A Bioequivalence Study of Empagliflozin/Metformin Fixed-Dose Combination in Healthy Subjects under Fasting Conditions

Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.

Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1αand inhibiting the RhoA/ROCK pathway

BACKGROUND Diabetic cardiomyopathy(DCM)increases the risk of hospitalization for heart failure(HF)and mortality in patients with diabetes mellitus.However,no specific therapy to delay the progression of DCM has been identified.Mitochondrial dysfunction,oxidative stress,inflammation,and calcium handling imbalance play a crucial role in the pathological processes of DCM,ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions.Empagliflozin,a novel glucoselowering agent,has been confirmed to reduce the risk of hospitalization for HF in diabetic patients.Nevertheless,the molecular mechanisms by which this agent provides cardioprotection remain unclear.AIM To investigate the effects of empagliflozin on high glucose(HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.METHODS Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG(30 mmol/L)were separately employed as in vivo and in vitro models.Echocardiography was used to evaluate cardiac function.Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells.Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential.Furthermore,intracellular reactive oxygen species production and superoxide dismutase activity were analyzed.Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression.Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase(AMPK)and myosin phosphatase target subunit 1(MYPT1),as well as the peroxisome proliferator-activated receptor-γcoactivator-1α(PGC-1α)and active caspase-3 protein levels.RESULTSIn the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin(10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis,accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease inthe phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment ofcardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis.However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG,empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylatedMYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressingPGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucosecotransporter (SGLT)2 protein expression was detected in cardiomyocytes.CONCLUSION Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HGconditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.

Empagliflozin治疗2型糖尿病达到HbA1c<7.0%的有效性及安全性评价

目的系统评价钠葡萄糖协同转运蛋白2(SGLT2)抑制剂empagliflozin治疗2型糖尿病(T2DM)达到HbA1c<7.0%的有效性与安全性。方法计算机检索Pubmed、Cochrane Library、EMbase,CBM和CNKI数据库发表empagliflozin的文献,检索时限均为建库至2015年10月,筛选合格随机对照试验(RCT)。根据Cochrane系统评价手册5.1评估纳入研究偏倚风险,采用RevMan 5.3软件进行统计分析。结果纳入8篇RCT,共4 728例研究对象。结果显示:empagliflozin使HbA1c<7.0%的达标率高于安慰剂(10mg RR=2.68,95%CI:2.06~3.47,P<0.05;25mg RR=3.25,95%CI:2.49~4.25,P<0.05),且不增加低血糖风险(10mg RR=1.04,95%CI:0.89~1.21,P>0.05;25mg RR=1.06,95%CI:0.91~1.23,P>0.05),同时能降低体质量(10mg WMD=-1.75,95%CI:-1.96^-1.55,P<0.05;25 mg WMD=-1.95,95%CI:-2.16^-1.74,P<0.05),收缩压和舒张压及改善空腹血糖;但增加了生殖道感染风险,在发生泌尿道感染和严重不良事件方面差异无统计学意义,且对T2DM患者肾功能无影响及不增加全因死亡率。结论 Empagliflozin能够有效地使T2DM患者达到HbA1c<7.0%,另有减轻体质量和降压的临床获益,且安全性好。

Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease.However,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice.METHODS We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 wk.Age-matched male db/+mice were included as non-diabetic controls.Parameters of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were assessed.We evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,respectively.Glomerular nephrin and transforming growth factor beta(TGF-β)were assessed by immunohistochemistry.RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were detected.Mesangial expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated mice.Podocytopathy was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were reduced.EMPA decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of nephrin.CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease.The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.

Bilateral gangrene of fingers in a patient on empagliflozin: First case report

BACKGROUND Sodium glucose cotransporter 2(SGLT2)inhibitors use has been associated with toe amputations and non-healing ulcers and gangrene mostly of lower extremities.There are no case reports about association of Empagliflozin with finger ulcers or gangrene.This is the first case report of Empagliflozin(Jardiance)an SGLT2 inhibitor causing gangrene of fingers and second case in literature about any SGLT2 inhibitor causing gangrene of upper extremity.CASE SUMMARY A 76-year-old man with type 2 diabetes mellitus sustained minimal trauma to both middle fingers,which started healing.He was started on empagliflozin a week later for management of type 2 diabetes mellitus and started developing gangrene to both middle finger tips along with neuropathic pain which worsened over the course of next four months.Investigations were negative for vascular insufficiency,infection and vasculitis and imaging of hand was normal.Discontinuation of empagliflozin slowed progression of gangrene and caused symptomatic improvement with reduction in neuropathic pain.CONCLUSION This case report suggests possible association of empagliflozin and finger gangrene and recommends that more research and awareness among clinicians is needed in this area.

Short Term Use of Empagliflozin Does Not Improve Left Ventricular Function in Non-Diabetic Hypertensive Patients: Results from a Non-Randomised Controlled Trial

Background: A selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), empagliflozin, has demonstrated its effects in reducing cardiovascular mortality and hospitalization rates for heart failure in type 2 diabetes patients. However, the cardiac-intrinsic mechanism for this cardiovascular benefit has not been sufficiently studied. We therefore aimed to investigate the effect of empagliflozin on left ventricular function in a group of patients with grade I hypertension. Methods: We carried out a single-arm non-randomized clinical trial at the National Obesity Centre in Yaoundé over a period of 8 months (October 2016 to May 2017), where patients were assigned to receive 25 mg of empagliflozin once daily. Cardiac ultrasound, 24-hour ambulatory blood pressure measurement, resting electrocardiography and biological assessment were carried out at baseline and at the end of a 6-week treatment period with empagliflozin. The primary outcome was the improvement of the left ventricular relaxation evaluation criteria. Ethical approval was obtained from the Centre Regional Ethics Committee in Yaoundé, Cameroon. Results: A total of 11 patients were treated (median observation time, 6 weeks). We noted a non-significant improvement in the early lateral annular velocity from 9.7 [9.2 - 11.4] cm/s to 9.1 [8.8 - 10.2] cm/s, p =0.21. We also noted a non-significant improvement of the mitral profile (E/A) from 0.71 [0.63 - 0.78] cm/s to 0.81 [0.58 - 0.88] cm/s, p = 0.08. There were no differences in E/E’ ratio, 5.0 [4.1 - 6.3] vs 5.6 [4.9 - 7.4], p = 0.07. There was a non-significant drop in both systolic (p = 0.06) and diastolic (p = 0.09) blood pressure. We also observed on ECG a drop of the PR interval from 200 [157 - 200] ms to 160 [143 - 186] ms, p = 0.04. Conclusion: Short-term treatment with empagliflozin does not show an improvement of the left ventricular function in grade I hypertensive patients with diastolic dysfunction. Trial registration: This study was retrospectively registered on Clinical Trial Registry with ClinicalTrials.gov Identifier: NCT04203914.

Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Sodium-glucose cotransporter 2(SGLT2)inhibitors have been reapproved for heart failure(HF)therapy in patients with and without diabetes.However,the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice.A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect.To address this issue,we conducted structural repurposing of EMPA,a representative SGLT2 inhibitor,to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2.Compared to EMPA,the optimal derivative JX01,which was produced by methylation of C2—OH of the glucose ring,exhibited weaker SGLT2-inhibitory activity(IC_(50)>100 nmol/L),and lower glycosuria and glucose-lowering side-effect,better NHE1-inhibitory activity and cardioprotective effect in HF mice.Furthermore,JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity,and good pharmacokinetic properties in both mouse and rat species.Collectively,the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs,and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

新型钠–葡萄糖协同转运蛋白2抑制剂empagliflozin

钠–葡萄糖协同转运蛋白2(SGLT2)抑制剂是近年来降糖药研究的新热点,通过抑制肾小管上皮细胞内的主要血糖转运蛋白SGLT2降低肾内滤过葡萄糖的重吸收,导致糖尿,从而降低血清内葡萄糖。新型SGLT2抑制剂empagliflozin具有良好的降糖效果,单次给药就能显著增加尿中排糖,多次给药后剂量相关性地降低FPG、HbA1c和体质量,作为补充药物治疗还能显著降低血压,目前正在进行Ⅲ期临床试验。

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

恩格列净与利拉鲁肽联合治疗肥胖/超重2型糖尿病患者的疗效及其对炎症因子的影响:一项前瞻、随机、开放、平行对照的临床研究

目的探讨恩格列净与利拉鲁肽联合治疗肥胖/超重2型糖尿病(T2DM)患者的临床疗效及其对炎症因子和胰岛功能的影响。方法选取2021年6月-2023年9月在河北医科大学第二医院住院治疗的肥胖/超重T2DM患者58例。采用随机数表法将受试者随机分为:试验组(Lira+Empa组)和对照组(Lira组),各29例。试验组接受恩格列净+利拉鲁肽联合治疗,对照组仅接受利拉鲁肽治疗,比较两组治疗前、后糖代谢指标、脂代谢指标、炎症因子、胰岛功能指标及不良反应。结果治疗后,两组空腹血糖(FPG)、餐后2 h血糖(2 hPPG)、糖化白蛋白(GA)、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、体重指数(BMI)、白细胞介素(IL)-6、IL-10水平明显低于治疗前,Lira+Empa组FPG、2 hPPG、GA、BMI、IL-6、IL-10水平均低于Lira组,差异有统计学意义(P<0.05)。治疗后,两组C肽、空腹胰岛素和稳态胰岛素分泌指数(HOMA-β)均较治疗前升高,其中,Lira+Empa组HOMA-β明显高于Lira组,差异有统计学意义(P<0.05)。两组不良反应发生率无明显差异。结论相较于利拉鲁肽单药治疗,恩格列净+利拉鲁肽联合治疗能进一步提高T2DM降糖疗效,明显改善患者血糖水平和胰岛功能,并有效降低体重,对炎症因子水平有改善作用,且安全性良好。

司美格鲁肽联合恩格列净与二甲双胍治疗初诊肥胖2型糖尿病患者的临床效果

目的观察司美格鲁肽联合恩格列净与二甲双胍治疗初诊肥胖2型糖尿病(T2DM)患者的临床效果。方法选取2021年4月—2023年4月三明市第二医院内分泌科收治的初诊肥胖T2DM患者160例,按照随机数字表法分为二联药物组与三联药物组,各80例。二联药物组予二甲双胍片+恩格列净片治疗,三联药物组在二联药物组基础上给予司美格鲁肽注射液皮下注射,2组均治疗12周。比较2组临床疗效,治疗前后血糖指标[空腹血糖(FPG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbA1c)]、胰岛素抵抗指数(HOMA-IR)、血糖变异性指标[葡萄糖目标范围内时间所占百分比(TIR%)、平均血糖波动幅度(MAGE)、血糖标准差(SDBG)、血糖变异系数(CVBG)],不良反应。结果三联药物组治疗总有效率为92.50%,高于二联药物组的78.75%(χ^(2)=6.144,P=0.013)。治疗12周后,2组FPG、2 hPG水平与HbA1c、HOMA-IR较治疗前均下降,且三联药物组下降幅度大于二联药物组(P<0.01);2组TIR%较治疗前升高,MAGE、SDBG、CVBG较治疗前下降,且三联药物组升高/下降幅度大于二联药物组(P<0.01)。二联药物组与三联药物组不良反应总发生率比较,差异无统计学意义(3.75%vs.6.25%,χ^(2)=0.132,P=0.717)。结论司美格鲁肽联合恩格列净与二甲双胍治疗初诊肥胖的T2DM患者临床疗效确切,可明显降低患者血糖,改善胰岛素抵抗,提高TIR%,降低血糖变异性,且安全性高。

Elucidating the cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibitors beyond glycemic control

Sodium-glucose cotransporter-2(SGLT2)inhibitors have emerged as a pivotal intervention in diabetes management,offering significant cardiovascular benefits.Empagliflozin,in particular,has demonstrated cardioprotective effects beyond its glucose-lowering action,reducing heart failure hospitalizations and improving cardiac function.Of note,the cardioprotective mechanisms appear to be independent of glucose lowering,possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic,anti-inflammatory,and anti-oxidative pathways.This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors,highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.

司美格鲁肽联合二甲双胍恩格列净治疗2型糖尿病合并非酒精性脂肪性肝病患者疗效及安全分析

目的 观察司美格鲁肽与二甲双胍恩格列净联合对2型糖尿病(Type 2 Diabetes Mellitus, T2DM)合并非酒精性脂肪性肝病(Non-alcoholic Fatty Liver Disease, NAFLD)患者治疗的临床应用价值。方法 选取2022年5月—2023年5月上海市松江区泗泾医院收治的100例T2DM合并NAFLD患者为研究对象,通过抽签法分为两组,各50例。对照组给予二甲双胍恩格列净,观察组在对照组的基础上加用司美格鲁肽。比较两组的血糖、肝功能、血脂和不良反应。结果 观察组治疗后空腹血糖、餐后2 h血糖、丙氨酸氨基转移酶、门冬氨酸氨基转移酶、谷氨酰转肽酶、总胆固醇、三酰甘油水平低于对照组,差异有统计学意义(P均<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论 二甲双胍恩格列净联合司美格鲁肽治疗T2DM合并NAFLD患者,能调节糖脂代谢异常情况,改善其肝功能,安全性可靠。

恩格列净对不合并2型糖尿病的射血分数保留的心力衰竭患者疗效观察

目的探讨恩格列净对不合并2型糖尿病的射血分数保留的心力衰竭(HFpEF)患者临床效果。方法选取2021年1月至2022年6月就诊于郑州市第七人民医院心血管内科的118例不合并2型糖尿病的HFpEF患者为研究对象,以随机数表法分为研究组(61例)和对照组(57例)。两组患者均予以包括沙库巴曲缬沙坦、美托洛尔、螺内酯等在内的常规抗心力衰竭治疗。研究组在对照组的基础上加用恩格列净(10 mg/d)。随访6个月,测定两组患者治疗6月后临床疗效,以及治疗前、治疗1月、3月、6月后由美国GE公司的Vivid7全数字彩色多普勒超声诊断仪采集左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、左室射血分数(LVEF)、二尖瓣舒张早期最大峰值流速(Ea)、二尖瓣舒张晚期最大峰值流速(Aa),以免疫比浊法测定血浆超敏C反应蛋白(hs-CRP),以酶联免疫吸附法检测N末端脑钠肽前体(NT-proBNP),以荧光测定法测定血管紧张素Ⅱ(AngⅡ),测定明尼苏达心力衰竭生活质量量表(MLHFQ)评分、6 min步行距离(6MWD)与治疗6月后心力衰竭再住院率、不良反应发生率,分析恩格列净对不合并2型糖尿病的射血分数保留的心力衰竭患者临床疗效。结果治疗6月后研究组总有效率高于对照组(P<0.05),心力衰竭再住院率低于对照组(P<0.05),两组不良反应发生率相当(P>0.05)。随着治疗时间的延长,两组LVEF、Ea、6MWD均较前升高(P<0.05),且研究组Ea、6MWD均高于对照组(P<0.05);两组LVEDD、LVESD、Aa、hs-CRP、NT-proBNP、AngⅡ、MLHFQ评分均较前降低,且研究组均低于对照组(P<0.05)。结论恩格列净可改善不合并2型糖尿病的HFpEF患者的心脏功能,降低其hs-CRP、NT-proBNP、AngⅡ水平,改善其临床症状、生活质量和运动耐力,降低其心力衰竭再住院率,具有良好的有效性及安全性。

恩格列净通过调控AMPK/eNOS信号通路改善ox-LDL诱导的内皮祖细胞功能障碍

目的研究恩格列净(EMP)对氧化低密度脂蛋白(ox-LDL)诱导内皮祖细胞(EPCs)损伤的保护作用及机制。方法通过密度梯度离心法提取、分离并培养小鼠骨髓来源的的EPCs。采用Dil标记乙酰化低密度脂蛋白(Dil-ac-LDL)联合FITC标记荆豆凝集素-1(FITC-UEA-1)双摄取法鉴定。将EPCs分为正常对照组,ox-LDL组以及ox-LDL联合不同浓度恩格列净实验组。CCK-8检测细胞活力,Transwell检测细胞迁移,FITC-Annexin V/PI检测细胞凋亡,ELISA检测细胞上清液中血管内皮细胞生长因子(VEGF)、基质细胞衍生因子-1α(SDF-1α)含量;流式细胞术检测一氧化氮(NO)的合成情况。Western blot检测AMPK、p-AMPK、eNOS、p-eNOS的蛋白表达。结果提取的EPCs诱导培养至第7天经鉴定为小鼠骨髓EPCs。与对照组比较,ox-LDL组细胞活力降低,迁移细胞减少,凋亡增加,VEGF、SDF-1α含量降低,NO合成减少(P<0.05);与ox-LDL组相比,不同浓度恩格列净组细胞活力有所提高,迁移细胞增多,凋亡减少,VEGF、SDF-1α含量升高,NO合成增加(P<0.05)。ox-LDL处理可明显抑制AMPK及eNOS磷酸化(P<0.05),恩格列净处理可以改善AMPK及eNOS磷酸化水平(P<0.05),而AMPK抑制剂Compound C可使恩格列净改善EPCs功能活性的作用受到明显的抑制(P<0.05)。结论恩格列净可改善ox-LDL诱导的EPCs功能障碍,其机制与调控AMPK/eNOS信号通路有关。

恩格列净在心血管疾病中的研究进展

恩格列净是一种通过抑制肾脏近端小管上的钠-葡萄糖协同转运蛋白-2 (sodium-dependent glucose transporters 2,SGLT2)来发挥降糖作用的新型降糖药物。恩格列净还可以降低心血管疾病(cardiovascular disease,CVD)终点事件的发生率,尤其是可以降低糖尿病合并射血分数降低的心力衰竭患者的住院率和死亡率。目前,恩格列净作为一种治疗CVD的药物,在临床上受到越来越多的关注,但恩格列净在CVD中发挥作用的机制尚未明晰。本篇综述主要围绕恩格列净与心力衰竭、急性心肌梗死、高血压和心律失常等疾病的相关研究进展进行综述。

二甲双胍恩格列净片治疗2型糖尿病合并HFpEF的临床效果

目的:探讨二甲双胍恩格列净片治疗2型糖尿病(T2DM)合并射血分数保留性心力衰竭(HFpEF)患者的临床效果和安全性。方法:选取2021年10月—2022年9月保定市第一中心医院80例T2DM合并HFpEF患者,通过随机数字表法将其分为观察组(n=40)和对照组(n=40)。对照组给予常规药物治疗,观察组在对照组的用药基础上联合二甲双胍恩格列净片治疗。两组均接受为期6个月的连续治疗。对比两组血糖指标、心功能指标及不良反应发生情况。结果:治疗后,两组空腹血糖(FBG)、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1c)均较治疗前下降,且观察组均低于对照组(P<0.05)。治疗后,两组左室射血分数(LVEF)、左室舒张末径(LVEDD)、左室收缩末径(LVESD)、脑钠肽(BNP)均优于治疗前,且观察组均优于对照组(P<0.05)。观察组不良反应发生率(5.0%)低于对照组(22.5%),差异有统计学意义(P<0.05)。结论:二甲双胍恩格列净片治疗2型糖尿病合并HFpEF临床效果显著,能够使患者的血糖水平下降并提高心功能相关指标,同时安全性较高。

Empagliflozin联用二甲双胍治疗2型糖尿病的有效性和安全性:Meta分析

目的评价empagliflozin联用二甲双胍(MET)治疗2型糖尿病(T2DM)的有效性和安全性。方法计算机检索Pubmed、Embase、Medline、Cochrane Library数据库,中国期刊全文数据库(CNKI)、万方数据库、维普信息资源系统(VIP)等数据库,筛选研究empagliflozin联用MET治疗T2DM的有效性和安全性的随机对照试验(RCTs)。根据Cochrane系统评价员手册进行质量评价,采用RevMan5.2软件进行Meta分析。结果共纳入7项研究,4 151例患者。与安慰剂组比较,empagliflozin能降低HbA1c水平[MD=-0.62,95%CI(-0.67,-0.56),P<0.01]、FPG水平[MD=-1.48,95%CI(-1.66,-1.31),P<0.01)]、体质量[MD=-1.83,95%CI(-2.02,-1.64),P<0.01]。与阳性药物组比较,empagliflozin组更能有效地改善HbA1c[MD=-0.22,95%CI(-0.40,-0.04),P=0.02]、FPG[MD=-1.43,95%CI(-2.18,-0.68),P=0.000 2]、体质量[MD=-3.07,95%CI(-3.77,-2.37),P<0.01]。在安全性方面,与安慰剂组及阳性药物组比较,总不良反应发生率、尿路感染发生率、神经系统疾病发生率、患者因不良反应退出方面无明显差异(P>0.05);生殖器感染发生的风险高于阳性药物组,心血管疾病的发生风险低于阳性药物组,差异有统计学意义(P<0.01)。低血糖发生率empagliflozin组与安慰剂组及阳性药物组无明显差异[RR=1.28,95%CI(0.93,1.76),P=0.13;RR=0.55,95%CI(0.18,1.65),P=0.28]。结论 Empagliflozin联合MET治疗T2DM安全、有效。

恩格列净对糖尿病小鼠肾脏保护作用的机制研究

目的探究恩格列净对肾脏保护作用的新机制。方法将8周龄雄性SPF级C57/BL6J小鼠随机分为两组,正常对照(NC)组(n=7)和高脂(HFD)组(n=23)。NC组常规饲料喂养,高脂组60%HFD喂养。HFD小鼠喂养12周后,腹腔注射0.1 mol/L柠檬酸钠缓冲液稀释的链脲佐菌素(STZ,30 mg/kg);NC组小鼠,腹腔注射等容积的0.1 mol/L柠檬酸钠缓冲液。将造模成功的小鼠随机分为糖尿病(DM)组(n=8)、DM+利格列汀干预(DM+Lina)组(10 mg/kg,n=7)、DM+恩格列净干预(DM+Empa)组(25 mg/kg,n=8)。药物干预12周后留取血尿标本,生化仪检测小鼠肝肾功能、ELISA法检测血β-羟丁酸(β-HB)及生化试剂盒检测尿微量白蛋白(MAU)、视黄醇结合蛋白(RBP)、β2微球蛋白(β2-MG)、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)等尿生化指标,留取肾脏组织,观察各组小鼠肾脏病理结构变化,并应用Western blot检测相关蛋白的表达。结果DM+Empa组的随机血糖、体重、总胆固醇、低密度脂蛋白水平、游离脂肪酸、肌酐低于DM组,DM+Empa组的血β-HB高于NC组、DM组及DM+Lina组,差异有统计学意义(P<0.05)。DM+Empa组的RBP、NAG、MAU低于DM组,差异有统计学意义(P<0.05),同时DM+Empa组的尿β-HB与NC组比较,差异无统计学意义(P>0.05)。糖尿病小鼠肾脏钠-偶联单羧酸转运蛋白1(SMCT1)低表达,恩格列净干预后可上调其表达水平;糖尿病小鼠存在肾脏超微结构损伤,恩格列净干预后可改善其病理损伤。结论恩格列净对肾脏保护作用之一可能是通过增加肾脏SMCT1的表达,SMCT1可能是治疗糖尿病肾脏病的一个新靶点。

恩格列净在射血分数降低型心力衰竭患者中的应用及其对心室重构的影响

目的探讨恩格列净治疗射血分数降低型心力衰竭患者的效果。方法选取江苏省东台市人民医院于2022年2月—2023年11月收治的60例射血分数降低型心力衰竭患者为研究对象,采用摸球法分为对照组(30例,常规治疗)与观察组(30例,常规治疗+恩格列净治疗)。比较两组患者的治疗效果。结果用药后3个月,观察组的氨基末端脑钠尿肽(N-Terminal Pro-Brain Natriuretic Peptide,NT-proBNP)以及估计肾小球滤过率(Estimated Glomerular Filtration Rate,eGFR)水平低于对照组,差异有统计学意义(t=15.024、4.561,P均<0.05)。观察组炎症因子相关指标以及心室重构相关指标水平均低于对照组,6 min步行试验(The 6-min Walking Distance,6MWD)数值高于对照组,差异有统计学意义(P均<0.05)。结论对射血分数降低型心力衰竭患者采用恩格列净治疗能够有效改善其心室重构。