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 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 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 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.

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

Food contaminants and programming of type 2 diabetes: recent findings from animal studies

2016 ◽  
Vol 7 (5) ◽  
pp. 505-512 ◽  
Author(s):  
S. Firmin ◽  
N. Bahi-Jaber ◽  
L. Abdennebi-Najar
Keyword(s):  
Type 2 Diabetes ◽  
Early Life ◽  
Animal Studies ◽  
Cell Mass ◽  
Later Life ◽  
Adult Health ◽  
Food Contaminants ◽  
Insulin Synthesis ◽  
Increased Risk

It is now accepted that the way our health evolves with aging is intimately linked to the quality of our early life. The present review highlights the emerging data of Developmental Origins of Health and Disease field on developmental disruption by toxicants and their subsequent effect on type 2 diabetes. We report adverse neonatal effects of several food contaminants during pregnancy and lactation, among them bisphenol A, chlorpyrifos, perfluorinated chemicals on pancreas integrity and functionality in later life. The described alterations, in conjunction with disruption of β cell mass in early life, can lead to dysregulation of glucose metabolism, insulin synthesis, which facilitates the development of insulin resistance and progression of diabetes in the adult. Despite limited and often inconclusive epidemiologic and experimental data, more recent data clearly show that infants appear to be at increased risk of type 2 diabetes in later life. This may be a result of continued exposure to chemical food contaminants during the critical window of pancreas development. In societies already burdened with increased incidence of non-communicable chronic diseases, there is a clear need for information regarding the potential harmful effects of chemical food contaminants on adult health diseases.

scholarly journals Efficacy of switching from dipeptidyl peptidase-4 inhibitors to dulaglutide in patients with type 2 diabetes

2019 ◽  
Author(s):  
Koki Chiba ◽  
Mayuko Oita ◽  
Hiroyuki Nakamura ◽  
Ayano Utsunomiya ◽  
Yui Kosumi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Plasma Glucose ◽  
Dipeptidyl Peptidase ◽  
City Hospital ◽  
Baseline Hba1c ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Agonists ◽  
Dipeptidyl Peptidase 4 Inhibitors

Abstract Background: Several reports showed that the effects of daily Glucagon-like peptidase-1 (GLP-1) receptor agonists for lowering plasma glucose and body weight are superior to those of dipeptidyl peptidase-4 (DPP-4) inhibitors, while the superiority of weekly GLP-1 receptor agonists, dulaglutide, is still unclear. The aim of this study was to evaluate the efficacy of dulaglutide therapy switching from DPP-4 inhibitors in patients with type 2 diabetes. Methods: We retrospectively evaluated the 79 Japanese patients with type 2 diabetes at the Diabetes Outpatient Clinic in Tomakomai City Hospital whose treatment was switched from DPP-4 inhibitors to dulaglutide. We investigated the change of hemoglobin A1c (HbA1c), casual plasma glucose (CPG) levels and body weight 4 weeks, 8 weeks and 12 weeks after switching from DPP-4 inhibitors to dulaglutide. In addition, we defined the group in which HbA1c was improved more than 1% as “improved group” (n = 37) and the group in which HbA1c was improved less than 1% as “non-improved group” (n = 42), and compared the patients’ background in both the groups. The subtraction of HbA1c at each weeks and baseline HbA1c was defined as ⊿HbA1c. Results: After switching to dulaglutide, HbA1c showed a significant decrease from 4 weeks later, and the effect was maintained even after 12 weeks. The “improved group” had lower estimated glomerular filtration rate (eGFR) and higher baseline HbA1c than the “non-improved group”. In the “improved group”, ⊿HbA1c showed a significant correlation with eGFR and baseline HbA1c. Conclusion: Switching from DPP-4 inhibitors to dulaglutide could improve HbA1c, especially in cases with low eGFR and high HbA1c.

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