Dipeptidyl Peptidase-4 Inhibitor Class Research Articles

PERSPECTIVES OF CLINICAL EXPERTS ON THE CURRENT USAGE PATTERNS AND THE PREFERENCE OF VILDAGLIPTIN IN THE TREATMENT OF TYPE 2 DIABETES

Objective: Although the efficacy and safety of vildagliptin have been proven in randomized clinical trials, data regarding the improved and up-to-date understanding on the management of Type 2 diabetes mellitus from the context of Indian diabetic patients, are scarce. This study was conducted to assess the opinions of clinical experts on the current usage patterns of vildagliptin in the management of Type 2 diabetes among Indian patients. Methods: A cross-sectional, questionnaire-based study was conducted to collect opinion among physicians in endocrinology across India between June 2022 and December 2022. Convenient sampling method was used. Descriptive statistics were used to summarize the characteristics of the study by employing frequencies and percentages. Results: It was observed that 95 out of 188 clinicians preferred dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4i) and only 35 out of 188 clinicians (18.6%) opted a combination of Metformin and DPP4 inhibitors as the first hypoglycemic agent for newly detected diabetes. In addition, 141 out of 188 (75%) prescribed vildagliptin only as their preferred drug in the class of DPP4 inhibitors. Further, the reason behind such a high-yielding response for vildagliptin among clinicians and their patients, was its weight-neutral property primarily and posing a low risk of adverse effects. Nearly, half of the clinicians reported a 0.6–1% drop in glycosylated hemoglobin (HbA1c) levels in patients within 3 months of vildagliptin use. Conclusion: This study concluded that the majority of the specialists preferred using vildagliptin among other DPP4 inhibitors and pointed out that vildagliptin lowered HbA1c within 3 months of use.

Antidiabetic omarigliptin dilates rabbit aorta by activating voltage-dependent K+ channels and the sarco/endoplasmic reticulum Ca2+ -ATPase pump.

We investigated the vasodilatory effect of omarigliptin, an oral antidiabetic drug in the dipeptidyl peptidase-4 inhibitor class, and its related mechanisms using phenylephrine (Phe)-induced pre-contracted aortic rings. Omarigliptin dilated aortic rings pre-constricted with Phe in a dose-dependent manner. Pretreatment with the voltage-dependent K+ channel inhibitor 4-aminopyridine significantly attenuated the vasodilatory effect of omarigliptin, whereas pretreatment with the inwardly rectifying K+ channel inhibitor Ba2+ , ATP-sensitive K+ channel inhibitor glibenclamide, and large-conductance Ca2+ -activated K+ channel inhibitor paxilline did not alter its vasodilation. Pretreatment with the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of omarigliptin. Neither cAMP/PKA-related signaling pathway inhibitors nor cGMP/PKG-related signaling pathway inhibitors modulated the vasodilatory effect of omarigliptin. Removal of endothelium did not diminish the vasodilatory effect of omarigliptin. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or small-conductance Ca2+ -activated K+ channel inhibitor apamin, together with the intermediate-conductance Ca2+ -activated K+ channel inhibitor TRAM-34, did not influence the vasodilatory effect of omarigliptin. In conclusion, omarigliptin induced vasodilation in rabbit aortic smooth muscle by activating voltage-dependent K+ channels and the SERCA pump independently of other K+ channels, cAMP/PKA- and cGMP/PKG-related signaling pathways, and the endothelium.

Bullous Drug Reaction with Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Hypoglycemic drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class are used as a second-line treatment for type 2 diabetes mellitus. With DPP-4 inhibitors, there have been a few reports of cutaneous side effects such as bullous response, fixed drug eruption, and photosensitivity. There is no definitive pathophysiology for the above mentioned allergic reactions. Sitagliptin phosphate belongs to the DPP-4 inhibitor class. This is a case report of a sitagliptin-induced bullous drug reaction manifesting three weeks after starting therapy. He had bullous pemphigoid-like eruptions all over the body. The patient showed improvement once sitagliptin was discontinued alon with oral and topical steroid treatment.

More recent, better designed studies have weakened links between antidiabetes medications and cancer risk.

An increasing number of studies have investigated associations of antidiabetes medications with cancer risk. Antidiabetes medications are classified by their mechanisms of action on tissues and organs. They potentially act as both causative and confounding factors in the temporal association of diabetes and cancer. To present the current evidence regarding both the carcinogenic and anti-carcinogenic effects of antidiabetes medications on cancer in humans. A review of the scientific literature. The most conclusive evidence shown of an association of antidiabetes medication with a specific cancer was for that of the thiazolidinedione pioglitazone with bladder cancer. Currently, there is inconclusive evidence regarding a possible association of incretin therapies, drugs of the dipeptidyl peptidase-4 inhibitor class, with the risk of pancreatic cancer. Insulin, sulfonylureas, metformin and sodium-glucose co-transporter-2 inhibitors appear not to be associated with increased risk of any cancer. Sparse evidence suggests possible protective effects against cancer incidence of metformin, sulfonylureas, thiazolidinediones, incretin-based drugs and sodium-glucose co-transporter-2 inhibitors. The conflicting evidence regarding associations of antidiabetes medications with cancer risk is apparently attributable to both methodological issues and to the complexity of the subject. More recent and better-designed studies have weakened the evidence for links between antidiabetes medications and cancer risk.

Clinical effectiveness of switching between DPP-4 inhibitors in patients with type 2 diabetes mellitus .

Dipeptidyl peptidase-4 inhibitors (DPP-4Is) can be classified into three categories according to their binding subsites. We wished to clarify the efficacy of switching between DPP-4Is according to their binding subsites. We undertook a retrospective study of the medical records of patients who switched from one DPP-4I to another. Among 62 patients eligible for study inclusion, the mean change in the glycated hemoglobin (HbA1c) level between different categories of DPP-4I was -0.35 (95% CI, -0.12 to -0.58; n = 59). The mean change in the HbA1c level between each class of DPP-4I was calculated. From class 3 to class 2 it was -0.45 (n = 25); from class 3 to class 1 it was -0.36 (n = 17); from class 1 to class 2 it was -0.24 (n = 7); from class 1 to class 3 it was 0.33 (n = 4); from class 2 to class 1 it was -0.30 (n = 5); from class 2 to class 3 it was -1.30 (n = 1). When switching DPP-4Is because of insufficient efficacy, consideration of their DPP-4 binding site may be beneficial.

CARMELINA: An important piece of the DPP-4 inhibitor CVOT puzzle

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of glucose-lowering agent for type 2 diabetes (T2D) that are commonly used in clinical practice. With the recent disclosure of data from the CARMELINA cardiovascular outcomes trial (CVOT), which investigated linagliptin, CV and renal outcomes data are now available for four agents in the DPP-4 inhibitor class that are approved in most markets. To consider how the CARMELINA study may be interpreted, and the relevance for our clinical practice, we convened as an expert group of diabetes specialists from the Central and Eastern Europe region to discuss the new disclosures. Our discussions revealed a general confidence in safety across the class that is further supported by CARMELINA. However, we also concluded that there are important differences in the available evidence level between agents in the setting of heart failure and data on renal outcomes. Here, we noted the clinical relevance to our practice of the study population in CARMELINA, which is unique among CVOTs in including a majority of patients with chronic kidney disease (CKD). Given the risk for future development of renal impairment that is associated with T2D even in patients without current overt CKD, we believe that the CARMELINA study provides important new insights that are clinically relevant for a broad range of patients. Finally, we discuss how these insights can be integrated into the approach to the pharmacotherapeutic management of hyperglycaemia that is recommended in newly updated guidelines.

Formulation Development and Evaluation of Vildagliptin Sustained Release Tablet

Introduction: The present research work was to design and develop the sustained release tablets of Vildagliptin. It is having a short biological half-life (1.5 h) so it is considered as a suitable drug for the formulation of sustained release tablets to prolong its therapeutic action. Vildagliptin is an oral antihyperglycemic agent of the new dipeptidyl peptidase-4 inhibitor class of drug. Materials and Methods: Sustained release tablets were prepared by direct compression technique,using polymers at different ratios. Powder blend was evaluated for bulk density, tapped density, angle of repose, Hausner’s ratio, compressibility index. Results: The physicochemical properties of tablets were found within the limits. The prepared tablets were evaluated for weight variation, thickness, hardness, % friability, % drug contents, and in vitro release. In vitro dissolution studies (USP dissolution rate test apparatus II, 50 rpm, 37°C ± 0.5°C) was carried out for 10 h using 0.1 N HCl (1.2 pH) as a dissolution medium. Conclusion: The optimized formulation F-3 was shown maximum drug release 98.43 % in 10 h of dissolution studies.

Efficacy and Safety of Teneligliptin 40mg in Type 2 Diabetes: A Pooled Analysis of Two Phase III Clinical Studies.

IntroductionTeneligliptin, an antihyperglycemic agent belonging to the dipeptidyl peptidase-4 inhibitor class, is usually prescribed at a dose of 20 mg/day. In Japan, the dose can be increased to 40 mg/day if needed. We examined the treatment response when the teneligliptin dose was increased from 20 to 40 mg in a post hoc pooled analysis of data from two 52-week, open-label, phase III clinical trials of teneligliptin 20–40 mg/day as monotherapy or combination treatment in Japanese patients with type 2 diabetes.MethodsIn both studies, patients received teneligliptin 20 mg for at least 28 weeks; thereafter the dose was increased if glycemic control was inadequate. The data set for this post hoc analysis comprised those patients whose teneligliptin dose was increased to 40 mg at week 28 (N = 204). We assessed (i) the proportion of patients achieving HbA1c reduction after teneligliptin dose increase [≤ − 0.1% change in HbA1c during weeks 28–52 (24 weeks); responders] and (ii) the response to teneligliptin 40 mg according to whether or not patients experienced HbA1c re-elevation (≥ 0.1% increase) during 28 weeks of teneligliptin 20 mg.ResultsOf 204 patients, 108 (52.9%) showed a response to teneligliptin 40 mg (HbA1c change ≤ − 0.1% during weeks 28–52) and had mean (± SD) HbA1c reduction of 0.50 ± 0.44%. Of patients showing re-elevation of HbA1c during treatment with teneligliptin 20 mg, 89/143 (62.2%) achieved HbA1c reduction after dose increase to 40 mg. Logistic regression analyses suggested that change in body weight is one of the parameters linked to HbA1c reduction after dose increase to teneligliptin 40 mg. The incidence of adverse events was not changed after teneligliptin dose increase.ConclusionIncreasing the dosage of teneligliptin from 20 to 40 mg/day has potential as a well-tolerated and effective option for treating type 2 diabetes.FundingMitsubishi Tanabe Pharma Corporation.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0372-x) contains supplementary material, which is available to authorized users.

Potentiation of endothelium-dependent vasorelaxation of mesenteric arteries from spontaneously hypertensive rats by gemigliptin, a dipeptidyl peptidase-4 inhibitor class of anti-diabetic drug.

Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are anti-diabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by 1 µM gemigliptin while not by saxagliptin and sitagliptin up to 10 µM. The ACh-EDR of SHR MA was also improved by 1 µM gemigliptin while similar recovery was observed with higher concentration (10 µM) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endotheliumdenuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with 30 µM pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.

DIPEPTIDYL DIPEPTIDASE-4: VIEW OF THE CLINICAL PHARMACOLOGIST

A deeper understanding of the pathogenesis of the 2nd type diabetes mellitus, including postprandial control of glucose homeostasis has led to new treatment strategies aimed at overcoming the dysfunction in the pancreatic islets and, in particular, acting on the incretin hormones of the gut. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are one of the first classes of oral drugs for the treatment of diabetes, developed specifically as antihyperglycemics drugs. The inhibition of the destruction of the incretin hormone -- glucagonoma peptide-1 -- has a positive effect on glucose homeostasis (including potentiation of glucose-induced increase in the level of insulin and suppression of glucagon secretion). Low risk of hypoglycemia, no significant side effects and effect on body weight distinguish the class of DPP-4 inhibitors from other groups of oral hypoglycemic tools.

Formulation Development and Evaluation of Sustained Release Matrix Tablets of Vildagliptin - Synthetic and Natural Polymers

Aim: The present research work was to design and develop the sustained release matrix tablets of vildagliptin. It is having a short biological half-life (1.5 h) so it is considered as a suitable drug for the formulation of sustained release tablets to prolong its therapeutic action. Vildagliptin is an oral antihyperglycemic agent of the new dipeptidyl peptidase-4 inhibitor class of drug. Materials and Methods: Matrix tablets were prepared by wet granulation technique, using synthetic and natural polymers at different ratios. Granules were prepared and evaluated for bulk density, tapped density, Hausner’s ratio, compressibility index. Statistical Analysis Used: The Fourier-transform infrared spectra of the vildagliptin and different polymers alone and in a combination show the compatibility of the drug with excipients. Results: The physicochemical properties of tablets were found within the limits. The prepared tablets were evaluated for weight variation, thickness, hardness, % friability, % drug contents, and in vitro release. In vitro dissolution studies (USP dissolution rate test apparatus II, 50 rpm, 37°C ± 0.5°C) was carried out for the first 2 h in 0.1 N HCl (1.2 pH) and followed 6.8 phosphate buffer for 10 h as a dissolution medium. Conclusion: The optimized formulation F-8 was shown maximum drug release 97.56 ± 0.72% in 12 h of dissolution. The release kinetic data of formulation F-8 shown zero order (R2 = 9902).

Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

AimsWe have shown that glycemic control with metformin or endothelin-1 (ET-1) inhibition with bosentan prevents and restores diabetes-mediated cerebral pathological remodeling and neovascularization. Our recent data suggest that linagliptin, a member of the dipeptidyl peptidase-4 inhibitor class of glucose-lowering agents, prevents cerebrovascular remodeling and dysfunction independent of its blood glucose lowering effects. We hypothesized that linagliptin prevents pathological neovascularization via the modulation of the ET-1 system. Materials and methods24-week old diabetic Goto-Kakizaki and nondiabetic Wistar rats were treated for 4weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to visualize the vasculature. Brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface in both the cortex and striatum. Retinal acellular capillary formation was measured. Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were treated with linagliptin with or without ET-1 dual receptor antagonist and tested for angiogenic properties with cell migration and tube formation assays. Key findingLinagliptin reduced all indices of cerebral neovascularization compared with control rats. In vitro, linagliptin normalized the augmented angiogenic properties of BMVECs isolated from diabetic animals and bosentan reversed this response. Cells from diabetic animals had higher ET-1 and less ETB receptors than in control cells. Linagliptin significantly decreased ET-1 levels and increased ETB receptors. SignificanceET system contributes to pathological neovascularization in diabetes as evidenced by restoration of functional angiogenesis by bosentan treatment and prevention of linagliptin-mediated improvement of angiogenesis in the in vitro model.

The clinical application of linagliptin in Asians.

Asia has a growing diabetic population. Linagliptin, a member of dipeptidyl peptidase-4 inhibitor class, is unique in its nonlinear pharmacokinetics with the characteristics of rapid attainment of steady state, little accumulation, predominantly nonrenal route of elimination, prolonged terminal half-life, and sustained inhibition of dipeptidyl peptidase-4 enzyme. No clinically relevant difference in pharmacokinetics was observed between Asians and non-Asians. The management of type 2 diabetes is increasingly challenging with the progression of disease, especially with the requirements of minimal hypoglycemia, weight gain, fluid retention, and other adverse effects. Linagliptin was efficacious and well-tolerated in Asian type 2 diabetes patients with or without renal or hepatic dysfunctions, comparable to that in Caucasians. This review will focus on the usage of linagliptin in clinical studies in Asians.

Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease?

Is There Evidence of Any Safety Differences Among DPP-4 Inhibitors in the Treatment of People with Type 2 Diabetes Mellitus and Reduced GFR Due to Chronic Kidney Disease?

PRM203 - Modeling the Effect of Combining Alogliptin With Dual therapy in Type 2 Diabetes

To estimate the impact of combining the dipeptidyl peptidase-4 (DPP-4) inhibitor, alogliptin, with metformin and sulfonylurea (alogliptin triple therapy) to achieve glycemic control in patients with type 2 diabetes. Since no clinical trial of alogliptin triple therapy has been conducted, the effect of adding alogliptin to dual therapy (metformin+sulfonylurea) was modeled using novel additive effect methodology, utilizing data from a previous mixed treatment comparison (MTC). The following assumptions were made: the efficacy of triple therapy can be estimated as a function of its constituent parts, and the efficacies of the constituent parts are equivalent. Pooled data for the absolute change from baseline in glycosylated hemoglobin (HbA1c) from trials of sitagliptin, linagliptin, and vildagliptin triple therapy, and for their constituent parts, informed the model. A weighting factor, β coefficient, derived from DPP-4 mono, dual, and triple therapy trials, was used to estimate the effect size for triple therapy using the sum of the constituent parts. The estimated mean β value was validated against the observed effect size of alogliptin+pioglitazone+metformin, using the pooled effect from the MTC. An estimated mean β coefficient value of 0.83 represented the DPP-4 inhibitor class. Validation of the approach resulted in a similar β coefficient for pioglitazone triple therapy (0.82). Absolute change in HbA1c from baseline for alogliptin triple therapy was estimated as -0.77% (95% CI -1.16, -0.39). Similar values were observed in the MTC for sitagliptin -0.94% (95% CI -7.34,5. 40), linagliptin -0.65 (95% CI -6.87,5. 60), and vildagliptin -0.80% (95% CI -7.00,5. 43). The wide confidence interval is consistent with expectations in the literature and is a limitation of the method employed, in that it requires the variance of the individual studies to be summated. Nevertheless, the method demonstrates the value of modeling when clinical trial evidence is not available.

What are the preferred strategies for control of glycaemic variability in patients with type 2 diabetes mellitus?

The aim of therapy in type 2 diabetes in terms of blood glucose control is to reduce to target levels HbA1c and to reduce glycaemic variability in order to avoid both hypoglycaemia and wide excursions of postprandial glucose. The first approach to reduce glycaemic variability should consider a dietary and behavioural approach aiming to limit the glycaemic index and the glycaemic load of food and the prescription and implementation of a physical activity plan appropriate for the subject. From the pharmacological point of view, the diabetes specialist has now a much richer therapeutic armamentarium. The therapeutic algorithms can help the physician to choose the most appropriate drug. The traditional approach involves: i) metformin, acting mainly on fasting blood glucose; ii) sulphonylureas, that have shown a number of drawbacks, including the high risk of hypoglycemia; iii) pioglitazone, with a substantial effect on fasting and postprandial glucose and a low risk of hypoglycaemia; iv) insulin, that can be utilized with the basal or prandial approach. The new drugs belonging to the class of dipeptidyl peptidase-4 inhibitors have shown the reduction of postprandial glucose, a neutral effect on weight increase, a good safety profile and preliminary positive cardiovascular effects. When excess weight prevails, the glucagon-like peptide-1 agonists may be the preferred choice for their effect on weight reduction, reduction of hyperinsulinism and glycaemic variability.

Safety of saxagliptin: rationale for and design of a series of postmarketing observational studies

To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. Forthcoming. This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

AHRQ's comparative effectiveness research on oral medications for type 2 diabetes: a summary of the key findings.

In 2007, the Agency for Healthcare Research and Quality(AHRQ) published a systematic review on the comparative effectiveness of oral medications for type 2 diabetes. The review included studies on the benefits and risks of oral medications used for achieving glycemic control in patients with type 2 diabetes. AHRQ published an updated review in March 2011 that summarized the benefits and harms of medications (metformin,second-generation sulfonylureas, thiazolidinediones, meglitinides,dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. To (a) familiarize health care professionals with the methods and findings from AHRQ's 2011 comparative effectiveness review on medications for adults with type 2 diabetes, (b) encourage consideration of the clinical and managed care applications of the review findings, and(c) identify limitations and gaps in the existing research with respect to the benefits and risks of oral diabetes medications. Type 2 diabetes mellitus is a major public health burden. Since the 2007 AHRQ systematic review of oral medications for type 2 diabetes, the FDA has approved several new drug classes. Therefore, in 2011, the original systematic review was updated with comparisons including the newer oral diabetes medications. The updated report expands beyond the scope of the original 2007 review by including comparisons of 2-drug combinations and the addition of more head-to-head comparisons, as well as additional adverse outcomes. A high strength of evidence showed that most medications were similarly efficacious at lowering hemoglobin A1c by about 1 absolute percentage point compared with baseline values. The addition of most oral medications to initial monotherapy further improved glycemiccontrol by lowering A1c by another 1 percentage point. The only exception was the DPP-4 inhibitor class, which did not lower A1c to the same extent as metformin when used as monotherapy. Overall, metformin was found to have a more favorable effect on body weight when compared with other medications. Two-drug combinations compared with each other demonstrated similar reductions in A1c levels. Metformin decreased low-density lipoprotein cholesterol (LDL-C) relative to pioglitazone, sulfonylureas,and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk of mild-to-moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus a thiazolidinedione. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas, and an increased risk for bone fractures relative to metformin. Diarrhea occurred more often for metformin users compared with thiazolidinedione users. Although the long-term risks and benefits of diabetes medications remain unclear, the evidence supports the use of metformin as a first-line agent.

Alogliptin: a new addition to the class of DPP-4 inhibitors

Alogliptin: a new addition to the class of DPP-4 inhibitors Radha Andukuri, Andjela Drincic, Marc RendellDivision of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, Nebraska, USABackground: Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 elevates levels of the incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation.Objective: To review the evolution of alogliptin and its pharmacokinetics, pharmacodynamics, clinical efficacy and adverse effects. In addition, we compared alogliptin to other DPP-4 inhibitors.Methods: A comprehensive literature search was performed using the term ‘alogliptin’. Original research articles and review articles as well as scientific abstracts were included. Results: Alogliptin raises postprandial levels of GLP-1. It has excellent bioavailability exhibiting a median Tmax ranging from 1 to 2 hours and a mean half-life of 12.4 to 21.4 hours across all doses. When given as monotherapy, mean hemoglobin A1c (HbA1c) reductions achieved were 0.5% to 0.6%. Combination therapy yielded similar reductions (−0.5% with metformin, −0.6% with glyburide, −0.8% with pioglitazone and –0.6% with insulin). Administration of alogliptin does not promote weight loss but has not resulted in weight gain. The agent is relatively well tolerated with few adverse effects, the major finding being a marginally higher rate of skin events, primarily pruritus.Conclusions: Alogliptin causes significant reductions in HbA1c when used alone or in combination with other oral agents in patients with type 2 diabetes similar to other DPP-4 inhibitors in current clinical use. The side effect profile also does not differ from that of other DPP-4 inhibitors. However, long-term studies are necessary before the place of alogliptin in the management of type 2 diabetes can be established.Keywords: alogliptin, DPP-4 inhibitors, GLP-1, vildagliptin, sitagliptin, saxagliptin

Alogliptin: a new addition to the class of DPP-4 inhibitors

Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 elevates levels of the incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation. To review the evolution of alogliptin and its pharmacokinetics, pharmacodynamics, clinical efficacy and adverse effects. In addition, we compared alogliptin to other DPP-4 inhibitors. A comprehensive literature search was performed using the term 'alogliptin'. Original research articles and review articles as well as scientific abstracts were included. Alogliptin raises postprandial levels of GLP-1. It has excellent bioavailability exhibiting a median T(max) ranging from 1 to 2 hours and a mean half-life of 12.4 to 21.4 hours across all doses. When given as monotherapy, mean hemoglobin A(1c) (HbA(1c)) reductions achieved were 0.5% to 0.6%. Combination therapy yielded similar reductions (-0.5% with metformin, -0.6% with glyburide, -0.8% with pioglitazone and -0.6% with insulin). Administration of alogliptin does not promote weight loss but has not resulted in weight gain. The agent is relatively well tolerated with few adverse effects, the major finding being a marginally higher rate of skin events, primarily pruritus. Alogliptin causes significant reductions in HbA(1c) when used alone or in combination with other oral agents in patients with type 2 diabetes similar to other DPP-4 inhibitors in current clinical use. The side effect profile also does not differ from that of other DPP-4 inhibitors. However, long-term studies are necessary before the place of alogliptin in the management of type 2 diabetes can be established.