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.     

DPP-4 inhibitors: focus on safety

Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i.

Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents.

Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.     

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.     

维格列汀联合门冬胰岛素30注射液对肥胖型2型糖尿病患者胰岛β细胞功能及血清糖化血红蛋白水平的影响

 目的 探讨维格列汀联合门冬胰岛素30注射液对肥胖型2型糖尿病患者胰岛β细胞功能及血清糖化血红蛋白(HbA₁c)水平的影响。方法 选取西安交通大学第一附属医院2017-03至2018-07肥胖型2型糖尿病患者157例,按照随机数字表法分为对照组(n=78)与联合治疗组(n=79),对照组采取门冬胰岛素30注射液治疗,联合治疗组在对照组基础上联合维格列汀治疗,疗程均为12周。观察对比两组疗效及不良反应发生率,并对两组治疗前后空腹血糖(fasting blood glucose,FPG)、餐后2 h血糖(2 h blood glucose,2 h PG)、糖化血红蛋白(HbA₁c)、胰岛β细胞功能指数(HOMA-β)及丝氨酸蛋白酶抑制药(visceral adipose tissue-derived serine protease inhibitor,VASPIN)水平进行比较。结果 联合治疗组HbA₁c达标率和控制理想率均明显高于对照组,差异有统计学意义(P<0.05)。两组治疗后FPG、2 h PG、HbA₁c水平均比治疗前降低,联合治疗组明显低于对照组,差异有统计学意义(P<0.05)。两组治疗后血清HOMA-β、VASPIN水平均较治疗前升高,联合治疗组较对照组明显升高,差异有统计学意义(P<0.05)。两组不良反应发生率差异无统计学意义。结论 维格列汀联合门冬胰岛素30注射液治疗肥胖型2型糖尿病效果确切,能改善患者的血糖和VASPIN水平,保护胰岛β细胞功能,降低低血糖事件的发生率。     

Early combination versus initial metformin monotherapy in the management of newly diagnosed type 2 diabetes: An East Asian perspective

Type 2 diabetes (T2D) in the East Asian population is characterized by phenotypes such as low body mass index, an index of β-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2D in East Asia achieve glycaemic targets recommended by national or regional guidelines, which may be attributable to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2D and present arguments for the need to use early combination therapy to intensify glycaemic control. This strategy is supported by the 5-year worldwide VERIFY study, which reported better glycaemic durability in newly diagnosed patients with T2D with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycaemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association and the European Association for the Study of Diabetes. In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2D early for combination therapy.     

抗糖尿病药物维达列汀

维达列汀是一种口服有效的特异性二肽基肽酶Ⅳ（DPP—Ⅳ）抑制剂，能增强胰高血糖样肽Ⅰ（GLP-1）活性和降低2型糖尿病患者的高血糖症状。研究表明，维达列汀无论是单用还是与其他抗糖尿病药物合用，均能明显降低具有临床意义的糖基化血红蛋白（HbA1c）水平，具有良好的耐受性，且无体重增加和浮肿等不良反应，低血糖和胃肠道等不良反应发生率也较低。现对其药理作用、药动学、临床研究和不良反应等进行综述。     

Translating science into clinical practice: focus on vildagliptin in combination with metformin

Vildagliptin is a potent and selective oral dipeptidyl peptidase-4 inhibitor that improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by increasing both α- and β-cell responsiveness to glucose. The efficacy, tolerability and safety of the combination of vildagliptin and metformin in the treatment of T2DM have been established in numerous trials in the extensive vildagliptin clinical programme. As add-on therapy in patients with inadequate glycaemic control on metformin, vildagliptin produces clinically significant reductions in glycated haemoglobin (HbA1c) and fasting plasma glucose, is well tolerated, and is associated with absence of weight gain and minimal risk of hypoglycaemia. Compared with thiazolidinedione add-on treatment, vildagliptin is associated with similar significant reductions in HbA1c without the weight gain seen with the former. Compared with sulfonylurea add-on treatment, vildagliptin is associated with similar efficacy in controlling glycaemia but absence of weight gain and a markedly lower risk of hypoglycaemia. In drug-naïve patients, single-tablet combinations of vildagliptin/metformin 50/500 and 50/1000 mg bid produced significantly greater reductions in HbA1c than monotherapy with either agent and were well tolerated, with no weight gain and minimal risk of hypoglycaemia. The combination of vildagliptin and metformin poses numerous advantages in the treatment of T2DM.     

Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus

Aims: To assess the long‐term safety and the sustained glycaemic control of vildagliptin compared with rosiglitazone over 2‐year treatment in drug‐naïve type 2 diabetes mellitus patients. Methods: This was an additional 80‐week, multicentre, double‐blind and active‐controlled extension to a 24‐week core study comparing the treatments of vildagliptin (50 mg b.i.d., n = 396) to rosiglitazone (8 mg q.d., n = 202). The primary efficacy variable was the mean change in haemoglobin A1c (HbA1c) from the core study baseline (day 1) to the end of 104 weeks (the extension endpoint). Results: Vildagliptin and rosiglitazone showed statistically significant and sustained HbA1c reductions from a core mean baseline of 8.6 and 8.7% to 7.8 and 7.3% respectively (both significant, p < 0.001). However, rosiglitazone‐treated patients showed significantly greater mean HbA1c reductions (mean difference 0.62%, s.e. 0.13, p < 0.001) compared with vildagliptin. The overall lipid profile significantly improved with vildagliptin compared to rosiglitazone treatment. Body weight remained unchanged in vildagliptin‐treated patients despite improvements in glycaemic control but significantly increased (mean change from core study baseline 4.67 kg) in rosiglitazone‐treated patients (p < 0.001). Notably, a lower incidence of peripheral oedema was seen with vildagliptin (4.6%) compared with rosiglitazone treatment (11.1%). More serious adverse events (SAEs) occurred in vildagliptin‐ than rosiglitazone‐treated patients (12.5 and 9.1% respectively), but only one SAE each in both treatment group was suspected to be related to study drug. Three non‐study drug‐related deaths (vildagliptin: 2 and rosiglitazone: 1) were reported. Four mild hypoglycaemic events were observed with vildagliptin. Conclusions: This study showed that the similar short‐term HbA1c reductions seen with both vildagliptin and rosiglitazone treatments were more durable after 104 weeks of treatment with rosiglitazone than vildagliptin. However, this greater durability with rosiglitazone was at the expense of weight gain (almost 5 kg), higher incidences of peripheral oedema and a less favourable plasma lipid profile compared with vildagliptin.     

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.