incretins and Neoplasms

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Neoplasms; Pancreatitis; Prospective Studies

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.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Pancreatic Neoplasms; Protective Factors; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; Urinary Bladder Neoplasms

Incretin contains two peptides named glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Drug therapy using incretin has become a new strategy for diabetic treatments due to its significant effects on improving insulin receptors and promoting insulinotropic secretion. Considering the fact that diabetes millitus is a key risk factor for almost all age-related diseases, the extensive protective roles of incretin in chronic diseases have received great attention. Based on the evidence from animal experiments, where incretin can protect against the pathophysiological processes of neurodegenerative diseases, clinical trials for the treatments of Alzheimer's disease (AD) and Parkinson's disease (PD) patients are currently ongoing. Moreover, the protective effect of incretin on heart has been observed in cardiac myocytes, smooth muscle cells and endothelial cells of vessels. Meanwhile, incretin can also inhibit the proliferation of aortic vascular smooth muscle cells, which can induce atherosclerogenesis. Incretin is also beneficial for diabetic microvascular complications, including nephropathy, retinopathy and gastric ulcer, as well as the hepatic-related diseases such as NAFLD and NASH. Besides, the anti-tumor properties of incretin have been proven in diverse cancers including ovarian cancer, pancreas cancer, prostate cancer and breast cancer.

Topics: Aging; Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Incretins; Liver Diseases; Neoplasms; Neurodegenerative Diseases; Stomach Ulcer

A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes.. A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel.. Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature.. While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Risk Factors; Thiazolidinediones

Incretin-based therapies, including the use of incretin mimetics of glucagon-like peptide-1 receptor (GLP-1R) agonists and incretin enhancers of dipeptidyl-peptidase 4 (DPP-4) inhibitors, are widely used by clinicians for glucose lowering in patients with type 2 diabetes mellitus. These agents have benefits of a lower risk of hypoglycemia, being neutral for body weight for DPP-4 inhibitors and having a potential for weight reduction with GLP-1R agonists. They may also have a neutral or beneficial cardiovascular effect. Despite these benefits, an increased risk of cancer (especially pancreatic cancer and thyroid cancer) associated with incretin-based therapies has been reported. In this article, we reviewed related literature of experimental animal and observational human studies, clinical trials, and meta-analyses published until December 15, 2014. Current studies suggested a probable role of GLP-1R activation on the development of pancreatic cancer and thyroid cancer in rodents, but such an effect in humans is not remarkable due to the lower or lack of expression of GLP-1R on human pancreatic ductal cells and thyroid tissues. Findings in human studies are controversial and inconclusive. In the analyses of the US Food and Drug Administration adverse events reporting system, a significantly higher risk of pancreatic cancer was observed for GLP-1R agonists and DPP-4 inhibitors, but a significantly higher risk of thyroid cancer was only observed for GLP-1R agonists. Such a higher risk of pancreatic cancer or thyroid cancer could not be similarly demonstrated in other human observational studies or analyses of data from clinical trials. With regards to cancers other than pancreatic cancer and thyroid cancer, available studies supported a neutral association in humans. Some preliminary studies even suggested a potentially beneficial effect on the development of other cancers with the use of incretins. Based on current evidence, continuous monitoring of the cancer issues related to incretin-based therapies is required, even though the benefits may outweigh the potential cancer risk in the general patients with type 2 diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Neoplasms; Pancreatic Neoplasms; Risk Factors; Thyroid Neoplasms

The aim of this review article is to discuss the epidemiological links between diabetes and cancer; the potential biological mechanisms linking diabetes, obesity and cancer; the risk of cancer associated with antidiabetic medications.. The data discussed in this review were obtained from the American Association of Clinical Endocrinologists Consensus Conference on Diabetes and Cancer, held in New York, NY, USA, September 2012.. The results of these studies demonstrate a significant association between diabetes and the risk of multiple cancers, including hepatocellular, pancreatic, endometrial, colorectal, breast, kidney, bladder, gastric, and ovarian cancer, non-Hodgkin lymphoma, T cell lymphoma and leukemia. There are multiple potential biological mechanisms that may link type 2 diabetes, obesity and cancer. Insulin resistance and hyperinsulinemia may lead to direct activation of the insulin receptors on tumor cells and promote tumor growth. Other potential mechanisms include increased circulating, local or bioavailable insulin-like growth factor 1, hyperglycemia, dyslipidemia, increased circulating or local estrogen, adipokines and direct and indirect effects of inflammatory cytokines. Epidemiological studies have had conflicting results regarding the associations between various classes of antidiabetic medication and cancer development. Animal studies have demonstrated increased tumor growth with certain medications, but their relevance to humans is uncertain. Metformin may, however, have protective effects on cancer development and may improve survival in patients with cancer.. We describe the current understanding of the links among diabetes, antidiabetic medication and cancer risk. We highlight some of the issues that should be addressed in the future to prevent cancer development and death in those with diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Neoplasms; Obesity; Risk Factors; Thiazolidinediones

A lot of contradictory data regarding the serious side effects of incretin-based therapies are currently available, with more being prepared or published every month. Considering the widespread use of these drugs it should be considered a priority to establish both short- and long-term risks connected with incretin treatment. We performed an extensive literature search of the PubMed database looking for articles dealing with connections between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Data obtained indicate that GLP-1 agonists and DPPIV inhibitors could increase the risk of pancreatitis and pancreatic cancer, possibly due to their capacity to increase ductal cell turnover, which has previously been found to be up-regulated in patients with obesity and T2DM. GLP-1 analogues exenatide and liraglutide seem to be connected with medullary thyroid carcinoma in rat models and, surprisingly, GLP-1 receptors have been found in papillary thyroid carcinoma, currently the most common neoplasm of the thyroid gland in humans. Changes in expression of DPPIV have been described in ovarian carcinoma, melanoma, endometrial adenocarcinoma, prostate cancer, non-small cell lung cancer and in certain haematological malignancies. In most cases loss of DPPIV activity is connected with a higher grading scale, more aggressive tumour behaviour and higher metastatic potential. In conclusion animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Models, Animal; Neoplasms; Outcome Assessment, Health Care; Pancreas; Pancreatic Diseases; Randomized Controlled Trials as Topic; Rats; Risk Factors

Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings.

Topics: Bias; Diabetes Mellitus, Type 1; Female; Hong Kong; Humans; Incretins; Insulin; Male; Neoplasms; Registries; Risk Assessment; Thiazolidinediones; Time Factors

With growing epidemiologic and molecular evidence linking the pathogenesis of diabetes mellitus and oncogenesis, the role of anti-diabetic drugs as antineoplastic agents becomes a subject of intense investigation. Several trials are underway assessing the effect of adding metformin to the existing chemotherapy regimen in the treatment of cancers. This review has a focus on other commonly used drugs classified into two broad groups, incretins and thiazolidinediones. The aim of this review is to discuss the common genetic polymorphisms implicated in the pathogenesis of type 2 diabetes mellitus (type 2 DM) and how they are linked to molecular pathways involved in carcinogenesis.

Topics: Glucose; Homeostasis; Humans; Incretins; Neoplasms; Polymorphism, Genetic; Thiazolidinediones

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.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Neoplasms; Receptors, Glucagon

Inhibitors of dipeptidyl peptidase-IV (DPP-IV) are a novel class of anti-diabetes drugs; inhibiting the breakdown of incretins, they increase their biological availability and decrease thus blood glucose levels. However, in addition to regulating glucose homeostasis, DPP-IV has many diverse functions, such as modulating cell growth, differentiation and transformation and immune function. Within the immune system, DPP-IV exerts mainly stimulating effects, while its relation to malignancies is highly variable. Therefore, long-term inhibition of this enzyme could have serious side effects including immune dysregulation or increased risk of cancer. Although the data on the effects of DPP-IV inhibitors in humans are scarce, the increased risk of infections and the tendency towards a higher incidence of some tumours fall in line with experimental evidence suggesting the possibility of their adverse immunological and oncological effects. Further research is obviously needed to clarify the effector mechanisms of DPP-IV inhibitors on immune function and tumour biology. Most important, however, is obtaining reassuring safety data from adequately powered, long-term trials of DPP-IV inhibitors in humans. In the meantime, all the potential risks of DPP-IV inhibitors should be kept in mind, and this class of drugs needs to be regarded with some degree of caution.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Immune System; Incretins; Neoplasms

Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82-0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

Topics: Aged; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Male; Neoplasms; Prospective Studies

Topics: Animals; Apoptosis; Cell Proliferation; Epitopes; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Haplorhini; Humans; Immunohistochemistry; Incretins; Neoplasms; Pancreas; Rats; Receptors, Glucagon; RNA, Messenger; Thyroid Gland