Sodium-glucose cotransporter 2 inhibitors’ mechanisms of action in heart failure

Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE-TIMI 58 with dapagliflozin)unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk,which seems to be the most sensitive outcome of SGLT2 inhibition.No other CVOT to date has shown any significant benefit on heart failure events.Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure:Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status.Nevertheless,despite their possible wide clinical implications,there is much doubt about the mechanisms of action and a lot of questions to unravel,especially now when their benefits translated to nondiabetic patients,rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms,direct cardiac as well as systemic,are suggested to explain their early cardiorenal benefits.These are:Anti-inflammatory,antifibrotic,antioxidative,antiapoptotic properties,then renoprotective and hemodynamic effects,attenuation of glucotoxicity,reduction of uric acid levels and epicardial adipose tissue,modification of neurohumoral system and cardiac fuel energetics,sodiumhydrogen exchange inhibition.The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis.All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.

Ipragliflozin: A novel sodium-glucose cotransporter 2 inhibitor developed in Japan

Sodium-glucose cotransporter 2(SGLT2) inhibition induces glucosuria and decreases blood glucose levels in diabetic patients and lowers hypoglycemic risk. SGLT1 is expressed in the kidney and intestine; SGLT1 inhibition causes abdominal symptoms such as diarrhea and reduces incretin secretion. Therefore, SGLT2 selectivity is important. Ipragliflozin is highly selective for SGLT2. In type 2 diabetes mellitus(T2DM), urinaryglucose excretion increased to 90 g/24 h after 28 d of treatment with ipragliflozin 300 mg/d. Twelve weeks of ipragliflozin 50 mg/d vs placebo reduced glycated hemoglobin and body weight by 0.65% and 0.66 kg, respectively, in Western T2 DM patients, and by 1.3% and 1.89 kg, respectively, in Japanese patients. Ipragliflozin(highly selective SGLT2 inhibitor) improves glycemic control and reduces body weight and lowers hypoglycemic risk and abdominal symptoms. Ipragliflozin can be a novel anti-diabetic and antiobesity agent.

Potential for sodium-glucose cotransporter-2 inhibitors in the management of metabolic syndrome: A systematic review and metaanalysis

BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors(SGLT2-Is)in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal diseases regardless of the presence of diabetes mellitus.However,studies evaluating the role of SGLT2-Is in metabolic syndrome(MetS)are limited.AIM This study primarily aimed to evaluate the impact of SGLT2-Is on the components of MetS.METHODS Two independent reviewers and an experienced librarian searched Medline,Scopus and the Cochrane central from inception to December 9,2021 to identify placebo controlled randomized controlled trials that evaluated the impact of SGLT2-Is on the components of MetS as an endpoint.Pre-and post-treatment data of each component were obtained.A meta-analysis was performed using the RevMan(version 5.3;Copenhagen:The Nordic Cochrane Center,The Cochrane Collaboration).RESULTS Treatment with SGLT2-Is resulted in a decrease in fasting plasma glucose(–18.07 mg/dL;95%CI:-25.32 to–10.82),systolic blood pressure(–1.37 mmHg;95%CI:-2.08 to–0.65),and waist circumference(–1.28 cm;95%CI:-1.39 to–1.18)compared to placebo.The impact on highdensity lipoprotein cholesterol was similar to placebo(0.01 mg/dL;95%CI:-0.05 to 0.07).CONCLUSION SGLT2-Is have a promising role in the management of MetS.

Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation:A review of literatures

Solid organ transplantation offers life-saving treatment for patients with endorgan dysfunction.Patient survival and quality of life have improved over the past few decades as a result of pharmacological development,expansion of the donor pool,technological advances and standardization of practices related to transplantation.Still,transplantation is associated with cardiovascular complications,of which post-transplant diabetes mellitus(PTDM)is one of the most important.PTDM increases mortality,which is best documented in patients who have received kidney and heart transplants.PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus,but also from specific posttransplant risk factors such as metabolic side effects of immunosuppressive drugs,post-transplant viral infections and hypomagnesemia.Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients.However,the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited.The favourable risk/benefit ratio,which is suggested by large-scale and long-term studies on new glucoselowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors,makes studies warranted to assess the potential role of these agents in the management of PTDM.

Mechanism Underlying Increase of the Serum Magnesium Concentration Observed Following Treatment with Sodium-Glucose Cotransporter 2 Inhibitors

Aim: The EMPA-REG OUTCOME study reported that the sodium-glucose cotransporter 2 inhibitor (SGLT2-i) suppressed cardiovascular (CV) events in patients with type 2 diabetes;we recently suggested that increase of the serum magnesium (Mg) by SGLT2-i’s can, in part, explain this reduction. The objective of this study was to elucidate the mechanism underlying the elevation of the serum Mg level induced by treatment with SGLT2-i’s. Methods: We analyzed the data of 37 patients with type 2 diabetes who underwent clinical evaluation and laboratory assessment at baseline and the end of 3 months. To investigate the relationship between the changes in the serum Mg concentrations during 3 months’ treatment (ΔMg) and other variables, we carried out simple linear regression analysis and multiple linear regression analysis. Results: Three months’ treatment with the SGLT2-i resulted in a significant improvement of the body weight (BW), BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose levels. The serum Mg increased significantly. Simple linear regression analysis revealed an association between the ΔMg and the serum triglyceride, serum Mg at baseline, change of the BW (ΔBW), and change of the HbA1c. Multiple linear regression analysis revealed a significant association between the ΔMg and the serum Mg level at the baseline (r = -0.55, P Conclusion: Our study revealed that a lower serum Mg level at the baseline and BW reduction were significantly associated with an increase in the serum Mg following 3 months’ treatment with SGLT2-i’s.

Sodium-Glucose Cotransporter 2 Inhibitors in Adult and Pediatric Congenital Heart Disease: Review of Emerging Data and Future Directions

Heart failure(HF)is common in patients with congenital heart disease(CHD)and there are limited medical therapies.Sodium-glucose cotransporter 2 inhibitors(SGLT2i)are a proven medical therapy in patients with acquired HF,though data are limited in patients with CHD.The aim of this review is to summarize the current evidence for use of SGLT2i in patients with CHD and identify future directions for study.In available publica-tions,SGLT2i in patients with CHD seem to be well tolerated,with similar side effect profile to patients with acquired HF.Improvement in functional capacity and natriuretic peptides are mixed,though there is a signal for potential reduction in HF hospitalizations.One prospective study in patients with systemic right ventricles showed an improvement in systolic function for patients already on maximal HF medical therapy.Though lim-ited,there is emerging data on use of SGLT2i in pediatric patients with CHD and HF.Future prospective studies are needed to evaluate for clinically meaningful endpoints,including HF hospitalization,as well as evaluate the hemodynamic impact in subtypes of CHD at high risk for HF.

Sodium-glucose co-transporter-2 inhibitor-associated euglycemic diabetic ketoacidosis that prompted the diagnosis of fulminant type-1 diabetes:A case report

Fulminant type 1 diabetes mellitus(FT1DM)is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of isletβcells.It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies.Diabetic ketoacidosis with normal blood glucose levels has been reported during sodiumglucose co-transporter 2(SGLT2)inhibitor therapy.CASE SUMMARY The patient was a 43-year-old woman that consulted a medical practitioner for malaise,thirst,and vomiting.Blood analysis showed high blood glucose levels(428 mg/dL),a mild increase of hemoglobin A1c(6.6%),and increased ketone bodies in urine.The patient was diagnosed with type 2 diabetes mellitus.The patient was initially treated with insulin,which was subsequently changed to an oral SGLT2 inhibitor.Antibodies to glutamic acid decarboxylase were negative.Four days after receiving oral SGLT2 inhibitor,she consulted at Mie University Hospital,complaining of fatigue and vomiting.Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels.The endogenous insulin secretion was markedly low,and the serum levels of islet-related autoantibodies were undetectable.We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis.The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication.She was discharged on day 14 with an indication of multiple daily insulin therapy.CONCLUSION This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels.This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.

Antihypertensive Effect of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists

An increasing body of evidence shows that new antidiabetic drugs—particularly sodium-glucose cotransporter 2(SGLT2)inhibitors and glucagon-like peptide 1(GLP-1)receptor agonists—have a beneficial effect on cardiovascular outcome.The majority of these studies have been performed in patients with heart failure and the results have shown first positive effect on blood pressure(BP)reduction.These effects are more pronounced with SGLT2 inhibitors than with GLP-1 receptor agonists.However,the reasons and mechanisms of action inducing BP reduction are still not sufficiently clear.Proposed mechanisms of SGLT2 inhibitors involve the natriuretic effect,modification of the renin-angiotensin-aldosterone system,and/or the reduction in the sympathetic nervous system.GLP-1 receptor agonists have several mechanisms that are related to glycemic,weight,and BP control.Current data show that SGLT2 inhibitors have a stronger antihypertensive effect than GLP-1 receptor agonists,which is mainly related to their renal effect.Briefly,SGLT2 inhibitors increase the response to diuretics and decrease the meal-related antinatriuretic pressure by lowering post-prandial hyperglycemia and hyperinsulinemia and prevent proximal sodium reabsorption.SGLT2 inhibitors can be used as second-line therapy in patients with diabetes mellitus or heart disease and concomitant hypertension.This article aims to summarize current knowledge regarding the antihypertensive effect of SGLT2 inhibitors and GLP-1 receptor agonists.

茵栀黄颗粒对胆管结扎大鼠肝细胞膜转运体Mrp2、Ntcp及Bsep表达的影响

目的通过考察茵栀黄颗粒(茵陈、栀子、金银花和黄芩)对肝细胞膜转运体多药耐药相关蛋白2(Multidrugresistance-associated protein 2,Mrp2/ABCC2)、Na+-牛黄胆酸共转运多肽(Na+/taurocholate cotransporter,Ntcp/SLC10A1)及胆盐输出泵(Bile salt export pump,Bsep/ABCB11)表达的影响。方法胆管结扎术制备胆汁淤积大鼠模型;生化检测和HE染色,观察茵栀黄颗粒的干预效果;流式细胞仪测定肝脏转运体Ntcp、Bsep和Mrp2的表达。结果与模型组相比,茵栀黄组肝细胞的脂肪病变和水肿较模型组显著减轻(P<0.05),Mrp2的表达显著升高(P<0.01);但Ntcp、Bsep的表达无明显变化。结论肝细胞膜转运体Mrp2的表达升高可能是茵栀黄颗粒的退黄利胆分子机制之一。

大鼠缰内侧核神经元缺少MAP2和KCC2的表达

为了观察神经元结构蛋白微管相关蛋白2(MAP2)和钾离子-氯离子共转运体2(KCC2)在缰内侧核神经元内的表达,本实验采用2组成年SD大鼠,一组作常规灌注固定,冰冻切片,KCC2和MAP2的免疫荧光组织化学染色;另一组断头取脑,分别取缰内侧核和缰外侧核,用Western blotting法检测KCC2和MAP2的表达。结果显示:KCC2和MAP2在缰内侧核内的表达非常弱,但在缰外侧核有丰富表达。以上结果表明,缰内侧核神经元缺少神经元结构蛋白MAP2和KCC2的表达。

达格列净对2型糖尿病合并颈动脉粥样硬化患者机体中性粒细胞与淋巴细胞比值、血小板与淋巴细胞比值、C反应蛋白、白介素6的影响

目的探究达格列净对2型糖尿病(T2DM)合并颈动脉粥样硬化患者机体中性粒细胞与淋巴细胞比值(NLR)、血小板与淋巴细胞比值(PLR)、C反应蛋白(CRP)、白介素6(IL-6)的影响。方法选取2019年8月~2020年1月郑州大学第二附属医院收治的100例T2DM合并动脉粥样硬化患者作为研究对象,按照随机数字表法将其分为Dap组与Con组,每组各50例。Con组患者采用原降糖方案,Dap组患者采用原降糖方案基础上加用达格列净,治疗20周。比较两组患者治疗前后的NLR、PLR、CRP、IL-6水平。结果治疗前两组患者的NLR、PLR、CRP及IL-6水平比较,差异无统计学意义(P>0.05)。治疗后两组患者的NLR、PLR、CRP及IL-6水平低于治疗前,差异有统计学意义(P<0.05);治疗后Dap组患者的NLR、PLR、CRP及IL-6水平低于Con组,差异有统计学意义(P<0.05)。结论达格列净可降低T2DM合并颈动脉粥样硬化患者NLR、PLR、CRP及IL-6水平,改善机体的低炎症反应状态。

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)have been substantiated by multiple clinical trials,resulting in increased interest in the multifarious pathways by which their mechanisms act.The principal effect of SGLT2i(-flozin drugs)can be appreciated in their ability to block the SGLT2 protein within the kidneys,inhibiting glucose reabsorption,and causing an associated osmotic diuresis.This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter.These include aberrant mitochondrial metabolism and oxidative stress burden,endothelial cell dysfunction,pernicious neurohormonal activation,and the development of inimical hemodynamics.Positive outcomes within these domains have been validated with SGLT2i administration.However,by modulating the sodium-glucose cotransporter in the proximal tubule(PT),SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention.Phosphatemia,even at physiologic levels,poses a risk in cardiovascular disease burden,more so in patients with type 2 diabetes mellitus(T2DM).There also exists an association between phosphatemia and renal impairment,the latter hampering cardiovascular function through an array of physiologic roles,such as fluid regulation,hormonal tone,and neuromodulation.Moreover,increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels,also detrimental to homeostatic cardiometabolic function.A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature.Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia,we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease,as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects.Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

Discovery of Novel N-Glycoside and Non-Glycoside hSGLT2 Inhibitors for the Treatment of Type 2 Diabetes Mellitus

Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.

钠-葡萄糖协同转运蛋白2抑制剂治疗晚期心力衰竭1例

目的 探讨晚期心力衰竭治疗策略。方法 报告钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂治疗晚期心力衰竭病人1例。该晚期心力衰竭病人合并多种并发症,应用多种利尿剂效果不佳后给予口服50 mg卡格列净,每日1次。结果 病人心力衰竭症状得以改善,N末端-B型钠尿肽前体(NT-proBNP)短期内下降及肾小球滤过率(eGFR)短期上升。结论 SGLT2抑制剂对晚期心力衰竭病人的治疗,短期有效,前景可期。

糖尿病合并心力衰竭老年患者SGLT2抑制剂应用研究进展

糖尿病及心力衰竭是老年人常见病、多发病,由于存在多种共同危险因素,两种疾病常共存,且预后不佳。钠-葡萄糖共转运蛋白2(sodium-glucose cotransport protein 2,SGLT2)抑制剂是一种新型降糖药物,近年大型临床试验证实其不仅可降低血糖,还具有改善心力衰竭预后、保护肾功能等作用。对于多病共存的老年患者,合理使用此类药物可有效改善疾病预后。综述了SGLT2抑制剂的药理作用、作用机制、适用范围及老年患者用药注意事项等,以期为此类药物合理应用提供参考。

SGLT2i通过HIF1α/NRF2/HO-1通路对缺氧-复氧心肌细胞老化的保护作用

目的探讨钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)卡格列净在缺氧心肌细胞修复损伤中的作用及机制。方法应用H9C2大鼠心肌细胞构建缺氧-复氧模型,将心肌细胞分为对照组、单纯SGLT2i组、缺氧-复氧组及缺氧-复氧+SGLT2i组。采用蛋白免疫印迹和荧光定量PCR检测心肌细胞老化相关因子SA-β-gal、p16、p21、p53及抗氧化应激相关核因子2相关因子(NRF2)和血红素氧合酶1(HO1)以及具有转录调节作用的低氧诱导因子1α(HIF1α)表达水平,采用微量酶标法检测超氧化物歧化酶(SOD)、丙二醛(MDA)、过氧化氢酶(CAT)及谷胱甘肽过氧化物酶(GSH-Px),免疫荧光检测HIF1α和NRF2核定位,双荧光素酶报告基因实验检测HIF1α与NRF2基因的相互作用。结果与对照组相比,缺氧-复氧组心肌细胞老化相关因子SA-β-gal、p16、p21和p53表达水平明显上升,氧化应激水平增强。给予SGLT2i预处理后,老化相关因子表达水平下降,氧化应激水平下调。进一步检测发现,缺氧-复氧组抗氧化应激相关分子NRF2和HO1蛋白表达下降,并伴随HIF1α表达上升;给予SGLT2i后NRF2与HIF1α表达恢复至正常水平;而下调NRF2基因表达则消除了SGLT2i对缺氧心肌细胞的保护作用。双荧光素酶报告基因检测发现,HIF1α可直接与NRF2基因启动子区域结合,并转录调控其表达。结论SGLT2i通过抑制低氧诱导的HIF1α激活,上调NRF2抗氧化通路,改善缺氧-复氧心肌细胞的氧化应激损伤和老化,对心肌细胞起保护作用。

New perspectives in the management of diabetic nephropathy

Diabetic nephropathy(DN)is the leading cause of end-stage renal disease and is also associated with increased risk for cardiovascular events.Until recently,strict glycemic control and blockade of the renin-angiotensin system(RAS)constituted the mainstay of treatment of DN.However,randomized controlled trials showed that sodium-glucose cotransporter 2 inhibitors further reduce the progression of DN.Therefore,these agents are recommended in all patients with DN regardless of DN stage and HbA1c levels.Moreover,additional blockade of the RAS with finerenone,a selective non-steroidal mineralocorticoid receptor antagonist,was also shown to prevent both the decline of renal function and cardiovascular events in this population.Finally,promising preliminary findings suggest that glucagon-like peptide 1 receptor agonists might also exert reno-and cardioprotective effects in patients with DN.Hopefully,this knowledge will improve the outcomes of this high-risk group of patients.

心力衰竭治疗药物新进展

心力衰竭是各种心脏疾病的最终阶段,也是心血管疾病的主要死因。近年来根据不同心衰发病机制研发的针对不同靶点治疗心衰的新药问世,使心衰患者的临床症状得以缓解,预期寿命延长,同时也为临床医生在治疗方案上提供了更多选择。本文将对治疗心衰的3种最新药物(沙库巴曲缬沙坦、维利西呱、达格列净)进行综述。

Berberine enhanced antidiabetic effects and attenuated untoward effects of canagliflozin in streptozotocininduced diabetic mice

OBJECTIVE To determine whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus.METHODS Streptozotocin-induced diabetic mice were introduced,and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated.RESULTS Berberine combined with canagliflozin(BC)increased reduction of fasting and postprandial blood glucose,diet,and water intake compared with berberine or canagliflozin alone.Interestingly,BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone.In addition,BC showed increased phosphorylated 5′AMP-activated protein kinase(pA MPK)expression and decreased tumor necrosis factor alpha(TNFα)levels in kidneys compared with berberine or canagliflozin alone.CONCLUSION These results indicated that BC is as tronger antidiabetic than berberine or canagliflozin alone with less negative side effectson the kidneys of diabetic mice.The antidiabetic effect is likely mediated by synergically promoting the expression of p AMPK and reducing the expression of TNFαin kidneys.This study first proved that canagliflozin combined withberberine is apromising treatment for diabetes mellitus.However,the exact mechanisms should be further investigated in future studies.

卡格列净对早期糖尿病肾病尿白蛋白/肌酐比值和尿足细胞相关蛋白裂隙素的影响

目的:探讨卡格列净(钠-葡萄糖耦联转运体2抑制药)对早期糖尿病肾病尿白蛋白/肌酐比值(urinary albumin-to-creatinine ratio,UACR)和尿液足细胞相关蛋白裂隙素的影响。方法:选取2018年1月至2019年7月期间在南方科技大学医院内分泌科住院的116例早期糖尿病肾病患者,随机数字表法1∶1分为卡格列净组和对照组,各58例。最终105例(90.5%)患者完成全部研究,卡格列净组51例,对照组54例。卡格列净组常规予以卡格列净100~300 mg/d,对照组接受基础胰岛素加氯沙坦钾片100 mg/d,均治疗24周。分别在治疗前、治疗12周及24周对患者生化指标进行检测,在此期间检测UACR、尿液足细胞相关蛋白裂隙素进行组间及组内自身对照比较。结果:卡格列净组和对照组在12周及24周后UACR及裂隙素2组指标较治疗前均有改善(P<0.05)。治疗前与治疗12周后,UACR及裂隙素2组指标差异无统计学意义(P>0.05);治疗24周,卡格列净组的UACR及裂隙素显著优于对照组(P<0.05)。结论:卡格列净可以持续降低早期糖尿病肾病患者尿液中足细胞相关蛋白裂隙素含量,推测钠-葡萄糖耦联转运体2抑制药肾脏保护作用独立于降糖之外。