Volume 219 - Issue 4
Current and emerging medications for the management of obesity in adults
Authors: Rosalind Walmsley and Priya Sumithran
Med J Aust 2023; 219 (4): 188-188. || doi: 10.5694/mja2.52031
Published online: 21 August 2023
Published online: 21 August 2023
Reply
In reply: We thank Inglis and colleagues1 for their interest in our review article2 and for highlighting the important issue of a possible signal for increased thyroid cancer risk with glucagon‐like peptide 1 (GLP‐1) receptor agonists raised in the study by Bezin and colleagues.3
We agree that the study's findings are interesting, but, as the authors and associated commentary4 acknowledge, they could also relate to detection bias and the higher prevalence of obesity (a risk factor for thyroid cancer5) in GLP‐1 receptor agonist users. There is also the possibility of ascertainment bias, given the higher prevalence of thyroid disorders — and, therefore, possibility of increased surveillance — in patients exposed to GLP‐1 receptor agonists.
Although sustained administration of GLP‐1 receptor agonists stimulated thyroid C cell hyperplasia in rats and mice,6 important species‐specific biological differences must be considered. The expression of GLP‐1 receptors in thyroid C cells in humans and non‐human primates is much lower than in rats and mice, and medullary thyroid cancer (MTC) did not develop in monkeys after 20 months of liraglutide treatment at doses up to 60‐fold higher than human clinical exposure levels.6
No signal for MTC was detected in meta‐analyses of clinical trials investigating GLP‐1 receptor agonists.7 Neither the Therapeutic Goods Administration nor the European Medicines Agency have requested the addition of a boxed warning about the risk of MTC, but the product information for GLP‐1 receptor agonists notes that thyroid C cell tumours occurred in preclinical studies, and that even though the relevance for humans is considered to be low, it cannot be completely excluded.
Further long term monitoring is required to establish the risks and benefits of prolonged use of GLP‐1 receptor agonists, including careful monitoring of thyroid cancer risks. We agree with Inglis and colleagues that clinicians and patients should always consider the overall balance of risks and benefits of treatments in relation to individual circumstances. Given the rarity of MTC, the data available at present indicate that for most patients treated with GLP‐1 receptor agonists for diabetes, a possible small increase in absolute risk (if confirmed) will be outweighed by the reduction in risk of cardiovascular and renal events.
Competing interests
Priya Sumithran has co‐authored manuscripts that have had medical writing assistance provided (Novo Nordisk). No medical writing assistance was received for this manuscript. Priya Sumithran is in the leadership group of the Obesity Collective.
Acknowledgements
Priya Sumithran is supported by an Investigator Grant from the National Health and Medical Research Council (1178482).
References
- Inglis JM, Kichenadasse G, Mangoni AA. Current and emerging medications for the management of obesity in adults [letter]. Med J Aust 2023; 219: 187‐188.
- Walmsley R, Sumithran P. Current and emerging medications for the management of obesity in adults. Med J Aust 2023; 218: 276‐283. https://www.mja.com.au/journal/2023/218/6/current‐and‐emerging‐medications‐management‐obesity‐adults
- Bezin J, Gouverneur A, Pénichon M, et al. GLP‐1 receptor agonists and the risk of thyroid cancer. Diabetes Care 2023; 46: 384‐390.
- Thompson CA, Stürmer T. Putting GLP‐1 RAs and thyroid cancer in context: additional evidence and remaining doubts. Diabetes Care 2022; 46: 249‐251.
- Kitahara CM, Pfeiffer RM, Sosa JA, Shiels MS. Impact of overweight and obesity on US papillary thyroid cancer incidence trends (1995–2015). J Natl Cancer Inst 2020; 112: 810‐817.
- Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon‐like peptide‐1 receptor agonists activate rodent thyroid C‐cells causing calcitonin release and C‐cell proliferation. Endocrinology 2010; 151: 1473‐1486.
- Sattar N, Lee M, Kristensen S, et al. Cardiovascular, mortality, and kidney outcomes with GLP‐1 receptor agonists in patients with type 2 diabetes: a systematic review and meta‐analysis of randomised trials. Lancet Diab Endocrinol 2021; 9: 653‐662.