sitagliptin-phosphate and Thyroid-Neoplasms

Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. However, it remains unclear whether DPP4 expression plays a prognostic role.. The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved.. We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model.. High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high-DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-β signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-β receptor I expression.. Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer.

Topics: Adult; Animals; Blotting, Western; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Immunohistochemistry; In Vitro Techniques; Male; Mice; Middle Aged; Molecular Targeted Therapy; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; RNA, Small Interfering; Signal Transduction; Sitagliptin Phosphate; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transforming Growth Factor beta; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

Whether sitagliptin may increase thyroid cancer risk has not been investigated in the Asian populations. This study evaluated the association in Taiwanese patients with newly diagnosed type 2 diabetes from 1999 to 2008 by using the reimbursement database of the National Health Insurance. They should have been followed for at least 6 months after March 1, 2009, the date when sitagliptin was approved for reimbursement. Patients newly treated with sitagliptin (n=58238, "ever users of sitagliptin") or other antidiabetic drugs (n =312853, "never users of sitagliptin") were followed until December 31, 2011. The treatment effect (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Results showed that the respective number of incident thyroid cancer in ever users and never users was 28 and 172, with respective incidence of 29.34 and 22.13 per 100,000 person-years. The overall hazard ratio (95% confidence interval) of 1.516 (1.011-2.271) suggested a significantly higher risk associated with sitagliptin use. In tertile analyses, the hazard ratio for the first ( < 6.53 months), second (6.53-14.00 months) and third ( > 14 months) tertile of cumulative duration was 1.995 (1.015-3.919), 2.516 (1.451-4.364) and 0.595 (0.244-1.449), respectively. Analyses after excluding patients with benign thyroid disease and in a subsample matched on baseline characteristics supported the findings in the original sample. In conclusion, sitagliptin use is associated with an increased risk of thyroid cancer, especially during the first year of its treatment.

Topics: Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Sitagliptin Phosphate; Thyroid Neoplasms

Topics: Animals; Breast Neoplasms; Calcitonin; Carcinoma, Medullary; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infections; Liraglutide; Pancreatitis; Pharmacovigilance; Pioglitazone; Pyrazines; Risk Assessment; Safety-Based Drug Withdrawals; Sitagliptin Phosphate; Species Specificity; Thiazolidinediones; Thyroid Neoplasms; Triazoles; Urinary Bladder Neoplasms

Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.. We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls. The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.. Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).. These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Topics: Adverse Drug Reaction Reporting Systems; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Odds Ratio; Pancreatic Neoplasms; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Thyroid Neoplasms; Triazoles; United States; United States Food and Drug Administration; Venoms

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Pancreatic Neoplasms; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Thyroid Neoplasms; Triazoles; Uncertainty; Venoms