Pharmacological profile of ASP8497, a novel,selective, and competitive dipeptidyl peptidase-IV inhibitor,in vitro and in vivo

Dipeptidyl peptidase (DPP)-IV is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibitors are expected to become a useful new class of antidiabetic agent. This report describes the pharmacological profile of the novel DPP-IV inhibitor, ASP8497 [(2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate], both in vitro and in vivo. ASP8497 inhibited DPP-IV in plasma from mice, dogs, and humans with median inhibition concentration (IC₅₀) values of 2.6 nM, 7.3 nM, and 6.2 nM, respectively. In contrast, ASP8497 did not potently inhibit human DPP8 or DPP9 activity (IC₅₀ = 1,700 nM and 100 nM, respectively) and exhibited selectivity against several proteases, including proline-specific proteases (IC₅₀ > 10 μM). Kinetic analysis indicated that ASP8497 is a competitive DPP-IV inhibitor. In normal mice, ASP8497 inhibited plasma DPP-IV activity even 12 h after administration. ASP8497 significantly inhibited increases in the blood glucose level during the oral glucose tolerance test (OGTT) conducted 0.5 h after administration. This was accompanied by increases in the plasma active GLP-1 and insulin levels. In addition, ASP8497 significantly inhibited increases in the blood glucose level during the OGTT conducted 8 h after administration. Furthermore, in Zucker fatty rats, ASP8497 dose dependently improved glucose tolerance with significance at doses of 1 mg/kg or higher. In contrast, ASP8497 did not cause hypoglycemia in fasted normal mice. These results indicate that ASP8497 is a potent, competitive, and selective DPP-IV inhibitor with antihyperglycemic activity.     

ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity

Dipeptidyl peptidase (DPP)-IV inhibitors are expected to become a useful new class of antidiabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, which is a novel DPP-IV inhibitor. ASP8497 inhibited DPP-IV in plasma from mice, rats, dogs and humans with IC(50) values of 3.86, 2.36, 5.53 and 5.30 nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC(50)>200 nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 (3 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30 mg/kg) did not cause hypoglycemia in fasted normal mice. Furthermore, administration of exogenous GLP-1 induced significant inhibition of gastric emptying and small intestinal transit rates, but ASP8497 (30 mg/kg) had no significant effects in normal mice. These present preclinical studies indicate that ASP8497 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.     

Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.     

Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes

Inhibition of dipeptidyl peptidase-4 (DPP-4) prevents the inactivation of glucagon-like peptide-1 (GLP-1). This increases circulating levels of active GLP-1, stimulates insulin secretion and inhibits glucagon secretion, resulting in lowering of glucose levels and improvement of glycemic control in patients with type 2 diabetes. Several DPP-4 inhibitors are emerging for therapeutic use. Most experience exists for sitagliptin, vildagliptin, saxagliptin and alogliptin. They all improve metabolic control in type 2 diabetes in monotherapy and in combination therapy with metformin, sulfonylurea and thiazolidinediones. Vildagliptin and alogliptin have also been shown to improve glycemic control when added to insulin therapy, and sitagliptin improves glycemic control in triple therapy with metformin plus thiazolidinedione. DPP-4 inhibition also shows a favorable safety profile, high tolerability, only a minimal risk of hypoglycemia, and body-weight neutrality. The main clinical indication for DPP-4 inhibitors will be in the early stage of type 2 diabetes, in combination with metformin or other treatments in subjects with inadequate glycemic control on these treatments alone. The durability and long-term safety of DPP-4 inhibition, as well as clinical positioning in relation to GLP-1 mimetics, remain now to be established.     

二肽基肽酶Ⅳ抑制剂的研究进展

胰高血糖素样肽-1(GLP-1)是一种肠促胰岛素,它通过刺激和保护胰岛B细胞,促进胰岛素的合成和分泌,降低餐后血糖.二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂能增强GLP-1的活性,降低2型糖尿病患者的高血糖症状,是一类新型的抗糖尿病治疗药物.临床研究表明DPP-Ⅳ单用或与二甲双胍、吡格列酮合用都有明显的降血糖作用,具有治疗效果显著、服用安全,耐受性好,不良反应少等特点,近年来已经成为糖尿病药物研究开发的热点.文中就其作用机制、国内外开发现状、构效关系及研究进展等进行综述.     

Alogliptin: a new,highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

Background: Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. Objective: To provide an overview of the mechanism by which alogliptin reduces hyperglycemia and to summarize the pharmacology, efficacy and safety of the drug. Methods: A Medline search was conducted and abstracts and presentations from recent American Diabetes Association and European Association for the Study of Diabetes (EASD) meetings were reviewed. The results of Phase II and Phase III human studies were evaluated for clinical efficacy, safety and tolerability in patients with type 2 diabetes. Results/conclusions: Alogliptin is effective as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin. It is well tolerated and has an excellent safety profile. Additional studies are needed to evaluate the long-term safety and efficacy of alogliptin.     

Nature of action of Sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals

Objective:

The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model.

Materials and Methods:

DPP-IV enzyme assay was carried out in human plasma (10 μL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC₅₀ values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC₅₀ values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o.

Results:

Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin.

Conclusion:

The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.     

胰岛素联合治疗的新选择——基础胰岛素+GLP-1受体激动剂

胰岛素治疗可提高外周葡萄糖的利用率, 减少肝糖原输出, 能有效降低空腹血糖, 但往往会引起低血糖、胰岛素抵抗等不良反应。胰高血糖素样肽-1（GLP-1)受体激动剂（GLP-1RA）和二肽基肽酶-4（DPP-4）抑制剂（DPP-4I）作为治疗2型糖尿病的新型药物也越来越受到关注。此类药物能够促进内源胰岛素的分泌, 抑制胰高血糖素的分泌, 同时还可延缓胃排空时间、增加饱腹感、降低食欲, 从而有效地降低餐后血糖, 其与胰岛素联合应用, 可扬长避短, 发挥协同互补的作用, 同时降低低血糖风险。从用药前后糖化血红蛋白的变化和低血糖的发生率方面论述GLP-1RA和DPP-4I对胰岛素血糖控制不良的2型糖尿病患者的有效性和安全性,以期为临床治疗提供参考。

     

Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients

Aims: To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM).

Methods and materials: We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link.

Results: The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9?mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses.

Limitations: Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results.

Conclusions: Our research suggests that liraglutide 0.9?mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.     

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: comparison,efficacy and safety

Introduction: Dipeptidyl peptidase (DPP)-4 inhibitors belong to one class of drugs that have been approved for treatment of type 2 diabetes (T2D) based on the glucose-lowering actions of the gastrointestinal hormone glucagon-like peptide (GLP)-1. Several different compounds are now available, and although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them.

Areas covered: The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov.

Expert opinion: Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy. They improve glycaemic control in T2D, without increasing the risk of hypoglycaemia or causing weight gain. They can be used as monotherapy or in combination with other anti-diabetic therapies, including insulin, regardless of renal or hepatic function, and are efficacious across the spectrum of patients with T2D, including those with long-standing disease duration. DPP-4 inhibitors may also have beneficial effects beyond glycaemic control, although this remains to be demonstrated in purpose-designed clinical trials.     

人胰高血糖素样肽-1类似物基因治疗对糖尿病大鼠机体代谢的影响

目的观察人胰高血糖素样肽-1(hGLP-1)类似物基因(2×Val2-hGLP-1)对糖尿病大鼠模型机体代谢的影响。方法建立糖尿病大鼠模型,尾静脉注射携带hGLP-1类似物基因的重组表达载体(pIRES2-EGFP/Val2-hGLP-1),观察30d,期间测定相关指标。结果治疗后糖尿病大鼠体重、进食及饮水量改善明显(P<0.01)。治疗15d后,血糖水平由(27.06±1.73)mmol/L降至(17.57±2.17)mmol/L(P<0.01),血清胰岛素水平由(5.53±0.79)mIU/L升高至(9.88±0.96)mIU/L(P<0.01)。总胆固醇水平降低(P<0.05或P<0.01)。hGLP-1蛋白在胰腺、肝、肾、肌肉组织中表达。结论 hGLP-1类似物基因可导入糖尿病大鼠体内并成功表达,基因治疗降低大鼠血糖,血脂水平,改善大鼠的机体代谢。     

Preclinical development of dipeptidyl peptidase IV inhibitor alogliptin: a brief overview

Introduction: Alogliptin is a pyrimidinedione-based potent and selective inhibitor of DPP IV that was discovered by Syrrx (Takeda San Diego) for the treatment of type 2 diabetes mellitus (T2D). Alogliptin is currently launched in Japan with the results of its clinical trials indicating that it is generally well tolerated and shows relatively fewer adverse side effects than other existing therapies for T2D.

Areas covered: The objective of the present review is to provide an overview of the various stages of preclinical development, for example, design, molecular modeling studies, synthesis and in vitro/in vivo pharmacological evaluation of alogliptin. An extensive literature search was conducted to collect abstracts, publications, patents and presentations from various sources. The authors review the information related to the preclinical development of alogliptin and summarize and present the relevant results.

Expert opinion: Alogliptin has shown greater in vitro selectivity for DPP IV over closely related enzymes, including DPP VIII and DPP IX, in comparison with other launched DPP IV inhibitors such as sitagliptin, saxagliptin and vildagliptin. Alogliptin has been evaluated in different diabetic animal models and is found to reduce glycosylated hemoglobin, plasma glucose, glucagon and triglycerides levels. Alogliptin also ameliorates β-cell function, with a significant increase in plasma insulin levels. The authors believe that this potent and selective inhibitor of DPP IV could compete with traditional oral anti-diabetic therapies in the future.     

Linagliptin,a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes

Importance of the field: Type 2 diabetes is a progressive disease for which current treatments are often unsatisfactory with respect to achieving therapeutic goals and unwanted side effects.

Areas covered: Preclinical and clinical studies of linagliptin, a new oral antidiabetic agent, including data presented at Scientific Meetings and peer-reviewed studies published since 2007.

What the reader will gain: This article reviews pharmacokinetic and pharmacodynamic characteristics of linagliptin. Linagliptin belongs to a new chemical class of dipeptidyl pepidase-4 (DPP-4) inhibitors, which comprise xanthine-based compounds. It is a potent, long-acting inhibitor with high selectivity for DPP-4 versus the related enzymes DPP-8 and DPP-9. The drug has modest oral availability in humans, but is absorbed rapidly to inhibit plasma DPP-4 activity by > 80% over 24 h. It is not metabolized appreciably in vivo, but binds extensively to plasma proteins, with elimination occurring primarily in the liver. Linagliptin reduces degradation of the incretin hormone glucagon-like peptide-1 and is associated with reduced fasting and postprandial glucose in preclinical and clinical studies. Limited data from longer duration clinical trials show it improves glycemic control in patients with type 2 diabetes.

Take home message: Linagliptin is a new oral antidiabetic agent associated with minimal risk of hypoglycemia, which holds promise for treatment of type 2 diabetes.     

Diabetes: the latest developments in inhibitors,insulin sensitisers,new drug targets and novel approaches

The 6th annual conference on diabetes, organised by the SMI group, was held on 18th – 19th October 2004 in London, followed by a one-day symposium on an executive briefing entitled Type 2 diabetes and beyond: the untapped commercial potential. More than 100 delegates from both academic and industrial institutes attended the two meetings. The presentations provided insights into the understanding of mechanisms and developments of novel drugs for treatments of insulin resistance, diabetes, and metabolic syndrome, as well as new approaches for therapeutic intervention including the development of dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues. This review offers a general overview of the fields in metabolic diseases and different strategies to develop new drugs. Discussions focused on several emerging therapeutic areas, including novel compound developments and target identification with the use of conventional methods and recently emerged technologies, such as siRNA, genomics and pro-teomics.     

重组人胰高血糖素样肽-1对实验性糖尿病大鼠血糖的影响

目的观察重组人胰高血糖素样肽 1[rhGLP 1(7 36 )NH2 和rhGLP 1(7 37) ]对实验性糖尿病大鼠模型血糖和血浆胰岛素水平的影响。方法正常SD大鼠按 3.2 4g/kg腹腔注射 5 0 %葡萄糖 ,诱发暂时性高血糖动物模型。腹腔注射不同剂量 (2 0、4 0、80 μg/kg)rhGLP 1(7 36 )NH2 和rhGLP 1(7 37) ,间隔取血测定血糖与血浆胰岛素水平。正常SD大鼠按 6 0mg/kg腹腔注射链脲佐菌素 ,建立实验性 1型糖尿病大鼠模型。静脉输注rhGLP 1(7 36 )NH2 [4.0ng/(kg·min) ]12 0min并观察血糖变化。结果腹腔注射 4 0、80 μg/kgrhGLP 1(7 36 )NH2 和rhGLP 1(7 37)处理组大鼠的血糖、血浆胰岛素水平与对照组之间的差别具有非常显著性意义 (P <0 .0 0 1) ,且呈现一定的量效关系。二者之间促胰岛素分泌和降血糖活性差异无显著性。静脉输注rhGLP 1(7 36 )NH2 6 0min后 ,血糖水平 (17.0 4± 1.31)mmol/L(P <0 .0 5 ) ,12 0min后血糖水平 (11.98± 1.0 5 )mmol/L(P <0 .0 0 1)。结论rhGLP 1能显著改善实验性糖尿病大鼠的血糖水平 ,这与其促胰岛素分泌活性有关。     

Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor,improves metabolic control in diabetic rodent models

Aim:

Dipeptidyl deptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents. The purpose of this study was to assess the acute and chronic effects of SHR117887, a novel DPP-4 inhibitor, on metabolic control and pancreatic β-cell function in normal or diabetic rodent models.

Methods:

In the acute experiments, ICR mice, diet-induced obese (DIO) rats and ob/ob mice were subjected to an oral glucose tolerance test (OGTT) following a single oral administration of SHR117887 (0.1, 0.3, 1 or 3 mg/kg). Blood samples were collected to measure glucose, insulin, DPP-4 activity and active GLP-1 level. In the chronic experiments, ob/ob mice was administered SHR117887 (3, 10 or 30 mg/kg) twice daily for 33 d to assess the effects on metabolic control and pancreatic β-cell function. Vildagliptin (LAF237) was used as a positive control in all the experiments.

Results:

Acute oral administration of SHR117887 dose-dependently decreased the serum DPP-4 activity and improved glucose tolerance in ICR mice, DIO rats and ob/ob mice. This was accompanied by significant increases in the serum active GLP-1 and insulin levels. Chronic administration of SHR117887 significantly decreased fasting blood glucose level and improved the lipid profiles in ob/ob mice by reducing the serum triglyceride and free fatty acid levels, and its efficacy was comparable with that of vildagliptin at the same molarity. Moreover, chronic administration of SHR117887 increased the insulin staining of islet cells, which is suggestive of improved β-cell function.

Conclusion:

SHR117887 is a potent DPP-4 inhibitor that improves metabolic control and β-cell function in diabetic rodent models, suggesting that it could be a new therapeutic agent for the treatment of type 2 diabetes.     

Novel N-substituted-2-cyanopyrrolidines as potent inhibitors of dipeptidyl peptidase IV in the treatment of non-insulin-dependent diabetes mellitus

This is the second patent application from Novartis describing N-substituted-2-cyanopyrrolidines as inhibitors of dipeptidyl peptidase IV (DPP-IV). DPP-IV is a serine protease which cleaves Xaa-Pro- or Xaa-Ala- amino terminal sequences from biologically active peptides, transforming them into inactive or even antagonistic species. Among them is glucagon-like peptide 1 (GLP-1), a major stimulator of pancreatic insulin secretion with additional properties in lowering the blood glucose level, which is normally secreted in response to food ingestion. By inhibiting DPP-IV the endogenous GLP-1 is preserved for longer periods, the inhibitors being useful in the treatment of the non-insulin-dependent diabetes mellitus (NIDDM), obesity, arthritis, osteoporosis and other diseases generated or enhanced by impaired glucose tolerance. The compounds claimed in this application are novel N-substituted 2-cyanopyrrolidines bearing adamantyl moieties as biocompatible lipophylic groups; their low nanomolar level of DPP-IV inhibition, as well as their in vivo therapeutic profile, are improved as compared with the results obtained in previous studies.     

前胰高血糖素样肽-1对非糖尿病小鼠降糖作用的实验研究

摘要目的：观察胰高血糖素样肽-1（glucagon—likepeptide-1，GLP-1）的前体药物前胰高血糖素样肽-1（Pro-GLP-1）对非糖尿病小鼠的血糖和血清胰岛素水平的影响。方法：C57BL／6小鼠皮下注射不同剂量Pro-GLP-1，不同时间间隔取血测定血糖及血清胰岛素水平。结果：非糖尿病小鼠注射Pro-GLP-1后，血糖血清和胰岛素水平均无明显改变；给予糖负荷后的小鼠Pro—GLP-1呈剂量依赖性降低血糖浓度，同时升高血清胰岛素水平。等剂量Pro-GLP-1的降糖作用较GLP-1作用强。于第一次糖负荷后150min给予第二次糖负荷，Pro—GLP-1仍能发挥其降糖作用。结论：Pro—GLP-1通过葡萄糖依赖方式促进胰岛素分泌，剂量依赖性降低过高血糖，不降低正常血糖，其降糖作用可以维持3h以上。     

GLP-1受体激动剂和DPP-4抑制剂对心血管系统的保护作用

胰高糖素样肽1(GLP-1)受体激动剂和二肽基肽酶-4(DPP-4)抑制剂是近年上市的治疗2型糖尿病的新型药物。GLP-1主要通过抑制心肌细胞凋亡、改善内皮细胞功能、减轻体重、降低血糖、降低血压、改善心肌收缩力、舒张血管等直接或间接发挥其心脏保护作用,GLP-1受体激动剂和DPP-4抑制剂对体重、血压和血脂等心血管危险因素有改善作用。GLP-1受体激动剂和DPP-4抑制剂作用于新靶点,具有其独特的优点,将会是一类抗糖尿病新药。