维格列汀和二甲双胍联合治疗2型糖尿病的疗效与安全性

维格列汀是一种二肽基肽酶4( DPP-4)抑制剂,常与二甲双胍合用治疗2型糖尿病.多个临床试验表明,维格列汀和二甲双胍合用可以有效降低2型糖尿病患者HbA1c、、空腹血精和餐后血糖,不增加体重,胃肠道耐受性好,而且低血糖发生率低.维格列汀通过增加血浆胰升糖素样肽1( GLP-1)促进胰岛素分泌,而二甲双胍除增加肝脏胰岛素敏感性,抑制肝糖输出外,尚有增强维格列汀增加GLP-1的作用.     

二肽基肽酶Ⅳ抑制剂:一种新型口服抗高血糖药物

目前认为二肽基肽酶Ⅳ(dipeptidyl peptidase-Ⅳ,DPP-Ⅳ)抑制剂通过可逆性抑制二肽基肽酶,延缓活性肠促胰岛激素如胰升糖素样肽1(glucagon-like peptide 1,GLP-1)的降解,从而降低2型糖尿病患者的空腹血糖、餐后血糖和HbA1C水平.现有证据表明,DPP-Ⅳ抑制剂如维格列汀、西他列汀能够有效地增加胰岛素分泌,抑制胰升糖素分泌,并且这种效应具有葡萄糖依赖性.本文主要回顾了在2型糖尿病患者中,这类药物单药治疗及联合其他降糖治疗的临床试验数据.结果显示,DPP-Ⅳ抑制剂降低HbA1C的幅度与治疗前的基础水平关系密切;不引起体重增加,所致低血糖和胃肠道不良反应的发生率亦很低.作为一种新型的口服抗高血糖药物,DPP-Ⅳ抑制剂作用机制独特,临床疗效确切,安全性和耐受性良好,必将成为2型糖尿病治疗的新选择.     

新型二肽基肽酶Ⅳ抑制剂利格列汀在特殊人群中的应用及安全性

新型二肽基肽酶Ⅳ（DPP-4）抑制剂利格列汀已在中国上市,作为2型糖尿病（T2DM）患者降糖治疗的重要选择,利格列汀不仅有效降低血糖,而且服用方便,每日口服一次,不良反应少.本文主要就其安全性以及在特殊人群中的应用进行综述.     

GLP-1受体激动剂与二肽基肽酶4抑制剂治疗2型糖尿病的比较

随着对肠促胰素在维持葡萄糖稳定作用认识的日益增多,促进了针对2型糖尿病患者肠促胰素活性缺乏治疗药物的研发.根据肠促胰素治疗药物不同的作用机制,可分为以下2类:(1)胰升糖素样肽1(GLP-1)受体激动剂,包括利拉鲁肽(liraglutide)、艾塞那肽每日2次制剂和艾塞那肽每周1次制剂;(2)二肽基肽酶4(DPP-4)抑制剂,包括西格列汀(sitagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)和维格列汀(vildagliptin),DPP-4抑制剂可限制内源性GLP-1的降解.这2类药物具有某些共性,如葡萄糖依赖性刺激胰岛素分泌,低血糖发生率低.然而这2类药物在疗效方面的表现却有所不同.本文综述了这2类基于肠促胰素治疗药物的药代动力学及其临床方面的疗效和安全性,阐明了此类药物在2型糖尿病治疗中的地位.     

维格列汀——治疗2型糖尿病的新型口服降糖药

维格列汀是一种高效的选择性二肽基肽酶-4(DPP-4)抑制剂,可通过抑制DPP-4的酶活性,阻止胰升糖素样肽1(GLP-1)裂解失活,提高活性GLP-1的血浆水平,葡萄糖依赖性地促进β细胞胰岛素分泌,抑制α细胞不适当的胰升糖素分泌.维格列汀单药或联合其他降糖药物可有效降低2型糖尿病患者的HbA1C、空腹血糖和餐后血糖水平,改善胰岛β细胞和α细胞功能,极少发生低血糖,不良反应发生率与安慰剂相似,且不增加体重.维格列汀作为一种新型口服降糖药物,作用机制独特,临床疗效确切,安全性和耐受性良好,将成为2型糖尿病治疗的新选择.

Abstract：

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), which can prevent the cleavage and inactivation of glucagon-like peptide-1 (GLP-1), and thus increases the plasma level of intact GLP-1. Such action promotes the insulin secretion from β cell and suppresses inappropriately glucagon secretion from α cell in a glucose-dependent manner. Vildagliptin used as monotherapy or in combination with other antidiabetic drugs can effectively reduce HbA1C, fasting and postprandial plasma glucose, and improve islet β cell and α cell function in type 2 diabetes mellitus patients with extremely few hypoglycemia and comparable adverse effects with placebo, but no weight gain. The unique drug action, reliable clinical efficacy, and favorable safety and tolerability of vildagliptin make it a novel oral antidiabetic drug for the treatment of type 2 diabetes mellitus.     

二肽基肽酶Ⅳ抑制剂西格列汀上市七年循证证据回顾

随着中国城市化、老龄化的进展与人民生活水平的提高，中国糖尿病治疗领域面临严峻挑战。西格列汀作为首个上市的二肽基肽酶IV（DPP-4）抑制剂，可通过增加活性肠促胰素水平而改善2型糖尿病患者的血糖控制。上市七年积累的大量循证医学证据表明，西格列汀降糖疗效与现有降糖药物相似，同时低血糖风险低，不增加体重，有潜在的心血管及微血管临床获益，满足2型糖尿病患者临床需要。     

二肽基肽酶Ⅳ抑制剂类降糖药的临床认识

2型糖尿病日益增长的患病率及疾病负担,使其成为世界范围内广为关注的慢性疾病。过去的几十年间,由于2型糖尿病治疗药物的深入研究,涌现了新一代的口服降糖药二肽基肽酶Ⅳ抑制剂(DPP-4 inhibitor),其中包括西格列汀、沙格列汀、维格列汀、阿格列汀和利格列汀。文章就现有临床证据对DPP-4抑制剂的作用特点和安全性进行了系统的回顾。谨以西格列汀作为该类药物的代表,探讨了其潜在的降糖作用机制、降糖效应以外的对心血管系统可能存在的潜在效应及在单药和联合的降糖治疗方案中的临床试验数据。现有临床证据显示,DPP-4抑制剂是有效的口服降糖药,且具有良好的安全性。因此为众多高影响力的指南所推荐,并且是国际糖尿病联盟(IDF)老年人群2型糖尿病治疗指南中推荐的可选一线药物之一。     

阿卡波糖联合维格列汀对2型糖尿病患者血糖控制及不良反应的影响

目的观察2型糖尿病患者应用阿卡波糖联合维格列汀治疗对其血糖控制效果的影响及治疗期间不良反应发生情况。方法选择该院2016年7月—2017年7月接收的2型糖尿病患者128例,随机分为观察组和对照组,各64例,观察组给予阿卡波糖联合维格列汀治疗,对照组给予阿卡波糖治疗,观察治疗效果。结果治疗前,观察组血糖、C肽及胰岛素指标值与对照组比较均差异无统计学意义(P0.05);治疗后,观察组血糖指标值、不良反应发生率低于对照组,C肽及胰岛素指标值均高于对照组,差异有统计这意义(P0.05)。结论临床应用阿卡波糖与维格列汀联合治疗2型糖尿病患者时,可良好控制血糖,改善胰岛素水平,预防病情进展,且可减少不良反应,安全有效。     

新型二肽基肽酶-4抑制剂利格列汀对2型糖尿病患者的疗效

二肽基肽酶-Ⅳ（DPP-4）抑制剂通过抑制DPP-4酶的活性,提高体内胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素肽（GIP）浓度,发挥葡萄糖依赖的促胰岛素分泌作用和抗胰高血糖素作用,从而降低血糖。自2006年上市以来,DPP-4抑制剂以其良好的降血糖疗效、不良反应少（低血糖风险低、体重影响中性）、服用方便等特点,成为2型糖尿病患者理想的降糖药物之一。     

二甲双胍联合二肽基肽酶4抑制剂治疗未达标的2型糖尿病患者应用格列喹酮的疗效研究

目的 比较格列喹酮、预混胰岛素对二甲双胍联合二肽基肽酶4抑制剂(DPP4I)血糖控制不佳的患者降糖效果.方法 选取2017年10月至2019年9月于天津市第四中心医院就诊的应用二甲双胍和DPP4I控制血糖不佳的2型糖尿病患者280例为研究对象,分为格列喹酮和预混胰岛素组,比较两组血糖、体重变化及低血糖情况.结果 格列喹...     

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.     

The scientific evidence: vildagliptin and the benefits of islet enhancement

Vildagliptin is an oral incretin enhancer that acts to increase active levels of the incretin hormone glucagon-like peptide-1 (GLP-1) by inhibiting the dipeptidyl peptidase-4 enzyme responsible for the rapid deactivation of GLP-1 in vivo . This activity results in improved glucose-dependent functioning of pancreatic islet β and α cells, addressing two central deficits in type 2 diabetes mellitus (T2DM). Vildagliptin treatment improves β-cell sensitivity to glucose, producing increased insulin secretory rate relative to glucose in both postprandial and fasting states. Improved α-cell function is shown as restoration of appropriate glucose-related suppression of glucagon and, therefore, reduced endogenous glucose production during both postprandial and fasting periods. There is evidence that long-term vildagliptin treatment may slow underlying deterioration of β-cell function in T2DM. There is also a potential synergistic effect of vildagliptin and metformin in increasing active GLP-1 levels, and this activity may contribute to the long-term improvements in β-cell function observed in patients with T2DM who have vildagliptin added to ongoing metformin therapy. Vildagliptin treatment has also been associated with beneficial extrapancreatic effects, including improved peripheral insulin sensitivity and improved postprandial triglyceride-rich lipoprotein metabolism. Improvement of β- and α-cell function through incretin enhancement with vildagliptin results in more physiologic meal-related and fasting glycaemia profiles.     

Measurements of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes

OBJECTIVE: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization. Research DESIGN AND METHODS: Participants with T2DM (n = 16) who had a baseline hemoglobin A(1c) of 7.1 +/- 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min x m(2) insulin infusions. RESULTS: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2-fold, respectively, reduced fasting plasma glucose and postprandial plasma glucose by 1.3 +/- 0.3 mmol/liter and 1.6 +/- 0.3 mmol/liter (both P <0.01), and improved glucose responsiveness of insulin secretion by 50% (P < 0.01). Vildagliptin lowered postprandial glucagon by 16% (P <0.01). Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (P < 0.01). CONCLUSIONS: Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.     

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.     

The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet α-cell and β-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves β-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.     

Autophagy deficiency in β cells blunts incretin-induced suppression of glucagon release from α cells

Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7^{Δβ cell}) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7^{Δβ cell} mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7^{Δβ cell} mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.     

Lipotoxicity impairs incretin signalling

The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies.     

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis

The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p < 0.0001). In the control group, we observed no such changes. Vildagliptin efficacy did not differ according to age or body mass index, but the GA reduction was significantly greater in the anti-diabetic agents-na?ve group. Furthermore, in patients with higher baseline GA levels, a higher vildagliptin dosage was required to produce a noticeable effect. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. Vildagliptin was effective as a treatment for diabetic patients undergoing HD.     

Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response

OBJECTIVE: A novel treatment option for diabetic patients is the enhancement of incretin hormone activity by inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4). This study was designed to establish a dose of the DPP-4-inhibitor vildagliptin (LAF237) that was effective in reducing HbA1c levels and was safe and well tolerated in patients with type 2 diabetes. PATIENTS AND METHODS: The study of 279 patients with type 2 diabetes consisted of a 4-week run-in phase where patients received placebo and a 12-week active treatment phase where they received one of the following dosages of vildagliptin: 25 mg twice daily, 25, 50 or 100 mg once daily (qd), or placebo. RESULTS: There was a statistically significant reduction in HbA1c levels in the vildagliptin 50 mg qd (p=0.003) and 100 mg qd groups (p=0.004) compared with the placebo group. The mean 4-h postprandial glucose level was significantly reduced from placebo in the vildagliptin 50 mg qd group (p = 0.012) and mean 4-h postprandial insulin was significantly increased from baseline vs. placebo in the vildagliptin 100 mg qd group (p=0.022). The assessment of beta-cell function (HOMA-B) was significantly increased in the vildagliptin 100 mg qd treatment group (p=0.007). The incidence of adverse events was similar in all treatment groups including placebo. CONCLUSIONS: Vildagliptin, at 50 and 100 mg qd, was effective in reducing HbA1c levels compared with placebo in patients with type 2 diabetes. Vildagliptin at dosages up to 100 mg qd appeared safe and well tolerated.