scholarly journals Is there a Chance to Promote Arteriogenesis by DPP4 Inhibitors Even in Type 2 Diabetes? A Critical Review

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 181 ◽  
Author(s):  
Srinivasan Vedantham ◽  
Anna-Kristina Kluever ◽  
Elisabeth Deindl
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Animal Studies ◽  
Heart Function ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
Type 2 Dm ◽  
Glucagon Like Peptide 1

Cardiovascular diseases (CVD) are still the prevailing cause of death not only in industrialized countries, but even worldwide. Type 2 diabetes mellitus (type 2 DM) and hyperlipidemia, a metabolic disorder that is often associated with diabetes, are major risk factors for developing CVD. Recently, clinical trials proved the safety of gliptins in treating patients with type 2 DM. Gliptins are dipeptidyl-peptidase 4 (DPP4/CD26) inhibitors, which stabilize glucagon-like peptide-1 (GLP-1), thereby increasing the bioavailability of insulin. Moreover, blocking DPP4 results in increased levels of stromal cell derived factor 1 (SDF-1). SDF-1 has been shown in pre-clinical animal studies to improve heart function and survival after myocardial infarction, and to promote arteriogenesis, the growth of natural bypasses, compensating for the function of an occluded artery. Clinical trials, however, failed to demonstrate a superiority of gliptins compared to placebo treated type 2 DM patients in terms of cardiovascular (CV) outcomes. This review highlights the function of DPP4 inhibitors in type 2 DM, and in treating cardiovascular diseases, with special emphasis on arteriogenesis. It critically addresses the potency of currently available gliptins and gives rise to hope by pointing out the most relevant questions that need to be resolved.

scholarly journals Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

2014 ◽  
Vol 221 (1) ◽  
pp. T43-T61 ◽  
Author(s):  
Benjamin J Lamont ◽  
Sofianos Andrikopoulos
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Preclinical Studies ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
Natural Progression ◽  
Glucagon Like Peptide 1

Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

scholarly journals GLP1 and cancer: friend or foe?

2012 ◽  
Vol 19 (5) ◽  
pp. F77-F88 ◽  
Author(s):  
Roman Vangoitsenhoven ◽  
Chantal Mathieu ◽  
Bart Van der Schueren
Keyword(s):  
Type 2 Diabetes ◽  
Animal Studies ◽  
Cell Mass ◽  
The United States ◽  
Premalignant Lesions ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Agonists ◽  
Beneficial Effects ◽  
Dpp4 Inhibitors

The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.

scholarly journals Assessing Scientific Soundness and Translational Value of Animal Studies on DPP4 Inhibitors for Treating Type 2 Diabetes Mellitus

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 155
Author(s):  
Nuno Henrique Franco ◽  
Sonia Batista Miranda ◽  
Nóra Kovács ◽  
Attila Nagy ◽  
Bùi Quốc Thiện ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Animal Models ◽  
Group Size ◽  
Animal Studies ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
Wide Range

Although there is a wide range of animal models of type 2 diabetes mellitus (T2DM) used in research; we have limited evidence on their translation value. This paper provides a) a comparison of preclinical animal and clinical results on the effect of five dipeptidyl peptidase-4 (DPP4) inhibitors by comparing the pharmaceutical caused glucose changes, and b) an evaluation of methodological and reporting standards in T2DM preclinical animal studies. DPP4 inhibitors play an important role in the clinical management of T2DM: if metformin alone is not sufficient enough to control the blood sugar levels, DPP4 inhibitors are often used as second-line therapy; additionally, DPP-4 inhibitors are also used in triple therapies with metformin and sodium-glucose co-transporter-2 (SGLT-2) inhibitors or with metformin and insulin. In our analysis of 124 preclinical studies and 47 clinical trials, (1) we found no evidence of species differences in glucose change response to DPP4 inhibitors, which may suggest that, for this drug class, studies in mice and rats may be equally predictive of how well a drug will work in humans; and (2) there is good reporting of group size, sex, age, euthanasia method and self-reported compliance with animal welfare regulations in animal studies but poor reporting of justification of group size, along with a strong bias towards the use of male animals and young animals. Instead of the common non-transparent model selection, we call for a reflective and evidenced-based assessment of predictive validity of the animal models currently available.

scholarly journals Liraglutide in Adults with Type 2 Diabetes: Global Perspective on Safety, Efficacy and Patient Preference

2011 ◽  
Vol 4 ◽  
pp. CMED.S5976 ◽  
Author(s):  
Daisuke Yabe ◽  
Yutaka Seino
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Glucagon Secretion ◽  
Japanese Patients ◽  
Global Perspective ◽  
Daily Injection ◽  
Efficacy And Safety ◽  
New Class ◽  
Glucagon Like Peptide 1

Incretin-based therapies have been gaining much attention recently as a new class of therapeutics for type 2 diabetes worldwide. Among them, glucagon-like peptide-1 receptor agonist liraglutide has been rapidly increasing its global usage. Once daily injection of liraglutide significantly ameliorates glycemic control in patients with type 2 diabetes by enhancing insulin secretion and suppressing glucagon secretion glucose-dependently. Liraglutide delays gastric emptying and suppresses food intakes, both of which contribute to glucose lowering and weight reduction. Efficacy and safety of liraglutide in management of type 2 diabetes have been well documented in several key clinical trials such as series of phase 3 Liraglutide Effect and Action in Diabetes (LEAD) trials, and the liraglutide-versus-sitagliptin trial. Recent two trials dealing with monotherapy and sulfonylurea combination therapy on Japanese patients with type 2 diabetes furthermore indicate liraglutide's effectiveness in non-obese diabetes. In this review, we summarize results from such clinical trials, and discuss efficacy and safety of liraglutide in management of type 2 diabetes in various countries, along with a pitfall of liraglutide usage in real clinical setting.

DPP4 Inhibitors in the Management of Hospitalized Patients With Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

2020 ◽  
Vol 37 (9) ◽  
pp. 3660-3675
Author(s):  
Soghra Rabizadeh ◽  
Mohammad Ali Tavakoli Ardakani ◽  
Marjan Mouodi ◽  
Masoume Bitaraf ◽  
Sakineh Shab-Bidar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Hospitalized Patients ◽  
Dpp4 Inhibitors

Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes

2010 ◽  
Vol 20 (15) ◽  
pp. 4395-4398 ◽  
Author(s):  
Robert P. Brigance ◽  
Wei Meng ◽  
Aberra Fura ◽  
Thomas Harrity ◽  
Aiying Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors
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