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Concept: Development of dipeptidyl peptidase-4 inhibitors


In recent years, various dipeptidyl peptidase IV (DPP-4) inhibitors have been released as therapeutic drugs for type 2 diabetes in many countries. In spite of their diverse chemical structures, no comparative studies of their binding modes in the active site of DPP-4 have been disclosed. We determined the co-crystal structure of vildagliptin with DPP-4 by X-ray crystallography and compared the binding modes of six launched inhibitors in DPP-4. The inhibitors were categorized into three classes on the basis of their binding subsites: (i) vildagliptin and saxagliptin (Class 1) form interactions with the core S1 and S2 subsites and a covalent bond with Ser630 in the catalytic triad; (ii) alogliptin and linagliptin (Class 2) form interactions with the S1' and/or S2' subsites in addition to the S1 and S2 subsites; and (iii) sitagliptin and teneligliptin (Class 3) form interactions with the S1, S2 and S2 extensive subsites. The present study revealed that the additional interactions with the S1', S2' or S2 extensive subsite may increase DPP-4 inhibition beyond the level afforded by the fundamental interactions with the S1 and S2 subsites and are more effective than forming a covalent bond with Ser630.

Concepts: Electron, Atom, Sociology, Hydrogen bond, Enzyme inhibitor, Covalent bond, Dipeptidyl peptidase-4, Development of dipeptidyl peptidase-4 inhibitors


Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents.

Concepts: Cohort study, Risk, Retrospective, Anti-diabetic drug, Dipeptidyl peptidase-4, Reliability engineering, Development of dipeptidyl peptidase-4 inhibitors, Dipeptidyl peptidase-4 inhibitors


Human immunodeficiency virus (HIV+) infection is associated with a greater risk for fasting hyperinsulinemia, impaired glucose tolerance, and higher incidence rates for vascular disease, myocardial infarction, or stroke despite effective antiretroviral therapy (cART). The underlying mechanism(s) may involve chronic low-grade systemic inflammation and immune cell activation. Dipeptidyl peptidase-4 inhibitors (DPP4i; sitagliptin) improve glucose tolerance, and may possess immunomodulatory effects, because leukocyte CD26 cell surface receptors express DPP4 activity.

Concepts: HIV, AIDS, Immune system, Inflammation, Myocardial infarction, Atherosclerosis, Dipeptidyl peptidase-4, Development of dipeptidyl peptidase-4 inhibitors


Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.

Concepts: Kidney, Diabetic nephropathy, Dipeptidyl peptidase-4, Development of dipeptidyl peptidase-4 inhibitors


Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT-2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function.

Concepts: Diabetes mellitus type 2, Diabetes mellitus, Metformin, Dipeptidyl peptidase-4, Incretin, Sitagliptin, Glucagon-like peptide-1, Development of dipeptidyl peptidase-4 inhibitors


There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI).

Concepts: Renal failure, Hypertension, Diabetes mellitus type 2, The Canon of Medicine, Anti-diabetic drug, Metformin, Development of dipeptidyl peptidase-4 inhibitors, Dipeptidyl peptidase-4 inhibitors


Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase-4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim of the present meta-analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i. Materials and Methods. Data Sources: An extensive Medline, Embase, and Cochrane Database search for “vildagliptin”, “sitagliptin”, “saxagliptin”, “alogliptin”, “linagliptin”, and “dutogliptin” was performed up to March 1st, 2013. Study Selection: Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration ≥12 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. Data Extraction and Synthesis: The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis.

Concepts: Epidemiology, Clinical trial, Medical statistics, Evidence-based medicine, Randomized controlled trial, Clinical research, Effect size, Development of dipeptidyl peptidase-4 inhibitors


This study demonstrates the Dipeptidyl peprtidase-4 (DPP-4) inhibition activity of citrus bioflavonoid nutraceuticals as compared to known gliptins. Citrus bioflavonoid standards and three commercially available citrus bioflavonoid supplements (Thompson’s Super Bioflavonoid Complex® (SB), Ethical Nutrient Citrus Plus Vitamin C® (EN), and Country Life Citrus Bioflavonoid & Rutin® (CB)) were considered in this study. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis was undertaken to identify the citrus bioflavonoids present in each supplement and the DPP-4 inhibitory activity was determined using the DPP-4 fluorometric assay. The UPLC-MS showed the retention time of standards eriocitrin 3.67 min, naringin 4.53 min, hesperidin 4.71 min, eriodictyol 5.87 min, naringenin 6.91 min, hesperetin 7.15 min. The DPP-4 inhibition of SB showed the best possible inhibition which was 99% in response to other supplements, while the DPP-4 inhibition with reference compounds and a starting concentration of 10 mg/ml was best shown for sitagliptin at 91% and vildagliptin at 91%. The citrus bioflavonoids standards were also tested for DPP-4 inhibition. Eriocitrin showed the maximum inhibition at 97%. Our data demonstrated that citrus bioflavonoids based supplements do possess DPP-4 inhibition activity. The SB had the highest activity. In particular, the naringin and hesperidin compounds have the best individual activity in comparison to that of the gliptins. Natural gliptin-like alternatives may make these supplements a promising group of natural products for use in improving blood glucose levels in prediabetes and early stages of type 2 diabetes.

Concepts: Nutrition, Diabetes mellitus, Blood sugar, Metformin, Flavonoid, Hesperidin, Flavanone, Development of dipeptidyl peptidase-4 inhibitors


Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes; however, a direct protective effect of tight glycemic control remains unproven. In fact, until 2008, when concerns related to rosiglitazone prompted regulatory agencies to mandate assessment of cardiovascular safety of new antidiabetic agents, little was known about how these medications affected cardiovascular outcomes. Since then, there has been a considerable increase in the number of cardiovascular trials, which employ a noninferiority design and focus on high-risk populations to establish safety in the shortest time possible. In this article, we summarize the 4 major cardiovascular outcome trials of oral antidiabetic agents, completed so far. These include 3 dipeptidyl peptidase-4 inhibitors (saxagliptin, alogliptin, and sitagliptin) and 1 sodium-glucose cotransporter-2 inhibitor (empagliflozin). We briefly discuss potential mechanisms, limitations, and provide an overview of the ongoing studies in this field.

Concepts: Diabetes mellitus, Diabetes, Anti-diabetic drug, Metformin, Pioglitazone, Sitagliptin, Thiazolidinedione, Development of dipeptidyl peptidase-4 inhibitors


Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes. Areas covered: An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycaemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed. Expert opinion: The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycaemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Of note, the incidence of pancreatic cancer is reduced. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.

Concepts: Hypertension, Insulin, Obesity, Randomized controlled trial, Adverse drug reaction, Pancreatic cancer, Pancreatitis, Development of dipeptidyl peptidase-4 inhibitors