Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

AIMS

To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.

METHODS

Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.

RESULTS

A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h⁻¹ (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).

CONCLUSIONS

Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.     

Combination therapy with metformin plus vildagliptin in type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is pathophysiologically characterized by a combination of insulin resistance and beta-cell dysfunction. Consequently, a proper treatment of such a disease should target both of these defects. Dipeptidyl peptidase-4 (DPP-4) inhibitors are among the most recent additions to the therapeutic options for T2DM and are able to increase circulating levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus stimulating glucose-dependent insulin secretion.

Areas covered: This paper provides an overview of the clinical results of combination therapy with metformin and the DPP-4 inhibitor vildagliptin in T2DM patients.

Expert opinion: Vildagliptin–metformin single-tablet combination is indicated for the treatment of T2DM patients not achieving a sufficient glycemic control at their maximally tolerated dose of metformin. Results from clinical trials provide evidence of vildagliptin efficacy administered in addition to metformin, as either first- or second-line treatment. The vildagliptin–metformin association seems to have favorable effects on beta-cell function and is characterized by good safety and tolerability profiles when compared with other antidiabetic agents. Of note, data available suggest that administration of fixed-dose combination products, together with the low incidence of adverse gastrointestinal events, may improve compliance and adherence of patients to therapy, resulting in an improved metabolic control.     

Mechanism-based population modelling of the effects of vildagliptin on GLP-1, glucose and insulin in patients with type 2 diabetes

AIM

To build a mechanism-based population pharmacodynamic model to describe and predict the time course of active GLP-1, glucose and insulin in type 2 diabetic patients after treatment with various doses of vildagliptin.

METHODS

Vildagliptin concentrations, DPP-4 activity, active GLP-1, glucose and insulin concentrations from 13 type 2 diabetic patients after oral vildagliptin doses of 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. The population PK/PD model was developed utilizing the MC-PEM algorithm in parallelized S-ADAPT version 1.56.

RESULTS

In the PD model, active GLP-1 production was stimulated by gastrointestinal intake of nutrients. Active GLP-1 was primarily metabolized by DPP-4 and an additional non-saturable pathway. Increased plasma glucose stimulated secretion of insulin which stimulated utilization of glucose. Active GLP-1 stimulated both glucose-dependent insulin secretion and insulin-dependent glucose utilization. Complete inhibition of DPP-4 resulted in an approximately 2.5-fold increase of active GLP-1 half-life.

CONCLUSIONS

The effects of vildagliptin in patients with type 2 diabetes on several PD endpoints were successfully described by the proposed model. The mechanisms of vildagliptin on glycaemic control could be evaluated from a variety of aspects such as effects of DPP-4 on GLP-1, effects of GLP-1 on insulin secretion and effects on hepatic and peripheral insulin sensitivity. The present model can be used to predict the effects of other dosage regimens of vildagliptin on DPP-4 inhibition, active GLP-1, glucose and insulin concentrations, or can be modified and applied to other incretin-related anti-diabetes therapies.     

拟肽类二肽基肽酶Ⅳ抑制剂的研究进展

二肽基肽酶Ⅳ(dipeptidyl peptidaseⅣ,DPP-Ⅳ)是抗2型糖尿病的新靶点之一,其抑制剂的研发已经成为当今抗糖尿病药物研究的热点,其中拟肽类DPP-Ⅳ抑制剂是一重要类型,此类抑制剂的研究最为深入和广泛,代表药物维格列汀(vildagliptin)和沙格列汀(saxagliptin)均已进入市场。本文从拟肽类DPP-Ⅳ抑制剂的发现过程、优化策略及构效关系等方面综述近年来该类抑制剂的研究进展。     

Emerging treatment options for type 2 diabetes

Type 2 diabetes mellitus (T2DM) is rapidly increasing in prevalence and is a major public health problem. It is a progressive disease which commonly requires multiple pharmacotherapy. Current options for treatment may have undesirable side effects (particularly weight gain and hypoglycaemia) and contraindications, and little effect on disease progression. Incretin based therapy is one of several newer therapies to improve glycaemia and is available in two different forms, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Use of these agents results in a ‘glucose-dependant’ increase in insulin secretion and glucagon suppression resulting in improved glycaemia with low incidence of hypoglycaemia. DPP-4 inhibitors are oral drugs which are weight neutral, while GLP-1 agonists are injected subcutaneously and help promote weight loss while improving glycaemia. GLP-1 agonists have also been shown to increase beta cell mass in rat models. Bariatric surgery is another option for the obese patient with T2DM, with blood glucose normalizing in over half of the patients following surgery. Other therapies in development for the treatment of T2DM include sodium-glucose transporter 2 (SGLT-2) inhibitors, glucagon receptor antagonists, glucokinase activators and sirtuins. In this article, we will review the various existing and emerging treatment options for T2DM.     

Pharmacokinetics of lipoyl vildagliptin,a novel dipeptidyl peptidase IV inhibitor after oral administration in rats

1. The pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV (DPP IV) inhibitor, was studied in rats after oral administration for developing it as an antidiabetic agent.

2. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine lipoyl vildagliptin in rat plasma. After an overnight fasting, rats were orally given lipoyl vildagliptin. Following a single oral dose of 25, 50, and 100?mg·kg^?1, T_max values were from 1.25 to 1.84?h, CL/F values were around 100?l h^?1 kg^?1. In the dose range, C_max values (63.9–296?μg·l^?1) and AUC_0–∞values (260–1214?μg·h·l^?1) were proportional to the doses.

3. In conclusion, this LC-MS/MS method for the determination of lipoyl vildagliptin in rat plasma was selective and sensitive. In rats, lipoyl vildagliptin displayed linear pharmacokinetics after a single oral dose in the range of 25–100?mg·kg^?1. Lipoyl vildagliptin might have very high CL/F values and V_d/F values, which indicated that the bioavailability of this drug might be low or lipoyl vildagliptin might distribute extensively or accumulate in tissues in view of its high liposolubility.

     

维格列汀联合二甲双胍治疗老年2型糖尿病的临床疗效研究

目的：研究维格列汀联合二甲双胍治疗2型糖尿病老年患者的临床疗效。方法选取符合2型糖尿病诊断标准的60岁以上老年患者120例,按双盲法随机分为治疗组（60例）,采用维格列汀联合二甲双胍治疗及对照组（60例）采用二甲双胍加安慰剂治疗,半年后观察对比分析两组患者的情况。结果治疗前无差异,治疗半年后,治疗组在FBG、2hPG、HbA1c及BMI方面明显低于对照组（P＜0.05）,而不良反应发生率在两组间没有明显差异。结论维格列汀联合二甲双胍对于治疗老年2型糖尿病有较好的疗效。     

Vildagliptin in the treatment of type 2 diabetes mellitus

Introduction: Inhibition of dipeptidyl peptidase IV (DPP-4) augments glucose-dependent insulin release and is a new approach to the treatment of type 2 diabetes (T2DM). Vildagliptin is a new DPP-4 inhibitor approved in many countries for the treatment of T2DM. This review provides an overview of vildagliptin with emphasis on its pharmacology and clinical effectiveness.

Areas covered: Results of preclinical and several Phase II and III studies from 2004 – 2010 are discussed.

Expert opinion: Vildagliptin acts to inhibit the breakdown of glucagon-like peptide (GLP)-1, which in turn enhances the beta-cell response to glucose and inhibits glucagon secretion. It is an effective agent alone or in combination in patients with T2DM, resulting in modest improvements in HbA1c usually in the 0.5 – 1% range. Advantages include weight neutrality and a lesser incidence of hypoglycemia. Concerns remain regarding its use in renal disease and potential complications seen in animal models.     

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.     

二甲双胍联合维格列汀治疗肥胖型2型糖尿病的临床观察

目的探究二甲双胍联合维格列汀治疗肥胖型2型糖尿病的临床疗效。方法选取2010年3月—2013年2月来重庆市忠县人民医院就诊的肥胖型2型糖尿病患者106例,依据分层随机分组法将患者分为治疗组(53例)和对照组(53例)。对照组给予常规疗法,随餐同服二甲双胍0.5 g/次,2次/d,后依据病情以0.5 g/2周逐渐增量,最大剂量不超过2.5 g/d,同时早餐前口服吡格列酮,起始剂量15 mg/d,最大剂量不超过45 mg/d;治疗组口服二甲双胍,用法用量同对照组,同时随餐口服维格列汀50 mg/次,2次/d。两组患者均治疗6个月。比较两组患者治疗前后体质量指数(BMI)、糖化血红蛋白(HbA1c)、糖化白蛋白(GSP)、空腹血糖(FBG)、餐后2小时血糖(2hPBG)、胰高血糖素样肽-1(GLP-1)、三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、治疗总有效率,同时观察两组患者可能出现的不良反应。结果治疗后两组患者的BMI、HbA1c、GSP、FBG、2hPBG、TG、TC及LDL-C均较治疗前有所下降,差异均有统计学意义(P<0.05);治疗后,治疗组患者的BMI、HbA1c、GSP、FBG、2hPBG、TG、TC及LDL-C均较对照组下降更加明显,差异有统计学意义(P<0.05)。治疗后治疗组患者的GLP-1和HDL-C均明显高于对照组,两组比较差异有统计学意义(P<0.05)。治疗后,治疗组和对照组的总有效率分别为98.11%、86.79%,两组比较差异有统计学意义(P<0.05)。结论二甲双胍联合维格列汀治疗肥胖型2型糖尿病可有效控制患者的血糖和体质量,且不增加低血糖风险,同时也可达到降低血脂的作用,值得临床推广应用。     

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.     

Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin

Background: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day).

Research design and methods: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500–2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks.

Results: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. ?0.15 ± 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01).

Conclusions: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.     

Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes

Background: Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet. Objective: To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin. Method: Review of Phase III clinical trials based on Medline search published up to April 2008. Results: The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 – 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost. Conclusion: Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.     

加用维格列汀对胰岛素治疗的2型糖尿病患者无症状低血糖发生率的影响

目的观察接受胰岛素治疗的2型糖尿病患者加用二肽基肽酶Ⅳ抑制剂维格列汀后,其低血糖(包括无症状低血糖事件)发生率能否降低。方法将2018年3月至9月于我院内分泌科接受胰岛素治疗的80例2型糖尿病患者随机分为研究组(联用维格列汀共40例)和对照组(不联用二肽基肽酶Ⅳ抑制剂共40例),监测其4周内发生的低血糖事件(包括无症状低血糖),比较两组发生低血糖的例数及事件数,并观察4周后所有患者血糖参数的变化。结果研究组和对照组发生低血糖总人数(18例次对23例次)[包括无症状低血糖的人数(10例次对16例次)]差异无统计学意义(P>0.05);研究组无症状低血糖事件数(14例次对27例次)少于对照组(P<0.05),总低血糖事件数(33例次对52例次)亦少于对照组(P<0.05)。Poisson回归分析显示无感知低血糖事件的发生与糖尿病病程(P<0.01)、空腹血糖(P<0.05)和研究组别(P<0.05)相关。4周后研究组和对照组的糖化血红蛋白、糖化白蛋白、空腹和餐后血糖均改善(P<0.05)。结论在接受胰岛素治疗的2型糖尿病患者中,加用维格列汀在改善其血糖控制同时,亦可降低无症状低血糖事件的发生率并减少总低血糖事件的发生。     

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.     

Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes*

ABSTRACT

Objective: Metformin is widely used for treating patients with type 2 diabetes, often as first-line therapy; however, many patients with type 2 diabetes are unable to maintain adequate glycemic control with metformin alone. Vildagliptin, an orally active, potent and selective dipeptidyl peptidase IV (DPP-4) inhibitor, may represent an appropriate antihyperglycemic agent for combination with metformin to improve glycemic control in such patients. This study assessed the effects of coadministration of vildagliptin and metformin on the steady-state pharmacokinetics of each drug.

Research design and methods: In this open-label, single-center, randomized, three-period, three-treatment crossover study, 17 patients with type 2 diabetes received vildagliptin 100?mg once daily; metformin 1000?mg once daily; or vildagliptin 100?mg once daily plus metformin 1000?mg once daily. Blood samples for pharmacokinetic sampling were taken frequently on the final day (Day 5) of each treatment period. Lack of pharmacokinetic interaction was defined as the ratio of geometric mean (GMR) and 90% confidence interval (CI) for combination:monotherapy being within the range 0.80–1.25.

Results: Coadministration with metformin had no effect on vildagliptin AUC_0–24 (GMR, 0.94; 90% CI 0.90, 0.99) although there was an 18% decrease in vildagliptin C_max (GMR 0.82; 90% CI 0.73, 0.91). Coadministration with vildagliptin had no effect on metformin C_max (GMR 1.04; 90% CI 0.94, 1.16). but caused a 15% increase in AUC_0–24 (GMR 1.15; 90% CI 1.06, 1.25). Both monotherapies and combination therapy were well tolerated. Seven patients reported a total of 10 adverse events; none was serious.

Conclusions: Coadministration of vildagliptin and metformin had a small effect on the pharmacokinetics of each drug in patients with type 2 diabetes; however, this is not likely to be clinically relevant. This small, open-label trial suggests that vildagliptin could be coadministered with metformin without any dose adjustment for either agent.     

DPP-IV抑制剂与二甲双胍联用对2型糖尿病的临床疗效观察

目的：探讨DPP-IV抑制剂联用二甲双胍对2型糖尿病的疗效。方法：将某医院90例2型糖尿病患者分为三组。对照组30例：单用二甲双胍治疗;治疗组A 30例：用磷酸西格列汀与二甲双胍联合治疗;治疗组B 30例：用利格列汀与二甲双胍联合治疗,疗程12周。比较治疗前后空腹血糖（FBG）、餐后2h血糖（2hPG）、糖化血红蛋白（HbA1c）、体重指数（BMI）、空腹胰岛素（FIns）的变化。结果：治疗12周后对照组FBG、2hPG、HbA1c、BMI、FIns分别为：（7.6±1.8）mmol/L;（10.6±1.8）mmol/L;（7.3±1.7）%;（24.3±1.7） kg/㎡;（10.6±1.1）μU/mL。治疗组A分别为：（6.3±1.7）mmol/L;（8.8±1.8）mmol/L;（6.7±1.3）%;（23.4±1.0）kg/㎡;（11.7±1.1）μU/mL。治疗组B分别为：（6.5±1.4）mmol/L;（8.6±1.6）mmol/L;（6.5±1.4）%;（24.1±1.2）kg/㎡;（11.2±1.1）μU/mL。三组均较治疗前明显下降（P<0.01）,治疗组A、B明显优于对照组（P<0.05）。结论：DPP-IV抑制剂联用二甲双胍对2型糖尿病疗效确切。     

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.     

Cardiovascular safety of therapies for type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.