Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP‐4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP‐4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose‐lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP‐4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half‐life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug‐drug interactions. The off‐target inhibition of selective DPP‐4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP‐4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once‐daily dosing. It is unknown if DPP‐4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP‐4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.     

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.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.     

二肽基肽酶Ⅳ抑制剂的研究进展

二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂通过抑制内源性的胰高血糖素样肽-1(GLP-1)的降解,提高GLP-1的水平,进而促进葡萄糖依赖的胰岛素分泌和抑制胰高血糖素产生,从而控制血糖的稳定。DPP-Ⅳ抑制剂具有不影响体重和不增加低血糖风险的优势,在2型糖尿病的治疗中发挥着越来越重要的作用。从结构特点上划分,DPP-Ⅳ抑制剂可分为肽类模拟物和非肽类。本文根据DPP-Ⅳ抑制剂的结构特点对此类抑制剂的最新研究进展进行综述,并对其构效关系进行分析。     

二肽基肽酶-Ⅳ抑制剂及其构效关系的研究进展

二肽基肽酶-Ⅳ（dipeptidyl peptidase Ⅳ，DPP-4）是经临床证实的治疗2型糖尿病的新靶点，近年来引起制药界的广泛关注。本文综述了几类主要的选择性DPP-4抑制剂及其构效关系的研究进展，特别是利用现有抑制剂-酶复合物晶体x线衍射研究得到的DPP-4结合位点的重要的结构信息，总结出抑制剂-酶紧密结合的重要分子间相互作用，为通过基于结构的药物设计来获得新型选择性DPP-4抑制剂提供依据。     

Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes

BI 1356, a xanthine-based DPP-4 inhibitor, has reached Phase III trials. The compound efficiently inhibits dipeptidyl peptidase 4 (DPP-4) in vitro and in vivo. In vivo GLP-1 levels increase to levels at or above the levels of other DPP-4 inhibitors. Preclinical trials suggest a once-daily administration of 5 mg to be efficient, long-lasting and without known side effects.     

Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Introduction:

Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.

Aims:

To evaluate the role of vildagliptin in the management of type 2 diabetes.

Evidence review:

Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.

Place in therapy:

Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2 diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs represents an important new therapeutic option in diabetes management.     

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.     

Acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low.     

Use of the dipeptidyl peptidase-4 inhibitor linagliptin in combination therapy for type 2 diabetes

Introduction: Most patients with type 2 diabetes mellitus (T2DM) are prescribed multiple medications – typically more than one for glycemic control alone, and others for the management of lipids and hypertension. Within a few years following diagnosis, many patients progress beyond an initial starting regimen of metformin and/or sulfonylurea in order to maintain glycemic control. With the broad selection of antidiabetes medications available today, the choice of which agents to add when progressing from monotherapy to combination therapy has led to much discussion on how to best tailor a treatment regimen to the individual patient's needs.

Areas covered: The aim of this paper is to review the literature describing the use of linagliptin as a component of combination therapy for the treatment of T2DM. Literature searches were conducted to retrieve articles reporting on linagliptin clinical trial data. For comparison of safety and efficacy, studies of linagliptin as monotherapy were included.

Expert opinion: Dipeptidyl peptidase-4 inhibitors are used across all stages of treatment, from monotherapy to dual or triple therapy regimens for glycemic control. Linagliptin has been studied in combination with the most commonly used classes of antihyperglycemic medications, with demonstrated efficacy and a safety profile comparable to placebo.     

Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon^TM) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise.

Areas covered: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed.

Expert opinion: Evogliptin is effective in improving glycosylated hemoglobin (HbA_1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.     

Once-weekly dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a systematic review and meta-analysis

Objective: To assess the efficacy and safety of omarigliptin and trelagliptin, novel dipeptidyl peptidase-4 inhibitors administered once-weekly (DPP-4i QW).

Methods: We systematically searched for placebo- and active-controlled randomized trials in adults with type 2 diabetes mellitus.

Results: Fifteen primary studies with 5709 participants were included. DPP-4i QW were more effective than placebo in reducing hemoglobin A_1c (HbA_1c) (Weighted Mean Difference (WMD) ?0.63%; 95% CI ?0.80, ?0.46; I² = 84%) and had a similar glucose-lowering effect with daily DPP-4i (WMD 0.01%; ?0.08, 0.11%; I² = 34%). Omarigliptin was less effective compared with oral antidiabetic agents, other than daily DPP-4i, (WMD 0.24%; 0.10, 0.38; I² = 12%). Omarigliptin did not affect body weight (WMD versus placebo 0.60 kg; 0.25, 0.96; I² = 0%). Risk for any hypoglycemia was similar between DPP-4i QW and placebo (Odds Ratio 1.32; 0.78, 2.22; I² = 0%). Incidence of other adverse events did not differ between DPP-4i QW and control.

Conclusions: DPP-4i QW were superior to placebo and similar to daily DPP-4i in terms of glycemic control, and were not associated with any specific adverse events. There is limited comparative effectiveness evidence against other agents, while their effect on hard clinical safety outcomes is unknown.     

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.     

二肽基肽酶Ⅳ抑制剂的药理作用及其机制研究

近些年来,二肽基肽酶Ⅳ(dipeptidyl peptidase IV,DPP-IV)抑制剂在治疗2型糖尿病的药物中异军突起,DPP-IV是一种2型多功能跨膜细胞表面糖基化蛋白,在临床治疗和临床试验中,发现了很多DPP-IV抑制剂潜在的药理作用。通过对国内外相关文献的检索,对DPP-IV抑制剂包括降糖、保护心脏、抗炎等药理作用进行了综述。     

二肽基肽酶4抑制剂联合二甲双胍治疗2型糖尿病的临床疗效

目的观察并初步探讨二肽基肽酶4(Dipeptidyl peptidase 4,DPP4)抑制剂西格列汀联合二甲双胍治疗2型糖尿病的临床疗效。方法选择2014年1月至2015年2月来我院就诊的63例2型糖尿病患者作为研究对象,随机分为3组。对照组单一给药二甲双胍(A组)、西格列汀(Sitagliptin)(B组),观察组(C组)给予西格列汀联合二甲双胍治疗,治疗12周后检测并观察各组总体疗效及相关生化指标。结果 C组治疗后空腹血糖(FBG)、餐后2小时血糖(2h BG)分别为(7.4±1.7)、(8.2±1.9)mmol/L,与A组、B组相比显著降低,差异有统计学意义(P<0.05)。C组糖化血红蛋白(Hb A1c)、体重指数(BMI)及血尿酸(UA)均较A组、B组呈下降趋势,但差异无统计学意义(P>0.05)。结论 DPP4抑制剂西格列汀联合二甲双胍治疗2型糖尿病疗效显著,能够全面控制血糖,降低体重,降低血尿酸,不增加低血糖的发生,具有良好的安全耐受性,值得临床应用推广。     

Inhibition of dipeptidyl peptidase IV activity as a therapy of Type 2 diabetes

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous, multifunctional, serine protease enzyme and receptor with roles in the control of endocrine and immune function, cell metabolism, growth and adhesion. As an enzyme, DPP IV cleaves the N-terminal dipeptide from the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This inactivates the hormones, thereby cancelling their prandial insulinotropic effect. One approach to restore incretin activity as a therapy for Type 2 diabetes has been the development of DPP IV inhibitors. Inhibitors of DPP IV have shown efficacy and tolerability when used to control the hyperglycaemia of noninsulin-dependent animal models and human Type 2 diabetes. These DPP IV inhibitors prolong active incretin hormone concentrations and may exert additional antidiabetic effects. If long-term clinical trials confirm sustained and safe control of blood glucose, DPP IV inhibitors (known as ‘gliptins’) may be expected to provide a new treatment modality for Type 2 diabetes.     

新型糖尿病治疗药物二肽基肽酶IV抑制药的研究进展

二肽基肽酶IV(DPP-IV)抑制药是治疗2型糖尿病的一类新型口服降糖药。DPP-IV抑制药能抑制DDP-IV活性,从而减少胰高糖素样肽1(GLP-1)、葡萄糖依赖性促胰岛素肽(GIP)等的降解,并在GLP-1及GIP的作用下,促进胰岛素的分泌,在有效降低血糖的同时还具有保护胰岛β细胞的功能。本文就该类药物的研究现状及应用前景进行综述。     

Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years.

Areas covered: An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case–control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment).

Expert opinion: The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended.     

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes

Type 2 diabetes is the most prevalent form of diabetes. Incretin hormones play an important role in normal and pathological blood glucose homeostasis. The role of dipeptidyl peptidase IV (DPP IV) in the inactivation of glucagon-like peptide-1 (GLP-1), one of the most important incretins, is wellestablished. Therefore, DPP IV inhibitors are investigated as new therapeutic agents for the treatment of Type 2 diabetes. A summary of DPP IV inhibitors reported until 1998 and a more extensive discussion of more recent inhibitors found in literature and patent applications will be provided. The therapeutic potential of several aminoacyl pyrrolidides, aminoacyl thiazolidides and aminoacyl pyrrolidine-2-nitriles will be reviewed.