Abstract
KEY POINTS
Glucagon-like peptide 1 receptor agonist (GLP-1RA) exposure did not alter tumor growth or progression in a cohort of patients with papillary thyroid carcinoma undergoing active surveillance.
Larger and longer studies are needed to confirm this novel study’s findings; however, in general, this supports the safety of GLP-1RAs in the setting of differentiated thyroid cancer.
Additional studies are needed to explore whether exposure to GLP-1RAs is associated with tumor volume reductions.
SUMMARY
Background
Over the past two decades, the advent of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) has not only revolutionized treatment for diabetes and obesity but also has had a substantial impact on the reduction of cardiometabolic complications that are associated with these disorders. 1 Ongoing innovation and demand in the field of GLP-1RAs are highly anticipated.
Currently, the Food and Drug Administration (FDA) has placed a black box warning on GLP-1RAs advising against use in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia (MEN) syndrome. This is based on studies in mice that demonstrated that exposure to GLP1-RAs increased calcitonin and C-cell proliferation. Importantly, this was determined to be independent of RET activation, which is often the associated proto-oncogene for MTC seen in humans. 2 To date, long-term evaluation of patients exposed to GLP1-RAs has not shown an increased incidence of MTC.3,4
Although initial concern focused on MTC, GLP-1 receptor expression is also present in thyroid follicular cells and papillary thyroid cancers (PTCs), 5 and naturally, this prompts the question of whether GLP-1RA exposure could impact differentiated thyroid cancer incidence and growth. Investigation thus far has been observational in nature and has yielded mixed results. Given the prevalence of thyroid nodules and thyroid cancer compounded with the prevalence of obesity and diabetes, it is imperative that we understand whether there is truly a causal correlation, as not treating diabetes and obesity with all tools available may lead to negative cardiometabolic consequences. This study 6 aimed to describe the outcomes of GLP-1RA exposure on low-risk PTC undergoing active surveillance.
Methods
This retrospective matched observational cohort study was performed at Memorial Sloan Kettering Cancer Center (MSKCC) in patients with low-risk PTC, ≤1.5 cm, undergoing active surveillance per previously described MSKCC study protocol. 7 Additional inclusion criteria were ultrasonography performed at MSKCC and follow-up for ≥6 months.
Of the 441 patients with low-risk PTC undergoing active surveillance at MSKCC, 22 had been exposed to GLP-1RAs (any route and any FDA-approved formulation, including dual agonists) for treatment of either diabetes or obesity. Of these 22 patients, only 18 were analyzed, 3 patients were excluded owing to lack of ultrasonography follow-up at MSKCC, and 1 patient was excluded owing to <6 months of GLP-1RA exposure.
This cohort of 18 patients with 19 low-risk PTCs ≤1.5 cm undergoing active surveillance with exposure to GLP-1RA for ≥6 months was matched 1:2 by body mass index (BMI) and tumor size, to a cohort of 37 patients with 38 PTCs who were undergoing active surveillance but who had not been exposed to GLP-1RA. Tumor size changes and tumor volume kinetics were then compared between these two cohorts.
Results
The median follow-up for the combined cohorts was 5.5 years. The median GLP-1RA exposure was 25 months (interquartile range, 14–34). At baseline, there were no significant differences in age, sex, BMI, race/ethnicity, or tumor size. The only significant baseline difference was a higher incidence of diabetes in the cohort exposed to GLP-1RA (p = 0.008).
There were no significant differences in PTCs that were exposed to GLP-1RA versus those not exposed to GLP-1RA in terms of tumor volume increase >72% (2 of 19 vs. 1 of 38, p = 0.21), growth by ≥3 mm (2 of 19 vs. 4 of 38, p = 1.0), or in multiple tumor kinetic parameters. Further analysis showed a significant and inverse correlation with time of GLP-1RA exposure and maximal volume change (Spearman rho, –0.51; p = 0.02). At study close, no patient in either cohort had opted for surgical intervention, and none were found to have developed locoregional or distant metastases.
Conclusions
This novel study demonstrates that GLP-1RA exposure in patients with PTC undergoing active surveillance does not alter tumor progression.
COMMENTARY
This study is the first to examine the effects of GLP-1RA exposure on patients with PTC undergoing active surveillance. We applaud the authors for their work, as this analysis of patients with a known diagnosis of PTC was much needed and provides additional perspective. This study, along with the long-term follow-up of randomized drug trials3,4 and recent large meta-analyses, 8 continues to suggest that the previously reported observational increased incidence of PTC is less likely due to the GLP-1RA exposure and more likely due to a detection bias.
In our practices as academic endocrinologists, we continue to see hesitancy to consider the use of GLP-1RAs among patients with a history of differentiated thyroid cancer or thyroid nodules, as well as hesitancy by providers to prescribe GLP-1RAs in these patients. We practice in the state of North Carolina, where over a third of the population has a BMI >30; diabetes is present in >10% of adults and is the seventh leading cause of death in the state.9,10 We worry that hesitancy and uncertainty could prevent shared decision-making conversations. This potentially leads to lost opportunities to provide life-changing results for patients by way of improved diabetes control and body-weight reductions not previously seen by other pharmacotherapies.
Interestingly, this study also showed a significant correlation between the time of GLP-1RA exposure and decrease in tumor volume; however, given the small numbers, it is unclear whether this is due to GLP-1RA exposure itself, associated weight loss, or other metabolic factors, as it has been shown that increased weight and elevated insulin levels themselves have been associated with increased incidence of thyroid cancer.11,12 These findings highlight the need for further investigation in larger cohorts with longer follow-up.
Overall, we encourage clinicians to have open conversations with their patients regarding what the current data show regarding possible GLP-1RA exposure and differentiated thyroid cancer associations. Although a lack of certainty can make these conversations more difficult, this empowers joint decision-making, weighing the possible risks of intervention with the risks of no intervention.