DPP-4抑制剂在2型糖尿病治疗中的应用

胰升糖素样肽1(GLP-1)可通过多个途径参与机体血糖稳态调节、改善胰岛功能、延缓甚至逆转2型糖尿病病程的进展.但内源性GLP-1在分泌释放入血后快速被二肽基肽酶4(DPP-4)裂解而失去活性.DPP-4抑制剂可选择性抑制DPP-4的酶活性,阻止GLP-1裂解失活,提高活性GLP-1的血浆水平,增强其生理作用,降低2型糖尿病患者的HbA1.、空腹血糖和餐后血糖水平.DPP-4抑制剂作为一类新型口服降糖药物,在2型糖尿病治疗中对血糖控制的有效性、良好的安全性和耐受性已经在大量的临床试验和实际应用中得到了证实.

Abstract：

Glucagon-like peptide-1 (GLP-1) can maintain glucose homeostasis, improve islet function,delay and even reverse deterioration of type 2 diabetes by several pathways.But shortly after secreting and releasing into the blood, endogenous intact GLP-1 is cleavaged by dipeptidyl peptidase-4 (DPP-4) into inactive forms.DPP4 inhibitors prevent the inactivation and enhance the physiological effects of GLP-1 through selectively suppressing the enzymic activity of DPP-4, resulting in reduction of HbA1C, fasting and postprandial plasma glucose in type 2diabetes mellitus.The favorable efficacy, safety, and tolerability of DPP-4 inhibitors, which have been well verified in numerous clinical trials and clinical practice for type 2 diabetes mellitus, render them a novel type of oral antidiabetic drugs.     

DPP-4抑制剂在2型糖尿病中的研究进展

2型糖尿病是一种慢性进展性疾病,诊断初期患者的胰岛β细胞功能即损失50％以上.肠促胰岛激素效应的发现和应用是近年来糖尿病治疗方面较新的研究领域之一,它是人类进食后由肠道内分泌L细胞分泌的一类激素,主要包括胰升糖素样肽1(GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(GIP),可以帮助机体产生部分餐后胰岛素效应.GLP-1是目前已知的最强的刺激胰岛素释放的物质之一,但是由于GLP-1的血浆半寿期很短(＜2分钟),体内一种蛋白酶-二肽基肽酶4(DPP-4)可裂解GLP-1氨基端的脯氨酸和丙氨酸,从而使GLP-1迅速降解,生物活性丧失.随着对糖尿病病理生理机制和肠促胰岛激素生理作用的深入研究,DPP-4抑制剂作为一种基于肠促胰岛激素机制的药物,给2型糖尿病的治疗提供了新的方法.我们就DPP-4抑制剂在2型糖尿病中的应用和研究进展作一综述.     

DPP-4抑制剂类药物在2型糖尿病治疗中的效果和经济性分析

目的 探究DPP-4抑制剂类药物在2型糖尿病治疗中的效果和经济性分析.方法 选取2018年12月—2019年12月于该院进行治疗的2型糖尿病患者30例,按照随机数字表法分为观察组及对照组,两组各15例.观察组选择格列美脲和DPP-4抑制剂类药物西格列汀联合治疗,对照组单纯性增加格列美脲剂量治疗.对比两组临床疗效、生活质...     

DPP-4抑制剂西格列汀对2型糖尿病患者的治疗作用

目的 探讨服用DPP-4抑制剂西格列汀对糖尿病患者空腹及餐后血糖、糖化血红蛋白(HbA1c)等的影响及临床不良反应发生情况.方法 已确诊的2型糖尿病(T2DM)患者60例随机分为西格列汀组与阿卡波糖组,治疗观察时间12w.比较治疗前后各项指标变化情况.结果 西格列汀治疗后,空腹及餐后2h血糖、HbA1c均较治疗前明显下降(P＜0.05).治疗期间未出现低血糖及其他临床不良反应.结论 西格列汀对于降低糖尿病患者的空腹及餐后血糖效果良好,对于HbA1c的达标有重要意义.     

DPP-4抑制剂治疗新诊断2型糖尿病的疗效分析

目的探讨给予新诊断2糖尿病患者DPP-4抑制剂治疗的临床疗效及安全性。方法从2005年1月—2015年12月该院收治的新诊断2型糖尿病患者中抽取100例患者作为研究对象,随机将入选患者均分成两组,每组各50例病患。单纯给予对照组患者胰岛素治疗,实验组则在对照组治疗基础上加用沙格列汀(安立泽)。治疗周期内,密切观察并记录两组患者的血糖值情况、糖化血红蛋白水平、身体质量指数及低血糖发生率。结果 1两组患者的FPG、2h PG、Hb Alc水平经治疗均有所下降,实验组2h PG水平和Hb Alc水平较对照组改善更为明显,组间对比差异有统计学意义(P0.05);2实验组胰岛素用量平均达标时间比对照组更短,,用药期间内本组患者的胰岛素维持剂量也逐渐减少;3对照组患者用药期间内4次中轻度低血糖,3次严重低血糖,实验组用药期间内仅1例患者出现轻微低血糖,后经进食逐渐缓解。提示DPP-4抑制剂联合胰岛素治疗可有效减少低血糖事件发生。结论 DPP-4抑制剂联合胰岛素治疗新诊断II型糖尿病疗效显著,安全可靠,值得临床推广使用。     

DPP-4抑制剂曲格列汀治疗2型糖尿病的临床应用评价

目的研究2型糖尿病通过DPP-4抑制剂曲格列汀来进行治疗,所取得的临床应用效果,并对其进行评价。方法通过对我国以及外国曲格列汀对2型糖尿病患者治疗的文献进行检索,将曲格列汀的各个方面的临床应用进行研究和评价。结果 2型糖尿病患者通过1次/周口服曲格列汀来进行治疗和1次/d服用1次阿格列汀来进行治疗,2种药物取得的治疗效果大致相同;2型糖尿病患者通过服用100 mg的曲格列汀,最长的达峰时间为1.3 h,3 d内的半衰期平均为18.5 h,7 d内的半衰期平均为54.3 h,患者均没有产生明显的蓄积效应;通过曲格列汀治疗,空腹时的血糖浓度均得到明显的降低效果,用食2 h后,患者的血糖浓度与用药时曲线下面积(AUC)得到显著改善,曲格列汀的剂量与效果呈正比;服用曲格列汀后体内的的糖化血红蛋白(HbA1c)含量明显改善;Ⅱ期剂量研究:患者通过服用剂量依次增加的曲格列汀,不良反应概率达到:37%、39%、40%、50%、51%,不良反应最常见为鼻咽炎,鼻咽炎的程度大多是轻度到中度,其中服用50 mg药量的患者中小肠结肠炎患者2例,服用200 mg药量的患者中糖尿病坏疽患者有2例,Ⅲ期验证研究:常见不良症状依旧是轻度或中度鼻咽炎。结论 2型糖尿病患者通过服用DPP-4抑制剂曲格列汀,药物疗效显著,该药在临床上的应用具有重要意义。     

DPP-Ⅳ抑制剂——2型糖尿病治疗的新策略

目前,传统的降糖药物虽可控制血糖和减缓靶器官的损伤,但迄今在全球范围内仍没有良好保护β细胞功能,缓解口服降糖药继发失效的药物。同时传统口服降糖药的安全性仍是值得关注的问题。英国前瞻性糖尿病研究（UKPDS）结果指出无论采取何种治疗手段,糖尿病患者胰岛β细胞功能均进行性丧失。因此,需要一种更有效的治疗方法来改善血糖控制和保护胰岛B细胞功能。     

基础胰岛素联合DPP-4抑制剂治疗2型糖尿病患者的临床观察

目的:探讨基础胰岛素联合二肽基肽酶Ⅳ(DPP-4)抑制剂在治疗2型糖尿病方面的临床疗效。方法:将80例2型糖尿病(FBS11.1 mmol/L)患者随机分成治疗组与对照组,各40例,全部患者均给予生活方式干预,治疗组给予地特胰岛素联合西格列汀100 mg,1次/d,餐前口服;对照组给予地特胰岛素联合瑞格那奈1 mg,3次/d,3餐前口服治疗。结果:经治疗16周后,治疗组患者在空腹及餐后2 h血糖(PBG、2h PBG),糖化血红蛋白(Hb A1C),血脂谱,体重指数(BMI)较前明显下降(P0.05);与对照组比较,结果具有显著性差异(P0.05);2组患者比较,胰岛β功能均较治疗前明显下降,但治疗组改善情况更为明显(P0.05);治疗期间2组患者均未出现低血糖反应,未见其它临床不良反应,2组比较无显著性差异(P0.05)。治疗组患者血糖达标率显著高于对照组,血糖达标中位时间显著短于对照组(P0.05)。结论:基础胰岛素联合DPP-4抑制剂在治疗2型糖尿病方面具有较好的临床疗效,且治疗安全性高。     

DPP-4抑制剂的作用机制及在2型糖尿病治疗中的应用

α及母细胞功能障碍在2型糖尿病的发生中发挥重要作用.二肽基肽酶4( DPP-4)抑制剂是一类基于肠促胰素的新型的口服降糖药物,通过增加内源性活性胰升糖素样肽-1( GLP-1)及葡萄糖依赖性促胰岛素分泌多肽(GIP)水平改善α及β细胞功能障碍,表现为α及β细胞对葡萄糖的敏感性增加,葡萄糖依赖性地促进胰岛素分泌并抑制胰升糖素分泌.同时还具有增加胰岛素敏感性及调节血脂代谢等胰腺外作用.并具有较少发生低血糖,对体重的影响中性,不影响胃排空等特点.临床研究证实其无论单药还是与其他药物联合使用均具有较高的有效性及良好的安全性和耐受性.     

观察DPP-4抑制剂对胰岛素治疗2型糖尿病患者血糖波动的影响

目的观察DPP-4抑制剂对胰岛素治疗2型糖尿病患者的血糖波动影响。方法将该院2017年1月—2018年3月收治的96例2型糖尿病患者纳入该次研究,运用信封法将其分为联合治疗组与单一治疗组,单一治疗组采用胰岛素进行治疗,而联合治疗组则在胰岛素治疗基础上联合西格列汀进行治疗,分析两组患者血糖波动情况、治疗效果、低血糖发生率。结果使用DPP-4抑制剂(西格列汀)的联合治疗组患者的日内血糖波动较单一治疗组更小,治疗有效率更高、低血糖发生率更低,差异有统计学意义(P0.05)。结论在2型糖尿病患者的治疗中使用DPP-4抑制剂可有效减轻患者血糖波动,降低患者低血糖发生率及提高治疗有效率,具有临床推广运用的价值。     

Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new pharmacological class of drugs for treating Type 2 diabetes. They improve the capacity of the organism to control glycemia by increasing the levels of active incretins. Their mechanism of action is thus radically different from those of other anti-diabetic drugs currently available. DDP-4 inhibitors use a physiological mechanism to control hyperglycemia, by stimulating the secretion of insulin from beta-cells, decreasing the secretion of glucagon from pancreatic alpha-cells, and at the same time reducing the production of glucose by the liver. DDP-4 inhibitors have shown significant efficacy in maintaining reduced levels of glycosylated hemoglobin for up to 1 year. In vitro and animal studies have shown that they can inhibit apoptosis of beta-cells and favor their regeneration and differentiation. The oral DPP-4 inhibitors vildagliptin, sitagliptin, and saxagliptin are efficacious both alone and in association with other oral anti-diabetic agents and may be administered in a single daily dose. Lastly, they have substantial advantages with respect to other anti-diabetic drugs, since they involve a low risk of hypoglycemia and do not affect body weight.     

DPP-4 inhibitors

Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.     

基础胰岛素联合DPP-4抑制剂对2型糖尿病患者的临床研究

摘要:目的：探讨基础胰岛素联合二肽基肽酶Ⅳ (DPP-4)抑制剂在治疗2型糖尿病方面的临床疗效。方法：选择我院2012年7月至2014年7月收治的80例2型糖尿病（FBS＞11.1mmol/L）患者，随机进行分组，治疗组与对照组，各40例，全部患者均给予生活方式干预，治疗组给予地特胰岛素联合西格列汀100mg，每日服用一次，餐前口服；对照组给予地特胰岛素联合瑞格那奈1mg，每日服用三次，三餐前口服治疗。结果：经治疗16周后，治疗组患者在空腹及餐后两小时血糖（PBG、2hPBG），HBA1C，血脂谱，体重指数（BMI）较前明显下降，具有统计学意义（P＜0.05）；与对照组比较，结果具有显著性差异（P＜0.05）；两组患者比较，胰岛β功能均较治疗前明显下降，但治疗组改善情况更为明显（P＜0.05）；治疗期间，两组患者均未出现低血糖反应，未见其它临床不良反应，两组比较，无显著性差异（P>0.05）。治疗组患者血糖达标率显著高于对照组，血糖达标中位时间显著短于对照组，两组数据具有显著性差异（P<0.05）。结论：基础胰岛素联合DPP-4抑制剂在治疗2型糖尿病方面具有较好的临床疗效，且治疗安全性高。 关键词:2型糖尿病；DPP-4抑制剂；胰岛素     

Looking to the future: focus on DPP-4 inhibitors for the treatment of type 2 diabetes and emerging therapies

Strong evidence exists demonstrating the benefits of tight glycemic control in type 1 and type 2 diabetes mellitus patients, but glycemic goals are not adequately achieved for many patients. Advancement in the knowledge surrounding the physiology of endogenous glucoregulatory peptide hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, has led to new therapeutic targets for the treatment of type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide practitioners with a novel mechanism of action to use for combination therapies for the treatment of type 2 diabetes mellitus. This article, part 3 of a 3-part series, reviews the new class of medications known as DPP-4 inhibitors as well as discusses a future buccal insulin formulation, Oral-Lyn, on the horizon for the treatment of diabetes mellitus.     

DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials.     

DPP-4抑制剂的抗炎作用及其在糖尿病治疗中的应用

二肽基肽酶-4（DPP-4）抑制剂作为一类新型口服降糖药物,其在2型糖尿病治疗中独特的降糖效果及良好的安全性已在大量研究中得到证实.随着糖尿病研究的深入,“炎性反应”在糖尿病发生、发展中的作用已得到广泛关注.研究发现,DPP-4抑制剂可通过抑制免疫细胞的活化,调节Toll样受体4（TLR4）及cAMP/蛋白激酶A（PKA）等信号通路达到抗炎效果.尽管目前其抗炎机制尚未明确,但已成为改善糖尿病慢性炎性反应状态新的研究热点,并为糖尿病及其并发症的防治提供了新的希望.