This past week, a close friend, Jesse Cogan, passed away. He was a dynamo in high school, went to YU, excelled in the public relations industry, and was a devoted husband and father. Oncology makes death a matter of quantity, but sometimes one has to reflect on quality, and Jesse brings that to the fore. Baruch Dayan Emet.
Diabetes is an extremely common disease in our society, in part stemming from the epidemic of obesity; thus, there are approximately 24 million people in the U.S. with type 2 diabetes. Diabetes has the possibility of profound negative aftereffects, so it is good that many new approaches to its management have been developed. How and when they are utilized varies and each has its positive aspects as well as its adverse effects.
One class of pharmacologic agents for diabetes are the glucagon-like peptide-1 receptor agonists, now widely used for the treatment of type 2 diabetes due to their ability to improve glucose control without causing significant hypoglycemia. I will not go into their mechanism of action, but simply indicate that they are used as first-line therapy for type 2 diabetics, especially in those with coronary artery disease, heart failure or obesity. A meta-analysis three years ago found a 12% reduction in overall mortality when these drugs were used under these conditions. They are frequently used off-label as well for type 1 diabetes or for other conditions, such as obesity and polycystic ovary syndrome. Recently they have gotten more press and discussion because of their use for weight control and obesity, as with the drug Ozempic, a member of this class of drugs.
GLP-1 receptor agonists are marketed by a number of pharmaceutical companies. The first one approved by the FDA was Byetta in 2005 (AstraZeneca). Other products in this class include Saxenda, Victoza, Tanzeum, Trulicity, Adlyxin, Ozempic, Mounjaro and others. As I mentioned, aside from their use in diabetes, they have been sought, on- or off-label, by celebrities and others for weight loss.
So why are they of interest to us in a column devoted to cancer? Studies as far back as 1986 in rodents found an increased risk of thyroid cancer, especially medullary thyroid cancer, in both rats and mice with exposure to this class of drugs. Exactly what the import of this was for humans was unclear. Medullary thyroid cancer is an uncommon form of thyroid cancer—there are only 600-800 cases of medullary thyroid cancer annually in the U.S. under normal circumstances. In addition, the levels of serum calcitonin, a hormone that is elevated in patients with medullary thyroid cancer, were found to be minimally elevated in some clinical trials of GLP-1 receptor agonists.
The FDA in its review for marketing approval decided that the risk for thyroid cancer was acceptably low. However, it did require that there be a warning label on the package and in advertising for this class of drugs. In addition, it required the drug manufacturers to establish a drug registry for a period of 15 years in order to monitor the national incidence rates of medullary thyroid cancer in the time period following the marketing of these drugs. (Note: I myself sit on the advisory committee for that study).
To investigate this issue in the meantime, a meta-analysis was recently published in the journal Diabetes Obesity and Metabolism by investigators from the University of Florence in Italy. They combined data from 64 trials and found a significant increase in the risk of thyroid cancer (relative risk 1.52, 95% confidence limit 1.01-2.29). No association was found for papillary thyroid cancer, the most common type of thyroid cancer. However, there was an increased risk of medullary thyroid cancer, but because of small numbers, the 95% confidence limits were wide (relative risk 1.44, 95% confidence limits 0.23-9.16). The investigators concluded that a longer follow-up time was needed in order to reach reliable conclusions.
Another study, conducted in France, was published in the journal Diabetes Care in 2023. This retrospective cohort study looked at approximately 48,000 patients with type 2 diabetes who were treated between 2006 and 2018. There were 2,562 patients in this cohort who were diagnosed with thyroid carcinoma. Looking at the risk of thyroid cancer for those exposed to a GLP-1 receptor agonist in the six years prior to the thyroid cancer diagnosis as compared to the 45,184 controls, the risk of thyroid cancer was found to be 1.58 (95% confidence interval 1.27-1.95). For medullary thyroid cancer, the observed risk was even greater, i.e., 1.78 (95% confidence interval 1.04-3.05). Certainly, this study does raise concerns that these drugs might increase the risk of these types of cancer. However, as the investigators caution, the absolute risks are not very high and these drugs are very beneficial, so perhaps we should not lose sight of the benefit/risk trade-off.
I should add a caveat that an interesting methodological bias may be operating in these studies. The clinicians and the patients are presumably aware that there is a possible increased risk of thyroid cancer in users of this class of drugs. Therefore, users of the drugs will be subjected to more intensive testing and monitoring for thyroid cancer than the general population. Since there is a well-known phenomenon of undiagnosed indolent thyroid cancer, this increased testing will possibly lead to increased diagnosis of thyroid cancer among users of GLP-1 agonist drugs, which will lead to the observation of an increased risk, but this may be an artifactual overestimate of the truth—a misleading elevated risk due to so-called detection bias.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.