钠-葡萄糖共转运蛋白2抑制剂对伴有严重肾功能不全的2型糖尿病患者心血管保护作用的Meta分析

目的 评价钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2,SGLT2)抑制剂对伴严重肾功能不全的2型糖尿病患者(diabetes mellitus type 2,T2DM)心血管保护作用及其不良反应.方法 检索Medline、Embase和Cochrane Library数据库,收...     

胰高糖素样多肽-1及受其体激动剂对2型糖尿病心血管病变的影响

随着人民生活水平的提高,我国2型糖尿病(T2DM)的患病率逐年上升,因糖尿病并发症而死亡的人数也逐年增多,其中,心血管并发症是T2DM患者的主要死亡原因。作为治疗T2DM的新药——胰高糖素样多肽-1(GLP-1)及其受体激动剂最近备受关注。研究表明,GLP-1受体激动剂不仅能够刺激胰岛素分泌、抑制胰高糖素分泌,减少肝糖输出,改善外周组织对胰岛素的敏感性,延缓胃排空,抑制食欲及摄食,而     

GLP-1受体激动剂联合二甲双胍治疗2型糖尿病合并代谢相关脂肪性肝病的荟萃分析

目的系统评价胰高血糖素样肽-1(GLP-1)类似物联合二甲双胍治疗2型糖尿病(T2DM)合并代谢相关脂肪性肝病(MAFLD)的临床疗效及安全性。方法通过检索PubMed、Cochrane、Embase、中国知网、万方、维普、CBM等数据库中GLP-1受体激动剂联合二甲双胍治疗T2DM合并MAFLD的全部随机对照试验(RCTs)的文献,时间截止至2021年4月,对所纳入的文献进行数据提取,并使用Cochrane量表进行质量评价,使用RevMan 5.3软件进行分析。结果共纳入7篇RCTs,均为中文文献,共计640例患者,其中试验组给予GLP-1类似物联合二甲双胍进行干预,对照组单独给予二甲双胍进行干预。最终Meta分析结果显示,试验组在降低空腹血糖(FBG)、糖化血红蛋白(HbA1c)、三酰甘油(TG)、总胆固醇(TC)、丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)水平方面优于对照组,差异有统计学意义(P<0.01,P<0.05);试验组不良反应发生率与对照组相比差异无统计学意义(P>0.05)。结论 GLP-1受体激动剂联合二甲双胍治疗T2DM合并MAFL...     

钠-葡萄糖协同转运蛋白2抑制剂对糖尿病肾病保护作用的研究进展

糖尿病肾病(diabetic nephropathy, DN)是糖尿病最严重的微血管并发症之一,现已成为终末期肾脏病的重要病因,因此防治DN的发生和发展是当今需要迫切解决的重要课题。钠-葡萄糖协同转运蛋白2(sodium-dependent glucose transporters 2, SGLT2)抑制剂(SGLT2 inhibition, SGLT2i)是一种新型降糖药物,可通过抑制肾脏近端小管的重吸收和促进尿中葡萄糖的排泄来降低血糖,被广泛用于2型糖尿病(diabetes mellitus type 2,T2DM)的治疗。SGLT2i不仅可以降低血糖,还可以保护肾脏,延缓肾功能衰竭的进展,改善患者生活质量。本文就SGLT2i对DN的肾脏保护作用机制作一综述,为DN的预防、治疗及新型降糖药物的应用提供理论基础。     

钠-葡萄糖协同转运蛋白2抑制剂对IgA肾病肾脏保护作用的研究进展

IgA肾病(IgA nephropathy, IgAN)是我国最常见的原发性肾小球疾病,也是引起终末期肾病(end-stage renal disease, ESRD)的重要原因,可发生于任何年龄段,但以青年男性最为多见。钠-葡萄糖协同转运蛋白2(sodium-glucose transporter 2,SGLT2)抑制剂是一种新型降糖药物,已在2型糖尿病(diabetes mellitus type 2,T2DM)患者中广泛应用。随着认识的不断深入,研究发现SGLT2抑制剂不仅可降低IgAN患者尿蛋白与血压、调节肾脏血流动力学、控制尿酸及体重,甚至对肾脏炎症及纤维化也有着积极的影响,可通过多种途径对肾脏起保护作用,有望治疗和延缓IgAN。本文通过对SGLT2抑制剂对IgAN肾脏保护的研究进展进行综述,旨在提供理论依据。     

铁代谢与2型糖尿病相关性及胰高血糖素样肽-1调控作用的研究进展

铁代谢在多种代谢性疾病中发挥调控作用,过量铁积累会增加代谢性疾病尤其是2型糖尿病(T2DM)的发生风险。铁沉积、铁过载和铁死亡等病理过程可激活氧化应激、脂质过氧化、细胞自噬等,促进机体炎症反应级联放大和抗氧化能力降低,使胰岛β细胞功能逐渐衰退,从而促进T2DM的发生发展。胰高血糖素样肽-1(GLP-1)是由肠道L细胞分泌的一种生理性激素,GLP-1类似物或GLP-1受体激动剂可调节机体铁代谢过程,抑制铁沉积、铁过载和铁死亡相关炎症反应,促进胰岛β细胞增殖及分化,进而减轻胰岛素抵抗,抑制内皮细胞损伤,在T2DM及其并发症的防治中发挥重要作用。     

GLP-1受体激动剂和DPP-4抑制剂分别联合二甲双胍治疗T2DM的疗效及对血清抗氧化因子、炎症因子的影响

目的 对比胰高血糖素样肽-1(GLP-1)受体激动剂和二肽基肽酶-4(DPP-4)抑制剂分别联合二甲双胍治疗2型糖尿病(T2DM)的疗效及对其血清抗氧因子、炎症因子的影响。方法 将2020年5月至2022年5月中国中医科学院广安门医院南区收治的120例T2DM患者纳入本次前瞻性研究,采用随机数字表法分成GLP-1联合组(n=40)、DPP-4联合组(n=40)和对照组(n=40)。GLP-1联合组患者治疗方案为二甲双胍治疗+利拉鲁肽,DPP-4联合组患者治疗方案为二甲双胍+沙格列汀,对照组患者仅口服二甲双胍治疗。治疗为期6个月。比较3组患者治疗前后的血糖相关指标[空腹血糖、餐后2 h血糖(2 h PPG)、糖化血红蛋白(HbA1c)]及胰岛素抵抗指数(HOMA-IR)、氧化应激指标[超氧化物歧化酶(SOD)和6-酮-前列环素F1α(6-Keto-PGF1α)]和炎症因子[肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)和超敏C反应蛋白(hs-CRP)]表达情况。结果 GLP-1联合组治疗后的空腹血糖、2 hPPG、HbA1c和HOMA-IR分别为(5.05±0.69) mmo...     

2型糖尿病降糖药物治疗进展

2型糖尿病(T2DM)是一种慢性疾病,是全球重要的公共卫生问题,也是患者致残、致死的主要原因。T2DM具有多重发病机制,因此糖尿病治疗应尽可能针对多种病因进行治疗,尽量逆转已知的病变,同时尽早预防和治疗糖尿病相关并发症。近些年,很多新型降糖药物不断涌现,与传统的降糖药物相比,前者更多兼顾了药物的简便性、安全性、有效性以及多靶点作用机制,同时也兼顾了心肾保护等作用,考虑了糖尿病并发症的获益因素。有些新型降糖药如胰高血糖素样肽1受体激动剂(GLP-1RA)和钠-葡萄糖协同转运蛋白2抑制剂(SGLT-2i)的治疗地位在多项指南中也得到了重要提升。本文系统地回顾了现有的降糖药物,并对目前的新型降糖药物作了详细的介绍。     

胰高血糖素样肽-1受体激动剂对初发2型糖尿病患者血脂代谢影响的研究

目的：本课题观察胰高血糖素样肽-1（ GLP-1）受体激动剂对2型糖尿病患者的治疗,通过对转氨酶、糖化血红蛋白、血脂及脂质运载蛋白-2的检测,探讨胰高血糖素样肽-1受体激动剂与血脂代谢间的关系,从而更有利于对2型糖尿病患者慢性并发症的控制。方法给药方法：两组初发2型糖尿病患者均口服二甲双胍1500 mg,根据治疗方式不同随机分成两组：二甲双胍联合GLP-1组（GL）24例,二甲双胍联合生理盐水组（ NS）24例,共给药16周。试验中随访体重指数、转氨酶、糖化血红蛋白、血脂及载脂蛋白-2。试验前3周为导入期,均注射生理盐水1 ml,皮下注射;第4～7周GL组给予GLP-1受体激动剂5μg,每日2次;第8～16周给予GLP-1受体激动剂10μg,每日2次。结果（1）两组体重、体重指数、糖化血红均降低（ P＜0.05）。（2）GL组甘油三酯、总胆固醇、低密度脂蛋白、载脂蛋白-2明显降低（P＜0.05）,NS组无明显降低（P＞0.05）。（3）GL组转氨酶明显降低（P＜0.05）。结论二甲双胍或二甲双胍联合应用GLP-1受体激动剂均可降低初发2型糖尿病患者的体重及糖化血红蛋白。 GLP-1可更加显著地降低糖尿病患者甘油三酯、总胆固醇、低密度脂蛋白、脂质运载蛋白-2的水平。     

胃转流术后非肥胖2型糖尿病患者血清胰高血糖素样肽-1浓度变化的研究

目的 研究胃转流(GBP)术后非肥胖2型糖尿病(T2DM)患者血清胰高血糖素样肽-1(GLP-1)浓度的变化,初步探讨GBP术后胃肠道肠促胰岛素的降糖机制.方法 选自接受GBP术的非肥胖T2DM患者28例；同期住院的28例非糖尿病患者.检测非肥胖T2DM患者及非糖尿病患者空腹及餐后2h血清胰高血糖素样肽-1( GLP-1)浓度,进行比较.非肥胖T2DM患者分别于术前、术后1周、术后1个月、术后3个月、术后6个月时检测口服葡萄糖耐量试验( OGTT)、空腹及餐后2·h血清GLP-1浓度,术后各时间点血清GLP-1浓度与术前进行比较.结果 非肥胖T2DM患者GBP术后3个月、术后6个月空腹及餐后1h.2h血糖水平较术前明显下降(P＜0.05)；非肥胖T2DM患者GBP术后1周、术后1个月、术后3个月、术后6个月检测空腹及餐后2h血清GLP-1浓度均高于术前；随着术后时间的延长,血清GLP-1浓度呈增高趋势,直至术后6个月最高(手术前后空腹比较P=0.045,手术前后餐后2h比较P=0.048).结论 GBP术后血清GLP-1浓度增加可能是治疗非肥胖T2DM的机制之一.     

Complementing Insulin Therapy to Achieve Glycemic Control

Introduction

Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy.

Methods

A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included “insulin combination therapy,” “add-on therapy diabetes,” “dipeptidyl peptidase-4 (DPP-4) inhibitors,” “glucagon-like peptide-1 (GLP-1) receptor agonist,” “sodium-glucose cotransporter 2 (SGLT2) inhibitors”, “insulin metformin,” “insulin sulfonylurea,” and “insulin thiazolidinedione.” Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed.

Results

Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight.

Conclusion

GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies.     

Ramping Glucosuria for Management of Type 2 Diabetes Mellitus: An Emerging Cynosure

Chronic hyperglycemia is a characteristic feature of type 2 diabetes mellitus (T2DM). The kidney plays a vital role in maintaining blood glucose homeostasis by recovering glucose from glomerular filtrate which is controlled by SGLT2 cotransporters expressed mainly in proximal tubule. In T2DM patients, inhibition of SGLT2 normalizes glycemic levels by preventing glucose from being reabsorbed through SGLT2 and re‐entering the circulation. Thus, SGLT2 inhibition seems to be a logical approach and pose a novel insulin‐independent mechanism of action for management of T2DM by promoting urinary glucose excretion in the body. Canagliflozin is the first SGLT2 inhibitor approved by US Food and Drug Administration (US FDA) followed by dapagliflozin while empagliflozin is under FDA review. Various other drug candidates in late‐stage clinical developments are also expected to hit the global markets in the coming years. In this review, studies on various early‐ and late‐stage SGLT2 inhibitors have been investigated and recent clinical developments summarized.     

Impact of EMPA-REG OUTCOME® on the management of type 2 diabetes mellitus: a review for primary care physicians

Cardiovascular (CV) disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Most published trials of glucose-lowering agents have shown no significant CV benefit or increased risk of death or heart failure, with the exception of metformin. Three novel classes of glucose-lowering agents, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium glucose cotransporter 2 (SGLT2) inhibitors, have been approved by the U.S. Food and Drug Administration for the treatment of T2DM in the United States and have also been available in other parts of the world in the past decade. Of the SGLT2 inhibitors, empagliflozin has demonstrated a CV benefit in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME®) while trials with other SGLT2 inhibitors are still ongoing. Empagliflozin has also provided possible renal protective benefit in those with mild-to-moderate renal impairment. The mechanisms behind the benefits seen with empagliflozin are likely multifactorial. Empagliflozin is the reasonable choice for add-on therapy in patients with long-standing T2DM who are at high CV risk as demonstrated in the EMPA-REG OUTCOME® study.     

Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus

Objective. To review the efficacy, safety, and tolerability of combination treatment regimens including a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). Methods. Clinical trials of combination therapies including a DPP-4 and/or SGLT2 inhibitor were identified through a PubMed database search. To be included, studies had to have a primary end point of change from baseline to ≥24 weeks in glycated hemoglobin, include ≥1 other oral antidiabetic drug (OAD), and have randomized more than 200 patients. Results were limited to medications approved by the US Food and Drug Administration at the time of the search (March 2015). Results. A total of 1534 articles for the DPP-4 inhibitor class and 434 articles for the SGLT2 inhibitor class were retrieved from PubMed. Of these, 33 articles from the DPP-4 inhibitor class and 24 articles from the SGLT2 inhibitor class were included for review. In each study, the addition of a DPP-4 or SGLT2 inhibitor as a second or third agent resulted in improved glycemic control versus comparator arms. Reductions in weight or lack of weight gain were consistently observed, as were low rates of hypoglycemic events, particularly when the combination regimen also included metformin. Overall, the pattern of adverse events observed in combination treatment groups was consistent with the known effects of the individual agents. Conclusion. Combination treatment with a DPP-4 and/or SGLT2 inhibitor is an efficacious option for patients with T2DM starting pharmacological therapy, or for patients who have received treatment but require additional glycemic control. Study findings indicate that the underlying mechanisms of action of DPP-4 inhibitors and SGLT2 inhibitors complement a variety of OADs.     

Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers

Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and elevates individuals’ risk for cardiovascular disease, the leading cause of morbidity and mortality in T2DM. Achieving and maintaining tight glycemic control is key to preventing development or progression of CKD; however, improving glycemic control may be limited by effects of renal impairment on the efficacy and safety of T2DM treatments, necessitating dosing adjustments and careful evaluation of contraindications. Understanding the treatment considerations specific to each class of T2DM medication is important in individualizing therapy and improving glycemic, renal, and cardiovascular outcomes.

Traditional glucose-lowering treatments include insulin, metformin, sulfonylureas, meglitinides, and thiazolidinediones. Each of these agents exhibits altered pharmacokinetics in patients with renal impairment except for the thiazolidinediones, which are metabolized by the liver and do not accumulate appreciably in patients with renal impairment. Newer glucose-lowering treatments include GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors. Of these, only the DPP-4 inhibitor linagliptin can be used across all stages of renal impairment without dosing restrictions or concerns regarding dose escalation, and all SGLT2 inhibitors are contraindicated when eGFR <45 mL/min/1.73m². Several of the newer treatments have also been investigated for effects on renal and cardiovascular outcomes, demonstrating potential benefits of the GLP-1 agonists liraglutide and semaglutide, as well as the SGLT2 inhibitors canagliflozin and empagliflozin, in reducing risk for some adverse renal and cardiovascular events. In addition, some DPP-4 inhibitors have been shown to reduce albuminuria, an indicator of glomerular dysfunction. Consideration of this information is useful in informing optimal management strategies for patients with T2DM and concomitant CKD. More clinical data from future and ongoing clinical trials, including data regarding potential renal and cardiovascular benefits, will be important in clarifying the safety and efficacy profiles of each of these agents in patients with CKD.     

LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.     

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

BACKGROUNDFulminant 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 islet β cells. 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 sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy.CASE SUMMARYThe 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.CONCLUSIONThis 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.     

Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium–glucose co-transporter 2 inhibitors

Elevated hemoglobin A_1c (HbA_1c) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors.

• Key messages

• Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs.

• The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium–glucose co-transporter 2 (SGLT2) inhibitor.

• SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM.