Sodium glucose cotransporter-2 inhibitors and heart disease:Current perspectives

Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful in the prevention of CV disease(CVD)in patients with diabetes mellitus(DM).Although DM as such is a huge risk factor for CVD,the CV benefits of SGLT-2i are not just because of antidiabetic effects.These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well.There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated.Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases.This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

SGLT2抑制剂托格列净的研究进展

托格列净(Tofogliflozin)是一种口服活性小分子SGLT2抑制剂,由日本中外(Chugai)制药开发并用于2型糖尿病(T2DM)的治疗。托格列净对SGLT2的选择性抑制作用是SGLT1的2900多倍,与达格列净、坎格列净、伊格列净、伊帕列净和鲁格列净相比具有更强的选择性。本文对托格列净的发现、药效学、药代动力学、副作用及合成路线进行综述。

钠-葡萄糖共转运体2抑制剂在治疗2型糖尿病中的应用

糖尿病患者需要长期应用降糖药物控制血糖及防止并发症,因此研发疗效好、不良反应少的降糖药物尤为重要。钠-葡萄糖共转运体2(SGLT2)抑制剂为近些年来研究较多的一种用于2型糖尿病的新药物,有望在糖尿病患者的治疗中取得良好的效果。本文对该类药物的发展过程、代表药物、药理作用及不良反应等方面进行综述。

SGLT2抑制剂联合ARB治疗糖尿病肾脏病的临床疗效

目的探讨钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂联合血管紧张素Ⅱ受体拮抗剂(ARB)对治疗2型糖尿病肾脏病(DKD)的疗效。方法2型糖尿病性肾病患者90例,随机分为3组,每组各30例,分别接受厄贝沙坦(厄贝沙坦组)、恩格列净(恩格列净组)、厄贝沙坦联合恩格列净(联合治疗组)治疗,控制血糖水平一致,持续治疗12周,比较尿蛋白排泄率(UAE)、肾小球滤过率(eGFR)及体重等。结果治疗后三组UAE、尿蛋白定量较治疗前均有下降(P<0.05),联合治疗组UAE和尿蛋白定量较其他两组明显降低(P<0.05);治疗后三组eGFR均有下降,联合治疗组eGFR下降率高于其它两组(P<0.05);且治疗后恩格列净组和联合治疗组体重明显降低(P<0.05)。结论厄贝沙坦和恩格列净均能减少DKD患者的蛋白尿,联合治疗效果优于单用;联合治疗后eGFR下降更明显;恩格列净减重作用优于厄贝沙坦;降压效果厄贝沙坦优于恩格列净。

Synthesis and Crystal Structure of 2,3,4,6-tetra-O-Acetyl-1-{4-chloro-3-[1-(4-ethoxyphenyl)-1-methylethyl]phenyl}-1-deoxy-β-D-glucopyranose

The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction.The crystal is of monoclinic system（C31H37ClO10,Mr = 605.06）,space group P21 with a = 11.882（5）,b = 10.106（5）,c = 13.816（6）,V = 1545.9（12）（A°）^3,Z = 2,Dc = 1.300 g/cm^3,F（000） = 640,μ = 0.179 mm^-1,the final R = 0.0430 and wR = 0.0595 for 4960 observed reflections（I 〉 2σ（I））.The title compound was confirmed to be a β-anomer by single-crystal X-ray diffraction and 1H NMR.The proximal benzene ring is nearly orthogonal to the glucopyranoside ring,and the two benzene rings are also almost orthogonal to each other.Four non-classical intermolecular hydrogen bonds observed in the crystal lattice help to stabilize the crystal.

A Fluorescent Glucose Transport Assay for Screening SGLT2 Inhibitors in Endogenous SGLT2-Expressing HK-2 Cells

The sodium-dependent glucose transporters 2(SGLT2)plays important role in renal reabsorption of urinal glucose back to plasma for maintaining glucose homeostasis.The approval of SGLT2 inhibitors for treatment of type 2 diabetes highlights the SGLT2 as a feasible and promising drug target in recent years.Current methods for screening SGLT2 inhibitors are complex,expensive and labor intensive.Particularly,these methods cannot directly measure nonradioactive glucose uptake in endogenous SGLT2-expressing kidney cells.In present work,human kidney cells,HK-2,was incubated with a fluorescent D-glucose derivant 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose(2-NBDG)and the fluorescent intensity of 2-NBDG was employed to measure the amount of glucose uptake into the cells.By optimizing the passages of HK-2 cells,2-NBDG concentration and incubation time,and by measuring glucose uptake treated by Dapagliflozin,a clinical drug of SGLT2 inhibitors,we successfully developed a new assay for measuring glucose uptake through SGLT2.The nonradioactive microplate and microscope-based high-throughput screening assay for measuring glucose can be a new method for screening of SGLT2 inhibitors and implied for other cell assays for glucose measurement extensively.

Synthesis and Crystal Structure of Tianagliflozin Triacetate

The title compound tianagliflozin triacetate 1 was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal belongs to monoclinic system （C27H31C108, Mr = 518.97）, space group P21 with a = 5.3913（11）, b = 16.137（2）, c = 15.411（3） A, β = 94.15（3）°, V = 1337.3（5） A3, Z = 2, Dc = 1.289 g/cm3, F（000） = 548,μ = 0.190 mm1, the final R = 0.0374 and wR = 0.0809 for 3981 observed reflections （I 〉 2σ（I））. The structure of 1, triacetate of a highly potent SGLT2 inhibitor tianagliflozin, was unambiguously determined by single-crystal X-ray diffraction, which helped to confirm the desired fl configuration at the anomeric center and the position where the deoxylation occurred. The two benzene rings in the lattice are basically orthogonal to each other. There are four intermolecular hydrogen bonds in the crystal, which helps to further stabilize the crystal.

Synthesis and Crystal Structure of 2,3,4,6-Tetra-O-acetyl-1-{2-[(4-nitrophenoxy)methyl]-1,3,4-thiadiazole-5-thione-4-yl}-1-deoxy-β-D-glucopyranose

The title compound has been synthesized and its crystal structure was determined by single-crystal X-ray diffraction.The crystal is of orthorhombic system （C23H25N3O12S2,Mr=599.58）,space group P212121 with a=6.2102（12）,b=17.803（4）,c=24.223（5）,V=2678.0（9）3,Z=4,Dc=1.487 g/cm3,F（000）=1248,μ=0.268 mm-1,the final R=0.0483 and wR=0.1108 for 4174 observed reflections （I 〉 2σ（I））.The C=S bond,which parallels to the anomeric C-H,adopts α orientation relative to the anomeric position of glucopyranoside.

Canagliflozin Regulates Ferroptosis, Potentially via Activating AMPK/PGC-1α/Nrf2 Signaling in HFpEF Rats

Aims:Sodium-glucose cotransporter-2(SGLT2)inhibitors have been found to ameliorate major adverse cardiovascular events in patients with heart failure with preserved ejection fraction(HFpEF),but the exact mechanism is unknown.Ferroptosis is a form of programmed necrosis.Herein,we verified that canagliflozin(CANA)ameliorates heart function in HFpEF rats,partly by regulating ferroptosis,which may be activated by AMPK/PGC-1α/Nrf2 signaling.Methods:An HFpEF model was established and subjected to CANA treatment.Blood pressure was monitored,and echocardiography was performed at the 12th week.Pathological examination was performed,and expression of ferroptosis-associated proteins and AMPK/PGC-1α/Nrf2 signaling related proteins was detected.Results:CANA had an antihypertensive effect and increased E/A ratios in HFpEF rats.Myocardial pathology was ameliorated,on the basis of decreased cross-sectional area and intercellular fibrosis.Acyl-CoA synthetase longchain family member 4(ACSL4)expression increased,whereas ferritin heavy chain 1(FTH1)expression decreased in HFpEF rats,which showed iron overload.CANA reversed changes in ACSL4 and FTH1,and decreased iron accumulation,but did not alter glutathione peroxidase 4(GPX4)expression.The expression of AMPK/PGC-1α/Nrf2 signaling related proteins and heme oxygenase 1(HO-1)in the HFpEF group decreased but was reverted after CANA treatment.Conclusions:CANA regulates ferroptosis,potentially via activating AMPK/PGC-1α/Nrf2 signaling in HFpEF rats.

A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena

Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug,the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors(SGLT2i)showed efficacy in decreasing overall mortality,hospitalization,and sudden death in patients of this very population,in whom chronic or acute ischemia count among the first cause.Remarkably,this benefit was observed independently from diabetic status,and benefited both preserved and altered ventricular ejection fraction.This feature,observed in several large randomized controlled trials,suggests additional effects from SGLT2i beyond isolated glycemia control.Indeed,both in-vitro and animal models suggest that inhibiting the Na+/H+exchanger(NHE)may be key to preventing ischemia/reperfusion injuries,and by extension may hold a similar role in ischemic damage control and ischemic preconditioning.Yet,several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules.Because of a large therapeutic margin with few adverse events,ease of prescription and potential pharmacological efficacity,SGLT2i could be candidate for wider indications.In this review,we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation,by first listing known mechanisms,including metabolic switch,prevention of lethal arrythmias and others,which portend the latter,and second,hypothesize how the former may interact with these mechanisms.

Protective Effect of SGLT2 Inhibitor on D-Galactose-Induced Senescence in Mice and Its Mechanism

Objective: To observe the cerebral protective effect of dagliflozin, a sodium-glucose co-transport protein 2 (SGLT2) inhibitor, in aging mice and to explore its molecular mechanism. Methods: 1. 66 male C57BL/6 mice were divided into control group (13) and model group (53), and the model group was moulded by subcutaneous injection of D-galactose into the back of the neck, while the control group was treated with equal amount of saline for 8 weeks. The weight of each group of mice was observed and recorded every 7 days, and two groups of mice were randomly selected for frozen sections of brain tissue at the end of the modelling period to verify the aging model. 2. After the aging model was successfully established, the aging groups were divided into 5 groups: model group, dagliflozin-treated group (high and low dose), and dagliflozin + ex527-inhibited group (high and low dose). Fasting blood glucose was measured in each group every 2 weeks for 8 weeks. At the end of treatment, Morris water maze was performed at the end of the treatment. After execution of the mice, the organ indices of heart, brain, liver, kidney and spleen were measured;the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined. Results: After the successful establishment of the aging model, it was found that during the treatment phase of dagliflozin. 1) The organ indices of mice in the aging group were significantly lower than those of other groups, and no significant hypoglycemia was observed throughout the treatment process. 2) In the water maze test, mice in the aging group had a significantly longer latency in the plateau phase compared to the control and treatment groups, while the number of times the mice crossed the original plateau and the percentage of time spent exploring the original plateau quadrant were reduced after the plateau was removed. 3) The nerve cells in the aging mice were disorganized and the nuclei of the mice were deeply stained;the dagliflozin group improved the morphological changes in the brain of aging mice. 4) In addition, compared with the control mice, the serum MDA level was significantly increased and the antioxidant enzyme SOD activity was significantly decreased in the aging group, while compared with the aging group, dagliflozin significantly decreased the MDA level and increased the SOD activity. 5) The expression of SIRT1 and PGC-1α was significantly upregulated in the low and high doses of dagliflozin compared to the aging group. Conclusion: The present study suggests that dagliflozin can delay organ aging, improve the learning and memory ability of aging mice, and exert antioxidant effects, probably through upregulating the SIRT1/PGC-1α signaling pathway.

Safety of Empagliflozin in Patients with Type 2 Diabetes Mellitus in Saudi Arabia: A Post-Authorisation Safety Study

Background: Empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor is used as a monotherapy or in combination for lowering the elevated blood glucose level in patients with type 2 diabetes mellitus (T2DM). It is often associated with certain adverse reactions (urinary tract infection (UTI), diabetes ketoacidosis (DKA), and genital infections). Thus, the Saudi Food and Drug Administration requested a post-authorisation safety study to monitor the safety of empagliflozin during the defined observation period. Methodology: The local, comparator, non-interventional, regulatory post-marketing study using “new user” design was conducted in patients with T2DM, treated with empagliflozin (10 or 25 mg) and dipeptidyl peptidase-4 (DPP-4) inhibitors (NCT03764631). Study was conducted from 2018 to 2020, wherein each patient was followed up for 12 months after the index period. Incidence and occurrence of DKA, severe UTIs, volume depletion and dehydration were observed along with metformin, insulin and treatment complexity status and adverse events in the index and Ramadan period. All data collected were analysed using descriptive statistics. Results: Among the 1502 patients enrolled (empagliflozin [n = 751] and DPP-4 inhibitors [n = 751]), 0.1% patients (n = 1) in each group and Conclusion: Empagliflozin was well tolerated over a period of 12 months, with no safety concerns and a favourable benefit/risk ratio.

Metabolic and Renal Protective Benefits of Magnesium Supplementation in the Long-Term Management of Patients with Type 2 Diabetes Mellitus

Magnesium deficiency is common in patients with type 2 diabetes mellitus (type 2 DM). When adequate magnesium supplementation is chronically given, patients with type 2 DM appear to have improved glucose control and may have delayed chronic complications. In addition, magnesium supplementation may slow the progression of chronic kidney disease (CKD) and decrease the risk of contrast-induced nephropathy in patients with type 2 DM. Keeping serum magnesium at 2.0 mEq/L or greater appears to accomplish these benefits for patients with type 2 DM. Periodically measuring serum magnesium and estimated glomerular filtration rate (eGFR) allows a physician to adjust the supplemental magnesium dose to accomplish these therapeutic goals while avoiding hypermagnesemia.

New insights into the cardio-renal benefits of SGLT2 inhibitors and the coordinated role of miR-30 family

Sodium-glucose co-transporter inhibitors(SGLTis)are the latest class of anti-hyper-glycemic agents.In addition to inhibiting the absorption of glucose by the kidney causing glycosuria,these drugs also demonstrate cardio-renal benefits in diabetic subjects.miR-30 family,one of the most abundant microRNAs in the heart,has recently been linked to a setting of cardiovascular diseases and has been proposed as novel biomarkers in kidney dysfunctions as well;their expression is consistently dysregulated in a variety of cardio-renal dysfunctions.The mechanistic involvement and the potential interplay between miR-30 and SGLT2i effects have yet to be thoroughly elucidated.Recent research has stressed the relevance of this clus-ter of microRNAs as modulators of several pathological processes in the heart and kidneys,raising the possibility of these small ncRNAs playing a central role in various cardiovascular complications,notably,endothelial dysfunction and pathological remodeling.Here,we review current evidence supporting the pleiotropic effects of SGLT2is in cardiovascular and renal out-comes and investigate the link and the coordinated implication of the miR-30 family in endo-thelial dysfunction and cardiac remodeling.We also discuss the emerging role of circulating miR-30 as non-invasive biomarkers and attractive therapeutic targets for cardiovascular dis-eases and kidney diseases.Clinical evidence,as well as metabolic,cellular,and molecular as-pects,arecomprehensively covered.

SGLT2抑制剂联合二甲双胍治疗2型糖尿病的安全性和有效性的Meta分析

目的:系统评价钠葡萄糖共转运子2(SGLT2)抑制剂联合二甲双胍(MET)治疗2型糖尿病(T2DM)的疗效及安全性。方法:计算机检索PubMed、The Cochrane Library、EMbase、CNKI、WanFang Data、VIP和CBM,收集SGLT2抑制剂联合MET与单用MET比较治疗T2DM的随机对照试验,检索时限均为建库至2013年11月,并追溯纳入研究的参考文献。由两位研究者按照纳入与排除标准独立筛选文献、提取资料和评价质量后,采用RevMan 5.1软件进行Meta分析。结果:共纳入9个RCT,3 422例患者。Meta分析结果显示:SGLT2抑制剂联合MET组较单用MET组能更有效地改善糖化血红蛋白水平[WMD=-0.51%,95%CI(-0.61,-0.41),P<0.000 01]、空腹血糖水平[WMD=-1.21mmol/L,95%CI(-1.46,-0.95),P<0.000 01],减轻体重[WMD=-2.07kg,95%CI(-2.40,-1.73),P<0.000 01],降低收缩压水平[WMD=-2.89mmHg,95%(-4.33,-1.45),P<0.000 01]、舒张压水平[WMD=-1.61mmHg,95%CI(-2.55,-0.67),P=0.000 8];增加了发生生殖系统感染的风险[RR=2.34,95%CI(1.45,3.78),P=0.000 5],但在发生低血糖的风险[RR=0.96,95%CI(0.58,1.60),P=0.89]、泌尿系统感染的风险[RR=1.37,95%CI(0.97,1.95),P=0.08]、常见不良反应的风险[RR=1.12,95%CI(0.99,1.26),P=0.07]及至少发生一次严重不良事件的风险[RR=1.09,95%CI(0.73,1.62),P=0.69]方面差异无统计学意义。结论:SGLT2抑制剂联合MET是一种安全且有效的治疗T2DM的降糖方法。上述结论尚有待开展更多大样本、高质量研究予以证实。

SGLT2抑制剂在2型糖尿病伴中度肾功能损害人群中应用的Meta分析

目的:了解钠-葡萄糖协同转运蛋白2抑制剂(sodium-dependent glucose transporters 2 inhibitor,SGLT2i)在中度肾功能损害2型糖尿病(T2DM)患者中改善血糖的效果和对肾功能的影响。方法:检索PubMed,EMBASE,Cochrane Library以及临床试验注册网站和学术会议报告等截至到2018年2月的公开资料,纳入在肾功能损害人群中开展的SGLT2i随机对照试验(RCTs),并进行质量评价,按设计要求提取有效信息并进行Meta分析。结果:共纳入已注册上市的SGLT2i的6项RCTs研究。经Meta分析,与安慰剂相比,SGLT2i在获批准的最大剂量下使糖化血红蛋白(HbAlc)较基线变化-0. 25%(95%CI:-0. 39,-0. 12),其中只有恩格列净(empagliflozin)和卡格列净(canagliflozin)在血糖改善方面与安慰剂的差异有临床意义。敏感性分析发现,只有在剔除至少3项研究后才能使I2<50%。SGLT2i治疗后血糖、体重和估计的肾小球滤过率(eGFR)均有所下降,未观察到肾相关不良事件在SGLT2i和安慰剂之间的差异。结论:不同SGLT2i在中度肾功能损害T2DM患者中的疗效存在差异,只有恩格列净和卡格列净能显著改善血糖,其他SGLT2i与安慰剂相比,HbAlc的改善均无临床意义。尚未发现eGFR下降与疗效和肾脏不良事件的相关性。对于SGLT2i降糖药,临床医生在给肾功能损害患者处方时应按照不同药物的特点、依据说明书用法用量规范用药。

Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

Sodium-glucose cotransporter 2(SGLT2)inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive.Here we demonstrated that the SGLT2 inhibitor,Empagliflozin(EMPA),suppresses cardiomyocytes autosis(autophagic cell death)to confer cardioprotective effects.Using myocardial infarction(Ml)mouse models with and without diabetes mellitus,EMPA treatment significantly reduced infarct size,and myocardial fibrosis,thereby leading to improved cardiac function and survival.In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated,EMPA directly inhibits the activity of the Na^(+)/H^(+)exchanger 1(NHE1)in the cardiomyocytes to regulate excessive autophagy.Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis.In contrast,overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation,which was effectively rescued by EMPA treatment.Furthermore,in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA s cardioprotective effects are at least in part through downregulation of autophagic flux.These findings provide new insights for drug development,specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after Ml in both diabetic and non-diabetic patients.

Design,synthesis and biological activity of cyclohexane-bearing C-glucoside derivatives as SGLT2 inhibitors

Seven cyclohexane-bearing C-glucoside derivatives（7,9,12,13 and 17-19） were designed and synthesized as SGLT2 inhibitors starting from a potent SGLT2 inhibitor we discovered in earlier work, （lS）-1-deoxy-l-[4-methoxy-3-（trans-n-propylcyclohexyl）methylphenyl]-D-glucose（1）.The in vitro and in vivo biological activities were evaluated by hSGLT2/hSGLTl inhibition and urinary glucose excretion （UGE）,respectively.Among the synthesized compounds 12,the 6-deoxy derivative of 1 was the most active and selective SGLT2 inhibitor（IC_（50）= 1.4nmol/L against hSGLT2;selectivity = 1576）.Compound 12 was a potent SGLT2 inhibitor,which could induce more urinary glucose than 1 and dapagliflozin in UGE.

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

Structural modifications of 3-OH in the glucose moiety of dapagliflozin（1）, an approved potent sodium-dependent glucose transporter 2（SGLT2） inhibitor, led to 3-oxodapagliflozin（16）, a highly potent and more selective SGLT2 inhibitor[IC50（hSGLT1）/IC50（hSGLT2）=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin（16） exhibited in vitro（IC50=1.0nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1） and in vivo activities comparable to those of dapagliflozin（1）. The bioactivities of 3-oxodapagliflozin （16） warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.

Design,synthesis and in vivo anti-hyperglycemic activity of gem-dimethyl-bearing C-glucosides as SGLT2 inhibitors

A series of gem-dimethyl-bearing C-glucosides were designed and synthesized as SGLT2 inhibitors,with anhydrous aluminum chloride-mediated Friedel-Crafts alkylation to construct the gem-dimethyl functionality being the key step.The in vivo anti-hyperglycemic activity was evaluated with mice oral glucose tolerance test（OGTT）,and all the synthesized compounds showed significant but less potent anti-hyperglycemic activity than the positive control dapagliflozin.