose-centric approach towards disease-modifying therapy. Attention is being paid to cardioprotective and nephroprotective effects. In patients with type 2 diabetes and CKD, drugs that affect the renin-angiotensin-aldosterone system, as well as sodium-glucose cotransporter type 2 inhibitors (iSGLT2) are widely used. Despite the proven positive effect of these drugs in preservation of renal functions, the pathogenesis of CKD contains links that have not yet been covered. In particular, the activity of fibrosis processes in the renal parenchyma is increased in patients with CKD due to high expression of mineracorticoid receptors. It may be a potential target for nephroprotective drugs. Thus, mineralocorticoid receptor antagonists (MCRA) may influence the residual risk of CKD progression. In particular, the effectiveness of the non-steroid selective AMCR finerenone has been proven in a number of large clinical studies, which confirmed its nephroprotective potential. In this regard, studies aimed at studying the joint effect of known nephroprotective drugs, as well as their combined effect on cardiovascular risk, are highly needed.This review marks the main mechanisms of the combined action of iSGLT2 and finerenone. Discussion of the results of main clinical studies with combined use of standard nephroprotective therapy, SGLT2 and finerenone is also presented.

Effect of Sodium Glucose Co-transporter Type 2 Inhibitors on The Infract size among Diabetic Patients With ST Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Effect of Sodium Glucose Co-transporter Type 2 Inhibitors on The Infract size among Diabetic Patients With ST Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to berequired to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Nouveautés dans la prise en charge de l’hyperkaliémie

Hyperkalemia is common in everyday clinical practice, and is a major risk factor for mortality. It mainly affects patients with chronic renal failure (CKD), diabetes or receiving treatment with inhibitors of the renin-angiotensin-aldosterone system (iRAAS). Therapeutic management aims not only to avoid the complications of hyperkalemia, but also to avoid discontinuation of cardio- and nephroprotective treatments such as iRAAS. The use of polystyrene sulfonate, widely prescribed, is often limited by patient acceptability. Recent data have cast doubt on its safety, particularly in terms of digestive tolerance. Two new potassium exchange molecules have appeared on the market: patiromer and zirconium sulfonate. Their value in clinical practice, and their acceptability in the event of prolonged prescription, remain to be demonstrated. The combination of a thiazide diuretic or an inhibitor of the sodium-glucose cotransporter type 2 (iSGLT2) with iRAAS therapy in CKD, may also improve control of kalemia. At present, there are no recommendations for the positioning of the various hypokalemic treatments. The choice of these treatments must be adapted to the patient's pathologies and consider the other expected effects of these molecules.

The use of sodium-glucose co-transporter type II (SGLT2) inhibitors in patients with chronic heart failure against the background of type 2 diabetes mellitus

The use of sodium-glucose co-transporter type II (SGLT2) inhibitors in patients with chronic heart failure against the background of type 2 diabetes mellitus

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease.

Outcome trials using sodium glucose cotransporter type 2 inhibitors have consistently shown their potential to preserve kidney function in diabetic and nondiabetic patients. Several mechanisms have been introduced which may explain the nephroprotective effect of sodium glucose cotransporter type 2 inhibitors beyond lowering blood glucose. This current narrative review has the objective to describe main underlying mechanisms causing a nephroprotective effect and to show similarities as well as differences between proposed mechanisms which can be observed in patients with diabetic and nondiabetic chronic kidney disease. We performed a narrative review of the literature on Pubmed and Embase. The research string comprised various combinations of items including "chronic kidney disease", "sodium glucose cotransporter 2 inhibitor" and "mechanisms". We searched for original research and review articles published until march, 2022. The databases were searched independently and the agreements by two authors were jointly obtained. Sodium glucose cotransporter type 2 inhibitors show systemic, hemodynamic, and metabolic effects. Systemic effects include reduction of blood pressure without compensatory activation of the sympathetic nervous system. Hemodynamic effects include restoration of tubuloglomerular feedback which may improve pathologic hyperfiltration observed in most cases with chronic kidney disease. Current literature indicates that SGLT2i may not improve cortical oxygenation and may reduce medullar oxygenation. Sodium glucose cotransporter type 2 inhibitors cause nephroprotective effects by several mechanisms. However, several mediators which are involved in the underlying pathophysiology may be different between diabetic and nondiabetic patients.

Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex

BackgroundThe sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown.ObjectiveWe performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex.DesignProspective randomized placebo-controlled trial.ParticipantsA total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes.InterventionDapagliflozin 10 mg versus placebo once daily.Main MeasuresPrimary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality.Key ResultsMedian follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope.ConclusionsDapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit.Trial Registryclinicaltrials.govNIH Trial Registry NumberNCT03036150

Effects of canagliflozin on cardiac remodeling and hemodynamic parameters in patients with type 2 diabetes mellitus

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated to reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) in large trials independent of glycemic control. The mechanisms of this cardioprotective property remain uncertain. Evidence suggests positive hemodynamic changes and favorable cardiac remodeling contributing to the clinical outcomes but results were conflicting. We aim to investigate the potential impact on hemodynamic parameters, cardiac structure and functions. This prospective observational study included T2DM patients receiving canagliflozin 100 mg per day in addition to their antidiabetic treatment. We analyzed hemodynamic parameters assessed by echocardiographic measurements and impedance cardiography (ICG) to evaluate systolic and diastolic functions from baseline to 24 weeks after treatment. A total of 47 patients (25 males and 22 females) averaging 64.6 ± 10.9 years had a significant reduction in HbA1c, body weight, and systolic blood pressure. Hematocrit increased significantly, while NT-proBNP remained unchanged. E/e′, left atrium (LA) volume, and LA stiffness were reduced, while left ventricle (LV) global longitudinal strain (GLS) and LA strain rates increased at 24 weeks by conventional and speckle tracking echocardiography. LV mass and ejection fraction showed no differences. ICG suggested significant improvement in hemodynamic parameters with increased stroke volume index and cardiac output index and decreased systemic vascular resistance index at 12 and 24 weeks. Canagliflozin improved hemodynamic parameters and had a favorable impact on LA and LV reverse remodeling. These changes may explain the beneficial effect on cardiovascular outcomes in large clinical trials.

Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) reabsorbs 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. The aim of this work was to obtain new potential SGLT2 inhibitors. A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived from spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. These compounds are proposed as potential SGLT2 inhibitors.