In Reply We appreciate letters about our Review on thyroid cancer. In response to the comments by Drs Beheshtirouy and Shayanfar, the causal association between GLP-1 RA use and thyroid cancer is complex and requires careful consideration of factors that directly or indirectly influence carcinogenesis pathways such as the direct biological effects of the drug, host susceptibility factors (eg, obesity or proinflammatory states), biases embedded in clinical trials, and length of follow-up. To date, evidence investigating causality of this association is inconclusive, so it is premature and inappropriate to include GLP-1 RA use as a risk factor for thyroid cancer. Increased expression of the GLP-1 receptor has been found in medullary thyroid cancer and in nonmedullary thyroid cancer human cell lines, but GLP-1 RAs did not significantly affect proliferation of these cell lines, signaling pathways, mitochondrial respiration, or glycolysis, suggesting that there is limited carcinogenic evidence of GLP-1 RA in human tissues, particularly in nonmedullary thyroid cancer. In a systematic review and meta-analysis of 64 randomized trials, there were only 26 reporting cases of thyroid cancer associated with use of GLP-1 RAs. Although there was an increased relative risk for thyroid cancer on the fixed-effect meta-analysis (odds ratio, 1.52 [95% CI, 1.01-2.29]), statistical significance was lost in the random-effect analysis (odds ratio, 1.41 [95% CI, 0.91-2.17]), and in the leave-one-out sensitivity analysis of 5 studies. In that systematic review, an analysis that focused on the specific diagnoses of papillary thyroid cancer and medullary thyroid cancer also did not reach statistical significance.
