共0篇 平均IF=NaN (-) 更多分析

    加载中

    logo
    Risk of genital and urinary tract infections associated with SGLT-2 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes mellitus: A retrospective cohort study in Korea. Yang Hyeri,Choi Eunmi,Park Eunjun,Na Eonji,Chung Soo Youn,Kim Bonggi,Han Soon Young Pharmacology research & perspectives Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are antidiabetic drugs with associated safety concerns regarding the risk of genital and urinary tract infections. This study assessed the risk of genital and urinary tract infections associated with prescription of SGLT-2 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes mellitus (T2DM) compared to dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylurea (SU), and thiazolidinedione (TZD). We conducted a retrospective cohort study using the NHIS-National Health Insurance-Database in Korea from 2014 to 2017. Patients aged ≥19 years and those diagnosed with T2DM prior to drug prescription were enrolled. The outcomes were genital and urinary tract infections. Analysis was performed using Cox's proportional hazard model following 1:1 propensity score matching to calculate the hazard ratio (HR) with a 95% confidence interval (CI). Among the 107 131 patients included in the study, a total of 7738, 7145, and 2175 patients were assigned to the DPP-4 inhibitors, SU, and TZD comparator groups, using the propensity score (PS) of each comparator based on 7741 people in the assessed drug SGLT-2 inhibitor group. SGLT-2 inhibitors were associated with a higher risk of genital infections than DPP-4 inhibitors (HR: 2.39, 95% CI: 2.07-2.76), SU (HR: 3.23, 95% CI: 2.73-3.81), and TZD (HR: 3.23, 95% CI: 2.35-4.44), as an add-on therapy to metformin. Similar results were observed for the risk of urinary tract infections. In conclusion, SGLT-2 inhibitors are significantly associated with a higher risk of genital and urinary tract infections compared to DPP-4 inhibitors, SU, and TZD. 10.1002/prp2.910
    SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Tuttle Katherine R,Brosius Frank C,Cavender Matthew A,Fioretto Paola,Fowler Kevin J,Heerspink Hiddo J L,Manley Tom,McGuire Darren K,Molitch Mark E,Mottl Amy K,Perreault Leigh,Rosas Sylvia E,Rossing Peter,Sola Laura,Vallon Volker,Wanner Christoph,Perkovic Vlado American journal of kidney diseases : the official journal of the National Kidney Foundation Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications. 10.1053/j.ajkd.2020.08.003
    Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function. Vallon Volker,Verma Subodh Annual review of physiology SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone. 10.1146/annurev-physiol-031620-095920
    New Therapeutic Horizons in Chronic Kidney Disease: The Role of SGLT2 Inhibitors in Clinical Practice. Evans Marc,Morgan Angharad R,Whyte Martin B,Hanif Wasim,Bain Stephen C,Kalra Philip A,Davies Sarah,Dashora Umesh,Yousef Zaheer,Patel Dipesh C,Strain W David Drugs Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes. 10.1007/s40265-021-01655-2
    SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function. Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Sodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured. RESULTS:In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both <0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both <0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (=0.35; =0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. CONCLUSIONS:In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517. 10.2215/CJN.11480821
    Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Current diabetes reports PURPOSE OF REVIEW:This review offers a critical narrative evaluation of emerging evidence that sodium-glucose co-transporter-2 (SGLT2) inhibitors exert nephroprotective effects in people with type 2 diabetes. RECENT FINDINGS:The SGLT2 inhibitor class of glucose-lowering agents has recently shown beneficial effects to reduce the onset and progression of renal complications in people with and without diabetes. Randomised clinical trials and 'real world' observational studies, mostly involving type 2 diabetes patients, have noted that use of an SGLT2 inhibitor can slow the decline in glomerular filtration rate (GFR), reduce the onset of microalbuminuria and slow or reverse the progression of proteinuria. The nephroprotective effects of SGLT2 inhibitors are class effects observed with each of the approved agents in people with a normal or impaired GFR. These effects are also observed in non-diabetic, lean and normotensive individuals suggesting that the mechanisms extend beyond the glucose-lowering, weight-lowering and blood pressure-lowering effects that accompany their glucosuric action in diabetes patients. A key mechanism is tubuloglomerular feedback in which SGLT2 inhibitors cause more sodium to pass along the nephron: the sodium is sensed by macula cells which act via adenosine to constrict afferent glomerular arterioles, thereby protecting glomeruli by reducing intraglomerular pressure. Other effects of SGLT2 inhibitors improve tubular oxygenation and metabolism and reduce renal inflammation and fibrosis. SGLT2 inhibitors have not increased the risk of urinary tract infections or the risk of acute kidney injury. However, introduction of an SGLT2 inhibitor in patients with a very low GFR is not encouraged due to an initial dip in GFR, and it is prudent to discontinue therapy if there is an acute renal event, hypovolaemia or hypotension. 10.1007/s11892-021-01442-z
    Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury. Aroor Annayya R,Das Nitin A,Carpenter Andrea J,Habibi Javad,Jia Guanghong,Ramirez-Perez Francisco I,Martinez-Lemus Luis,Manrique-Acevedo Camila M,Hayden Melvin R,Duta Cornel,Nistala Ravi,Mayoux Eric,Padilla Jaume,Chandrasekar Bysani,DeMarco Vincent G Cardiovascular diabetology BACKGROUND:Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS:Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg day, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS:Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS:Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression. 10.1186/s12933-018-0750-8
    SGLT2 inhibitor therapy in patients with type-2 diabetes mellitus: is acute kidney injury a concern? Baker Megan Leila,Perazella Mark Anthony Journal of nephrology Sodium-glucose co-transporter-2 (SGLT2) inhibitor drugs are effective for treatment of type-2 diabetes mellitus. These medications target the SGLT2 transporter in the proximal convoluted tubule to prevent reabsorption of filtered glucose, resulting in glucosuria. Other clinically meaningful benefits beyond glycemic control include reductions in blood pressure, weight, and albuminuria. Three large clinical trials and subsequent meta-analyses studying SGLT2 inhibitors demonstrated significant cardiovascular benefits including reductions in heart failure hospitalizations, as well as reduced risk of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. In addition, these agents produced kidney benefits including significant reductions in worsening estimated glomerular filtration rate, progression to end-stage kidney disease, and progression of chronic kidney disease in patients with type-2 diabetes mellitus and albuminuric chronic kidney disease. However, despite these beneficial cardiovascular and kidney effects, numerous reports of acute kidney injury, including need for dialysis and death, have been reported to the FDA adverse events reporting system raising concern among providers and a warning announcement from the FDA. This review will examine the clinical effects of the SGLT2 inhibitor drugs, mechanisms behind both kidney protection and harm, and clinical recommendations for their use. 10.1007/s40620-020-00712-5
    Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Cherney David Z I,Dekkers Claire C J,Barbour Sean J,Cattran Daniel,Abdul Gafor Abdul Halim,Greasley Peter J,Laverman Gozewijn D,Lim Soo Kun,Di Tanna Gian Luca,Reich Heather N,Vervloet Marc G,Wong Muh Geot,Gansevoort Ron T,Heerspink Hiddo J L, The lancet. Diabetes & endocrinology BACKGROUND:SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. METHODS:DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18-75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m, and who were on stable renin-angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. FINDINGS:Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730-1560), and mean HbA was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI -16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by -6·6 mL/min per 1·73 m (-9·0 to -4·2; p<0·0001) at week 6. This reduction was fully reversible within 6 weeks after dapagliflozin discontinuation. Compared with placebo, bodyweight was reduced by 1·5 kg (0·03-3·0; p=0·046) with dapagliflozin; changes in systolic and diastolic blood pressure and concentrations of neurohormonal biomarkers did not differ significantly between dapagliflozin and placebo treatment. The numbers of patients who had one or more adverse events during dapagliflozin treatment (17 [32%] of 53) and during placebo treatment (13 [25%] of 52) were similar. No hypoglycaemic events were reported and no deaths occurred. INTERPRETATION:6-week treatment with dapagliflozin did not affect proteinuria in patients with chronic kidney disease without diabetes, but did induce an acute and reversible decline in mGFR and a reduction in bodyweight. Long-term clinical trials are underway to determine whether SGLT2 inhibitors can safely reduce the rate of major clinical kidney outcomes in patients with chronic kidney disease with and without diabetes. FUNDING:AstraZeneca. 10.1016/S2213-8587(20)30162-5
    Comparison of the effects of 10 GLP-1 RA and SGLT2 inhibitor interventions on cardiovascular, mortality, and kidney outcomes in type 2 diabetes: A network meta-analysis of large randomized trials. Wei Xu-Bin,Wei Wei,Ding Liang-Liang,Liu Shu-Yan Primary care diabetes The relative efficacy of different sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in reducing cardiorenal events in type 2 diabetic adults is unclear. We searched PubMed and Embase. Three primary endpoints were major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and kidney function progression (KFP). Bayesian network meta-analysis was conducted to synthesize hazard ratio (HR) and 95% confidence interval (CI). We calculated surface under the cumulative ranking curve (SUCRA) to rank drug treatments. Subcutaneous semaglutide (HR 0.73, 95% CI 0.55-0.96) and albiglutide (HR 0.76, 95% CI 0.63-0.93) significantly reduced MACE versus lixisenatide. Canagliflozin (HRs: 0.69, 0.68, 0.67 and 0.58) and empagliflozin (HRs: 0.70, 0.69, 0.68 and 0.59) significantly reduced HHF versus dulaglutide, exenatide, lixisenatide and subcutaneous semaglutide. Dapagliflozin (HRs: 0.62, 0.60, 0.68 and 0.63) and empagliflozin (HRs: 0.64, 0.61, 0.69 and 0.64) significantly reduced KFP versus dulaglutide, exenatide, liraglutide and lixisenatide. Different drug treatments had the maximum SUCRA values as for preventing different cardiorenal endpoints. Different GLP-1 RAs and SGLT2 inhibitors have different efficacy in preventing cardiorenal endpoints in type 2 diabetes, and the most efficacious drugs are different as for preventing different cardiorenal endpoints. 10.1016/j.pcd.2020.08.017
    Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats. Thomson Scott Culver,Vallon Volker American journal of physiology. Renal physiology Inhibitors of the main proximal tubular Na-glucose cotransporter (SGLT2) mitigate diabetic glomerular hyperfiltration and have been approved by the United States Food and Drug Administration for slowing the progression of diabetic kidney disease. It has been proposed that SGLT2 inhibitors improve hard renal outcomes by reducing glomerular capillary pressure (PGC) via a tubuloglomerular feedback (TGF) response to a decrease in proximal reabsorption (J). However, the effect of SGLT2 inhibition on PGC has not been measured. Here, we studied the effects of acute SGLT2 blockade (ertugliflozin) on J and glomerular hemodynamics in two-period micropuncture experiments using streptozotocin-induced diabetic rats fed high- or low-NaCl diets. PGC was measured by direct capillary puncture or computed from tubular stop-flow pressure (PSF). TGF is intact while measuring PGC directly but rendered inoperative when measuring PSF. Acute SGLT2 inhibitor reduced J by ∼30%, reduced PGC by 5-8 mmHg, and reduced glomerular filtration rate (GFR) by ∼25% (all < 0.0001) but had no effect on PSF. The decrease in PGC was larger with the low-NaCl diet (8 vs. 5 mmHg, = 0.04) where PGC was higher to begin with (54 vs. 50 mmHg, = 0.003). Greater decreases in PGC corresponded, unexpectedly, to lesser decreases in GFR ( = 0.04). In conclusion, these results confirm expectations that PGC would decline in response to acute SGLT2 inhibition and that a functioning TGF system is required for this. We infer a contribution of postglomerular vasorelaxation to the TGF responses where decreases in PGC were large and decreases in GFR were small. It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation. 10.1152/ajprenal.00552.2020
    Kidney outcomes using a sustained ≥40% decline in eGFR: A meta-analysis of SGLT2 inhibitor trials. Cherney David Z I,Dagogo-Jack Samuel,McGuire Darren K,Cosentino Francesco,Pratley Richard,Shih Weichung J,Frederich Robert,Maldonado Mario,Liu Jie,Wang Shuai,Cannon Christopher P, Clinical cardiology BACKGROUND:A recent meta-analysis of sodium-glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials. HYPOTHESIS:The apparent heterogeneity of the meta-analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials. METHODS:We performed a meta-analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE-TIMI 58 (NCT01730534), and EMPA-REG OUTCOME (NCT01131676). RESULTS:Data from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51-0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I  = 0.0%). CONCLUSIONS:Our meta-analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors. 10.1002/clc.23665
    Swertisin, a novel SGLT2 inhibitor, with improved glucose homeostasis for effective diabetes therapy. Bhardwaj Gurprit,Vakani Mitul,Srivastava Abhay,Patel Dhaval,Pappachan Anju,Murumkar Prashant,Shah Hemal,Shah Rushabh,Gupta Sarita Archives of biochemistry and biophysics Failing pancreas and subsequent loss of pancreatic β cells worsen diabetic conditions which are further alleviated by the mounting up of glucose levels. Inhibition of sodium glucose cotransporter 2 (SGLT2) in the kidney responsible for glucose reabsorption strikingly reduces blood glucose levels. Bioactive swertisin showed a promising glucose-lowering effect. Hence, we aimed to mechanistically dissect the glucose lowering property of swertisin. A systematic in silico, in vitro, and in vivo approach was directed for target analysis of swertisin. Molecular docking was performed with Swertisn-hSGLT2 complex. Glucose uptake assay and protein expression for SGLT2 and regulatory proteins were performed under swertisin effect. Various physiological and metabolic parameters were evaluated in STZ induced BALB/c mice using swertisin treatment. SGLT2 expression was evaluated in the kidney tissue of mice. Swertisn-hSGLT2 molecularly docked complex showed similar binding energy compared to the Canagliflozin-hSGLT2 complex. Swertisin inhibited glucose uptake and decreased expression of SGLT2 in HEK293 cells. Swertisin does not affect GLUT mediated glucose transport. Swertisin treated diabetic mice demonstrated remarkable improvement in overall glucose homeostasis. Reduced expression of SGLT2 was found in kidney tissue along with reduced PKC expression which is one of the key regulators of SGLT2. Our study explored SGLT2 as a selective target of swertisin for its swift glucose-lowering action which not only inhibits SGLT2 but also reduces its expression in diabetic condition. Thus, the potential property of swertisin as a glucose-lowering agent is remarkable which points towards the likelihood of a wider avenue of diabetes therapy. 10.1016/j.abb.2021.108995
    Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nature reviews. Nephrology Chronic kidney disease (CKD) and heart failure affect many people worldwide. Despite the availability of pharmacological treatments, both diseases remain associated with considerable morbidity and mortality. After observations that sodium-glucose co-transporter 2 (SGLT2) inhibitors - originally developed as glucose-lowering agents - improved cardiovascular and renal outcomes in patients with type 2 diabetes, dedicated trials were initiated to evaluate the cardiovascular and kidney protective effects in patients with CKD or heart failure. The results of these clinical trials and subsequent detailed analyses have shown that the benefits of SGLT2 inhibitors are consistent across many patient subgroups, including those with and without type 2 diabetes, at different stages of CKD, and in patients with heart failure with preserved or reduced ejection fraction. In addition, post-hoc analyses revealed that SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia in patients with CKD. With respect to their safety, SGLT2 inhibitors are generally well tolerated. More specifically, no increased risk of hypoglycaemia has been observed in patients with CKD or heart failure without diabetes and they do not increase the risk of acute kidney injury. SGLT2 inhibitors therefore provide clinicians with an exciting new treatment option for patients with CKD and heart failure. 10.1038/s41581-022-00535-6
    SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. Ke Qingqing,Shi Caifeng,Lv Yunhui,Wang Lulu,Luo Jing,Jiang Lei,Yang Junwei,Zhou Yang FASEB journal : official publication of the Federation of American Societies for Experimental Biology Large clinical trials and real-world studies have demonstrated that the beneficial effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal outcomes regardless of the presence of diabetes. However, the mechanism remains obscure. Here, we analyze the anti-fibrotic and anti-inflammatory effects of dapagliflozin, a SGLT2 inhibitor, on renal alternations using the ischemia/reperfusion-induced fibrosis model. Transcriptome and metabolome analysis showed that the accumulation of tricarboxylic acid (TCA) cycle metabolites and upregulation of inflammation in fibrosis renal cortical tissue were mitigated by dapagliflozin treatment. Moreover, dapagliflozin markedly relieved the activation of mammalian target of rapamycin and hypoxia inducible factor-1α signaling and restored tubular cell-preferred fatty acid oxidation. Notably, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation was strikingly blocked by dapagliflozin. We further demonstrated that the immunomodulatory metabolite itaconate derived from the TCA cycle was significantly boosted as a result of decreased isocitrate dehydrogenase 2 and increased immune-responsive gene 1 and mitochondrial citrate carrier in dapagliflozin-treated mice, which contributed to the inhibitory effect of dapagliflozin on NLRP3 inflammasome activation. Furthermore, administration of cell-permeable itaconate surrogate prevented activation of NLRP3 inflammasome and protected kidney against fibrosis development. Our results identify a novel mechanism coupling metabolism and inflammation for kidney benefits of SGLT2 inhibition in progressive chronic kidney disease. 10.1096/fj.202100909RR
    A Comparative Study between Mean Platelet Volume and Hba1c Levels in Patients of Type 2 Diabetes Mellitus. The Journal of the Association of Physicians of India Diabetes mellitus is a major global health problem, increasingly affecting the population across the world. Diabetic patients have an increased risk of developing micro and macro vascular diseases, and platelets may be involved as a causative agent with respect to altered platelet morphology and function. There are studies evaluating the association between Mean Platelet Volume (MPV) and HbA1c and its role in predicting glycaemic control with conflicting results. Thus the present study was conducted to assess the relationship between HbA1c levels and platelet activity (MPV), determine the association among MPV, glycemic control, and diabetic vascular complications and to evaluate the influence of improved glycemic control on MPV in type 2 diabetic patients. MATERIAL:This was a hospital based observational comparative study on 100 cases of diabetes mellitus divided in 2 groups i.e Group A (HbA1c &lt;7) and Group B (HbA1c &gt;7) and 50 healthy controls in Group C in hospital wards and OPD of SMS Medical College, Jaipur. INCLUSION CRITERIA:Age more than 18 years, and newly diagnosed or old cases of diabetes mellitus using the definition given by American Diabetes Association. EXCLUSION CRITERIA:Abnormal platelet count (&lt;100 and &gt;450×103/μL), Acute febrile illness, Use of drugs affecting platelet function, Male patients with Hb&lt;12.5mg/dl and females with Hb&lt;11.5 mg/dl and Pregnant females. OBSERVATION:It was observed that mean MPV(fl) was maximum in Group B (13.35±1.27), followed by Group A (10.77±.77) and Group C (9.09±.85) and a significant (p-value&lt;0.05) relation was found statistically. We also observed that mean HbA1c (%) was maximum in Group B (8.82±1.41), followed by Group A (6.66±.004) and Group C (5.67±.45) and a significant (p-value&lt;0.05) relation was found statistically in these 3 groups. In group B, at baseline MPV(fl) levels were more (13.35±1.26) than at follow up after glycemic control of 3mths (12.13±1.20) and this was found to be statistically significant. CONCLUSION:We found that Mean platelet volume in diabetic mellitus type 2 patients was significantly higher than non-diabetic group. We also found that the mean platelet volume in uncontrolled diabetic group (HbA1c more than 7 percent) was significantly higher than controlled diabetic group (HbA1c less than 7 percent). Our study showed that in diabetes mellitus, platelets become more reactive and aggregable and their mean volume (MPV) is increased. We also found that increase in HbA1c concentration was directly proportional to increased MPV.