Abstract
Introduction: The first GLP-1 receptor agonist (GLP-1 RA) was approved for the treatment of type 2 Diabetes mellitus in 2005. This class has gained popularity due to its anti-glycemic effect, weight loss and reduction in Cardiovascular disease outcomes1. The effects of this drug class on human thyroid cells are not well known. We hereby report a case of a woman who developed medullary carcinoma of thyroid (MTC) after using Dulaglutide.
CaseA 63-year-old female with T2DM for 3 years, taking dulaglutide for 2 years, who presented with a lump in the neck. She had no personal or family history of MEN 2 syndrome, radiation exposure or cancer. Examination showed a 2cm firm nodule in the left lower neck. Thyroid ultrasound revealed a large nodule in the left upper lobe of thyroid. Lab work showed TSH of 1.55mIU/L (0.27-4.2 mIU/L) and serum calcitonin level of 1903 pg/ml (0.0-5.1 pg/mL). FNA biopsy of the nodule showed MTC. She tested negative for RET MEN 2 gene mutation. She underwent total thyroidectomy and neck dissection. Pathological examination confirmed MTC. Post-op calcitonin improved to 2.1 pg/ml.
Discussion: GLP-1 RAs provide glycemic control by many mechanisms, including increase in insulin secretion, reduction in postprandial glucagon secretion, delaying gastric emptying, increasing satiety and weight loss. Although they have proved effective in T2DM management, the potential effects on thyroid C-cells should not be ignored. Several in-vitro studies have shown GLP-1 receptors on the rat thyroid tissue C-cells. Stimulation of these receptors resulted in increased production of calcitonin in a dose dependent manner and increased risk of C-cell tumor formation at 104 weeks. Studies initially done by Knudsen et al2 showed that this effect was not seen in humans due to lower expression of GLP-1 receptors in human thyroid tissue C cells. However, a study conducted by Gier et al showed the expression of GLP-1 receptor in some patients with C-cell hyperplasia as well as papillary and medullary carcinoma3. FDA adverse event reporting system database suggested an increased risk of thyroid cancer associated with GLP-1 RAs. It is unclear whether dulaglutide contributed to the development of MTC in this patient. She had not had a baseline calcitonin level prior to the initiation of dulaglutide. The consequence of long-term use of GLP-1 RAs in the thyroid gland in humans still remains unknown and further studies to determine if they increase the risk of MTC are warranted.
References: 1. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311. Epub 2016 Jun 13. 2. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473. Epub 2010 Mar 3. Glucagon Like Peptide-1 Receptor Expression in the Human Thyroid Gland
1,25-Dihydroxyvitamin D3Silences 3′,5′-Cyclic Adenosine Monophosphate Enhancement of Somatostatin Gene Transcription in Human Thyroid C Cells