Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes

INTRODUCTION: Increasing population age, obesity and physical inactivity mean that type 2 diabetes mellitus (T2DM) is increasingly common. Current treatments may be limited by adverse events, drug-drug interactions or contraindication/need for dose adjustment in patients with renal impairment. AREAS COVERED: This paper reviews studies that evaluate the pharmacokinetics, pharmacodynamics and clinical efficacy and safety of linagliptin , a dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the US, Japan and Europe for the treatment of T2DM. EXPERT OPINION: Oral linagliptin, 5 mg once daily, is an effective, well-tolerated DPP-4 inhibitor, suitable for use in a wide range of patients with T2DM. It is weight-neutral, without increasing the risk of hypoglycemia, and can be administered either alone or in combination with other diabetes treatments. It has a unique pharmacological profile within its class and, unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal impairment.     

Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation)

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes (T2DM). The novel compound linagliptin has important different pharmacokinetic (PK) properties, when compared with previously commercialized DPP-4 inhibitors, which may offer some advantages in clinical practice. Linagliptin has a unique PK/pharmacodynamic (PD) profile and is the first DPP-4 inhibitor with a nonrenal elimination route. Therefore, it can be administered in patients with renal impairment without dose adjustment or monitoring of renal function. The drug has a low potential for drug-drug interactions (DDIs) and no clinically relevant ones were reported so far. AREAS COVERED: An extensive literature search was performed to analyse primarily PK and secondarily PD characteristics of linagliptin in both healthy volunteers and patients with T2DM (treated with linagliptin as monotherapy or combined therapy). Updated information about linagliptin PK either after single administration (large dose range) or after chronic administration (steady state) were also included. A special focus has been put on DDIs and on PK/PD of linagliptin in patients with renal impairment. EXPERT OPINION: Head-to-head comparative studies and/or increased clinical experience with DPP-4 inhibitors will determine the clinical advantage, if any, of one agent over another.     

Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences

The dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic β cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in-class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007, although approval in the US is still pending), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011 and is undergoing regulatory review in Japan and the EU. As the number of DPP-4 inhibitors on the market increases, potential differences among the different members of the class become important when deciding which agent is best suited for an individual patient. The aim of this review is to provide a comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors, and to pinpoint pharmacological differences of potential interest for their use in therapy. Despite their common mechanism of action, these agents show significant structural heterogeneity that could translate into different pharmacological properties. At the pharmacokinetic level, DPP-4 inhibitors have important differences, including half-life, systemic exposure, bioavailability, protein binding, metabolism, presence of active metabolites and excretion routes. These differences could be relevant, especially in patients with renal or hepatic impairment, and when considering combination therapy. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. Data on nonglycaemic parameters are scant at present and do not allow a comparison among DPP-4 inhibitors. Several phase III trials of DPP-4 inhibitors are currently ongoing; these trials, along with post-marketing surveillance data, will hopefully increase our knowledge about the long-term efficacy and safety of DPP-4 inhibitor therapy, the effect on pancreatic cell function and peripheral glucose metabolism, and the effect on cardiovascular outcomes in patients with type 2 diabetes.     

二肽基肽酶4抑制剂在控制2型糖尿病透析患者代谢指标中的作用

目的：研究3种不同二肽基肽酶4（DPP-4）抑制剂对终末期肾病合并2型糖尿病患者代谢参数的影响。方法：对200例应用DPP-4抑制剂（西格列汀、维格列汀或利格列汀）治疗2型糖尿病的终末期肾病患者进行前瞻性队列研究。DPP-4抑制剂治疗12周前后评估糖化血红蛋白（HbA1c）、空腹血糖和代谢指标的变化。结果：西格列汀、维格列汀、利格列汀治疗组HbA1c水平下降无显著性差异（分别为-0.74±1.57、-0.39±1.45和-0.08±1.40，P=0.076），空腹血糖及血脂变化亦无显著差异。在血液透析患者（n=115）中，3组间HbA1c水平变化无差异。相比之下，腹膜透析患者（n=85）用西格列汀治疗12周后，HbA1c比用维格列汀和利格列汀治疗12周降低得更多（分别为-1.58±0.95，-0.46±0.98，-0.04±1.22，P=0.001）。结论：在终末期肾病患者中使用不同DPP-4抑制剂的降糖作用差异无显著性。在腹膜透析患者中，西格列汀比其他DPP-4抑制剂可使HbA1c水平降低更多。     

Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors collectively comprise a presently unique form of disease management for persons with type 2 diabetes mellitus. The aim of this review is to compare the clinical pharmacokinetics of available DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin) for the purpose of identifying potential selection preferences according to individual patient variables and co-morbidities. DPP-4 inhibitors are readily absorbed orally. Following oral ingestion, absorption occurs mainly in the small intestine, with median times to maximum (peak) plasma concentration ranging from 1 to 3 hours. The fraction of each dose absorbed ranges from approximately 30% with linagliptin to 75-87% for all others. Numerical differences in maximum (peak) plasma drug concentrations and areas under the plasma concentration-time curve among the DPP-4 inhibitors vary by an order of magnitude. However, functional capacity measured in terms of glucose-lowering ability remains comparable among all available DPP-4 inhibitors. Distribution of DPP-4 inhibitors is strongly influenced by both lipophilicity and protein binding. Apparent volumes of distribution (V(d)) for most agents range from 70 to 300 L. Linagliptin exhibits a V(d) of more than 1000 L, indicating widespread distribution into tissues. Binding to target proteins in plasma and peripheral tissues exerts a major influence upon broadening linagliptin distribution. DPP-4 inhibitor metabolism is widely variable, with reported terminal half-lives ranging from approximately 3 to more than 200 hours. Complex relationships between rates of receptor binding and dissociation appear to strongly influence the durations of action of those DPP-4 inhibitors with comparatively shorter half-lives. Durations of activity often are not reflective of clearance and, with the exception of vildagliptin which may be administered either once daily in the evening or twice daily, these medications are effective when used with a once-daily dosing schedule. Saxagliptin and, to a lesser extent, sitagliptin are largely metabolized by hepatic cytochrome P450 (CYP) 3A4 and 3A5 isoforms. With the exception of the primary hydroxylated metabolite of saxagliptin, which is 2-fold less potent than its parent molecule, metabolic products of hepatic biotransformation are minimally active and none appreciably contribute to either the therapeutic or the toxic effects of DPP-4 inhibitors. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Accordingly, the number of clinically significant drug-drug interactions associated with these agents is minimal, with only saxagliptin necessitating dose adjustment if administered concurrently with medications that strongly inhibit CYP3A4. Linagliptin undergoes enterohepatic cycling with a large majority (85%) of the absorbed dose eliminated in faeces via biliary excretion. Other DPP-4 inhibitors predominantly undergo renal excretion, with 60-85% of each dose eliminated as unchanged parent compound in the urine. Systematic reviews of clinical trials suggest that the overall efficacy of DPP-4 inhibitors in patients with type 2 diabetes generally is similar. Apart from these generalizations, pharmacokinetic distinctions that potentially influence product selection are tentative. When considered in total, data reviewed in this report suggest that the best overall balance between potency and the clinical pharmacokinetic characteristics of distribution, metabolism and elimination may be observed with linagliptin followed closely by vildagliptin, saxagliptin, sitagliptin and alogliptin.     

口服降糖药二肽基肽酶Ⅳ（DPP-4）抑制剂的多器官保护作用

二肽基肽酶Ⅳ（DPP-4）抑制剂是近年来新上市的一种新型口服降糖药物。 DPP-4抑制剂通过抑制DPP-4来抑制胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）降解,发挥降低血糖的作用。 DPP-4抑制剂不仅能双向控制血糖,且具有降糖外的胰腺、心血管、肾脏、肝脏等多器官保护作用和抗炎作用。本文对已有的DPP-4抑制剂及其多器官保护作用进行综述,总结其优势及进一步发展的趋势,为临床用药提供参考。     

Linagliptin for the treatment of type 2 diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic agents that have been rapidly adopted since their introduction in 2006. There are now five agents in global use, with three approved for treatment of patients with type 2 diabetes (T2D) in the USA. The results of Phase III clinical trials for linagliptin, a new addition to this class of inhibitors (approved by the FDA on 2 May 2011), have now been published. We reported on a 24-week Phase III trial of linagliptin administered as monotherapy in patients with T2D. This agent is characterized by a pharmacokinetic and metabolic profile that may have important implications for the choice of treatment in certain patient populations.     

Linagliptin for the treatment of type 2 diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic agents that have been rapidly adopted since their introduction in 2006. There are now five agents in global use, with three approved for treatment of patients with type 2 diabetes (T2D) in the USA. The results of Phase III clinical trials for linagliptin, a new addition to this class of inhibitors (approved by the FDA on 2 May 2011), have now been published. We reported on a 24-week Phase III trial of linagliptin administered as monotherapy in patients with T2D. This agent is characterized by a pharmacokinetic and metabolic profile that may have important implications for the choice of treatment in certain patient populations.     

A review of gliptins in 2011

INTRODUCTION: Dipeptidylpeptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes (T2DM). AREAS COVERED: This paper is an updated review, providing an analysis of both the similarities and the differences between the various compounds known as gliptins, currently used in the clinic (sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin). This paper discusses the pharmacokinetic and pharmacodynamic characteristics of gliptins; both the efficacy and safety profiles of gliptins in clinical trials (compared with classical glucose-lowering agents), given as monotherapy or in combination, including in special populations; the positioning of DPP-4 inhibitors in the management of T2DM in recent guidelines; and various unanswered questions and perspectives. EXPERT OPINION: The role of DPP-4 inhibitors in the therapeutic armamentarium of T2DM is evolving, as their potential strengths and weaknesses become better defined. Future critical issues may include the durability of glucose control, resulting from better β-cell protection, positive effects on cardiovascular outcomes and long-term safety issues.     

Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux

Linagliptin is a selective, competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the USA, Japan and Europe for the treatment of type 2 diabetes. It has non-linear pharmacokinetics and, unlike other DPP-4 inhibitors, a largely non-renal excretion route. It was hypothesised that P-glycoprotein (P-gp)-mediated intestinal transport could influence linagliptin bioavailability, and might contribute to its elimination. Two studies evaluated the role of P-gp-mediated transport in the bioavailability and intestinal secretion of linagliptin in rats. In the bioavailability study, male Wistar rats received single oral doses of linagliptin, 1 or 15 mg/kg, plus either the P-gp inhibitor, zosuquidar trihydrochloride, or vehicle. For the intestinal secretion study, rats underwent bile duct cannulation, and urine, faeces, and bile were collected. At the end of the study, gut content was sampled. Inhibition of intestinal P-gp increased the bioavailability of orally administered linagliptin, indicating that this transport system plays a role in limiting the uptake of linagliptin from the intestine. This effect was dependent on linagliptin dose, and could play a role in its non-linear pharmacokinetics after oral dosing. Systemically available linagliptin was mainly excreted unchanged via bile (49% of i.v. dose), but some (12%) was also excreted directly into the gut independently of biliary excretion. Thus, direct excretion of linagliptin into the gut may be an alternative excretion route in the presence of liver and renal impairment. The primarily non-renal route of excretion is likely to be of benefit to patients with type 2 diabetes, who have a high prevalence of renal insufficiency.     

A dipeptidyl peptidase-4 (DPP-4) inhibitor,linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4

Dipeptidyl peptidase-4 (DPP-4) inhibitors not only improve impaired glucose tolerance in diabetes, but also have pleiotropic extra-pancreatic effects such as preconditioning effect for myocardial ischemia-reperfusion injury. Here, we investigated the anti-remodeling effects of linagliptin, a DPP-4 inhibitor, by use of DPP-4-deficient rats.After the induction of myocardial infarction (MI), Fischer 344 rats with inactivating mutation of DPP-4 were orally administrated with a DPP-4 inhibitor, linagliptin (5 mg kg^?1·day^?1), or vehicle in drinking water for 4 weeks. Linagliptin did not affect hemodynamic status, body weight, and infarct size. In echocardiography, linagliptin tended to improve left ventricular (LV) systolic function, and significantly improved LV diastolic function, surprisingly. Interstitial fibrosis in marginal region and macrophage infiltration were significantly lower in the linagliptin group than those in the vehicle group. Fibrosis-related gene expressions, such as collagen I and transforming growth factor-β1 (TGF-β1), and inflammation-related expressions, such as macrophage chemotactic protein 1 and matrix metalloproteinase-2 (MMP-2), were significantly suppressed in marginal area of the linagliptin-treated rats compared with the vehicle rats. The TGF-β1 and MMP-2 protein levels were attenuated by linagliptin in DPP-4-deficient cardiac fibroblasts.Linagliptin can attenuate MI-induced cardiac remodeling via a DPP-4-independent pathway.     

二肽基肽酶Ⅳ抑制剂治疗2型糖尿病的系统评价再评价

目的对二肽基肽酶Ⅳ（DPP-4）抑制剂治疗2型糖尿病的有效性及安全性进行评价。方法计算机检索Cochrane图书馆、PubMed、EMBASE、ScienceCitationIndex、中国期刊全文数据库、中文科技期刊数据库、中国生物医学文献数据库、万方医学数据库,检索时间截至2013年8月。英文检索词包括sitagliptin、vildagliptin、saxagliptin、linagliptin、alogliptin、dipeptidyl-peptidase1V、systematicreviews和meta-analysis,中文检索词包括西格列汀、维格列汀、沙格列汀、利格列汀、阿格列汀、二肽基肽酶Ⅳ抑制剂、系统评价和meta分析。根据纳入和排除标准,提取符合标准的系统评价／meta分析,用OQAQ量表评价其方法学质量并赋分（1-7分,分数高者质量好）,用描述性分析的方法分析资料,主要结局指标包括糖尿病患者糖化血红蛋白（HbAlc）、稳态模型的p细胞功能指数（HOMA-B）和不良事件发生率。结果共纳入18个系统评ffF／meta分析,方法学质量评分为6．0～7．0者16个占89％。18篇文献中13篇评价了DPP-4抑制剂对2型糖尿病患者HbAlc水平的影响,西格列汀、维格列汀、沙格列汀和利拉列汀在降低HbAlc水平方面与其他口服降糖药相似,沙格列汀与西格列汀降低HbAlc疗效相似。5篇文献评价了DPP-4抑制剂对2型糖尿病患者HOMA·母的影响。与安慰剂相比,西格列汀、维格列汀、沙格列汀能有效改善2型糖尿病患者的HOMA—p水平;西格列汀改善2型糖尿病患者HOMA．B水平的疗效不优于其他口服降糖药。14篇文献评价了DPP-4抑制剂治疗过程中的不良事件发生率,应用西格列汀、维格列汀、沙格列汀和利拉列汀治疗的患者不良事件发生率和低血糖发生率与应用安慰剂的患者比较差异无统计学意义;西格列汀和维格列汀诱发低血糖的概率低于其他口服降糖药。结论DPP-4抑制剂能有效控制2型糖尿病患者的血糖,短期安全性较好。     

Safety of dipeptidyl peptidase 4 inhibitors for treatment of type 2 diabetes

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new class of drugs introduced in 2006 for treatment of type 2 diabetes. In clinical trials lasting up to 2 years, these agents are well tolerated. Incidence of hypoglycemia associated with the use of DPP-4 inhibitors is similar to placebo, but is markedly increased when used in conjunction with sulfonylureas (SUs). DPP-4 inhibitors have neutral effect on body weight but their combination with a thiazolidinedione (TZD) results in slight weight gain averaging 0.5 to 1.3 kg compared with placebo. Other adverse effects recorded more commonly with DPP-4 inhibitors versus placebo are mild, and include nasopharyngitis, headache, and possibly urinary tract infections (UTIs). In the postmarketing period, new adverse effects are reported such as angioedema, increased rates of infection, and skin toxicity. Pancreatitis is inconsistently reported in relationship to sitagliptin, and one analysis links this agent to elevated risk of pancreatic cancer. Pancreatitis is also a rare adverse effect observed in linagliptin clinical studies. There is no evidence that DPP-4 inhibitors increase cardiovascular events or death. Overall, although short-term safety of DPP-4 inhibitors is reassuring, their safety needs to be established by long-term clinical trials and close surveillance during the postmarketing period.     

Clinical pharmacokinetics and pharmacodynamics of linagliptin

Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/L) and AUC (～150 nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inhibition constant 1 nmol/L), and trough drug concentrations achieved with therapeutic dosing inhibit >80% of plasma DPP-4 activity, the threshold associated with maximal antihyperglycaemic effects in animal models. There are no clinically relevant alterations in linagliptin pharmacokinetics resulting from renal impairment, hepatic impairment, coadministration with food, race, body weight, sex or age. In vitro, linagliptin is a weak substrate and weak inhibitor of cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) but not of other CYP isozymes or ATP-binding cassette transporters. Clinical studies have revealed no relevant drug interactions when coadministered with other drugs commonly prescribed to patients with type 2 diabetes, including the narrow therapeutic index drugs warfarin and digoxin. Linagliptin plasma exposure is reduced by potent inducers of CYP3A4 or P-gp. Linagliptin has demonstrated a large safety window (>100-fold the recommended daily dose) and clinically relevant antihyperglycaemic effects in patients with type 2 diabetes.     

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.     

Reno-protective effect of linagliptin against gentamycin nephrotoxicity in rats

BackgroundRecent studies demonstrated the reno-protective effects of two dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin and sitagliptin, against gentamycin-induced renal injury. However, none of these studies investigated whether renal DPP-4 contributes to the pathogenesis of this nephrotoxicity or not. This prompted us to test this hypothesis and to assess, for the first time, the potential reno-protective effect of linagliptin and whether this action is related or not to DPP-4 inhibition. Lingliptin was chosen since it is mainly excreted through a non-renal pathway and can therefore be used safely in individuals with renal injury.MethodsMale Sprague-Dawley rats were administered gentamycin (100 mg/kg/day, ip for 10 days) alone or combined with linagliptin (3 mg/kg/day, orally for 14 days). Gentamycin was administered once daily during the last ten days of the linagliptin treatment.ResultsLinagliptin administration ameliorated gentamycin-induced renal injury and restored renal functional, oxidative, inflammatory, apoptotic and histopathological changes. Furthermore, the current study highlighted the role of increased plasma and renal DPP-4 in the pathogenesis of gentamycin renal insults and showed that the potential reno-protective effect of linagliptin is partly, mediated via inhibition of DPP-4, in addition to other antioxidant, anti-inflammatory and anti-apoptotic actions.ConclusionLinagliptin may serve as a beneficial adjutant to reduce gentamycin-induced renal injury.     

Clinical Effects of Exposure to DPP-4 Inhibitors as Reported to the National Poison Data System

DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin) are approved for the treatment of diabetes. They are considered safe due to their hyperglycemia dependent mechanism of action. We examined all isolated exposures to DPP-4 inhibitors reported to the National Poison Database System since 2006 to determine if significant toxicity occurs after exposure with attention to pediatric and intentional overdoses. NPDS data regarding DPP-4 ingestions in all age groups between January 2006 and March 2013 was collected. Cases were reviewed, and the following inclusion criteria applied: (1) reported ingestion of a DPP-4 inhibitor and (2) known clinical outcome. Exclusion criteria included the following: (1) exposure to more than a single substance, (2) no known outcome, and (3) clinical outcome judged to be unrelated to the exposure. One thousand four hundred seventy-six cases were reviewed while 826 were excluded. Of 650 included cases, 562 developed no clinical effects. Mild effects were noted in 77. There were no deaths. Moderate/major effect cases were investigated: two medication-naive nondiabetic individuals with accidental exposures developed clinically significant hypoglycemia requiring treatment. One diabetic patient on a DPP-4 inhibitor developed prolonged hypoglycemia requiring admission and continuous exogenous dextrose. Of 650 included exposures to DPP-4 inhibitors, 639 (98.3%) had either no or minor clinical effects. Three resulted in clinically significant hypoglycemia requiring intervention. None of the moderate or major clinical outcomes were the result of intentional overdoses for the purpose of self-injury. No exploratory ingestions resulted in moderate or major effects. Based on this data, exposure to DPP-4 inhibitors may rarely result in clinically significant hypoglycemia.     

Vascular protection of DPP-4 inhibitors in retinal endothelial cells in in vitro culture

People with diabetes are at high risk of developing diabetes-related eye disease, termed as diabetic retinopathy, due damage being caused to the blood vessels in the retina. An efficient medical treatment to reduce diabetic retinopathy can improve the quality of life for diabetes patients. In our study, we show that linagliptin, a commercially available DPP-4 inhibitor, plays a protective role in retinal vascular endothelial cells. The presence of linagliptin protects retinal endothelial cells against TNF-α-induced cytotoxicity and enhances their viability. Linagliptin treatment suppresses TNF-α-induced production of reactive oxygen species and improves mitochondrial membrane potential. Moreover, linagliptin suppresses TNF-α-induced production of pro-inflammatory and pro-adhesive vascular cytokines including IL-6, IL-8, ICAM-1, and VCAM-1. The presence of linagliptin in cell media can reduce the number of THP-1 cells that adhere to retina endothelial cells. Mechanistically, linagliptin potently suppresses TNF-α-induced accumulation of NF-κB nuclear protein p65 and activation of NF-κB promoter. Our data indicate that linagliptin is an anti-inflammatory diabetic agent, with the potential to be applied as a treatment for diabetic retinopathy.     

Dipeptidyl peptidase-4 inhibitors as add-on therapy to insulin: rationale and evidences

Type 2 diabetes mellitus being a progressive disease will eventually require insulin therapy. While insulin therapy is the ultimate option, many patients still fall short of target glycemic goals. This could, perhaps be due to the fear, unwillingness and practical barriers to insulin intensification. Hypoglycemia, oedema and weight gain is another limitation. Newer therapies with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 (SGLT-2) inhibitors are exciting options as both classes do not cause hypoglycemia and are either weight neutral or cause weight loss. DPP-4 inhibitors are an appealing option as an add-on therapy to insulin especially in elderly and patients with renal impairment. Moreover, glucose-dependent insulinotropic polypeptide (GIP) mediated augmentation of glucagon by DPP-4 inhibitors could also protect against hypoglycemia. These collective properties make these class a potential add-on candidate to insulin therapy. This article will review the efficacy and safety of DPP-4 inhibitors as an add-on to insulin therapy.