The rodent thyroid C-cell signal and its human relevance
What is the evidence that glucagon-like peptide-1 receptor agonism increases the risk of medullary thyroid carcinoma in humans?
§1Abstract
§1.1Review question
What is the evidence that glucagon-like peptide-1 receptor agonism increases the risk of medullary thyroid carcinoma in humans?
§1.2PICO frame
Table 1. The registered PICO frame. Any change made after protocol registration is recorded in the amendment log at §5 and is identified there as post hoc.
| Element | As registered |
|---|---|
| Population | Humans exposed to a glucagon-like peptide-1 receptor agonist. |
| Intervention | Any agent in the class. |
| Comparator | Non-exposure. |
| Outcomes | Medullary thyroid carcinoma; calcitonin elevation; thyroid C-cell hyperplasia. |
§1.3Method in brief
A review of harms, in which the absence of an event in a trial of conventional size is treated as uninformative rather than as reassurance. The protocol was registered with the Institute's secretariat before the search was executed. The search was run on 16 January 2024 across 8 sources and is reproduced in full at §2. Screening, extraction and certainty assessment were performed independently by two members of the secretariat with disagreement resolved by a third.
§1.4Conclusion
Low certainty evidence bears on this question. The rodent finding that motivates the boxed warning is reproducible and dose-dependent; the density of glucagon-like peptide-1 receptors on rodent thyroid C cells substantially exceeds that in humans, which provides a mechanistic reason to expect the finding not to transfer. Human evidence consists of calcitonin monitoring within the trial programmes, which has not shown a consistent signal, and of pharmacovigilance analyses, which are subject to notoriety bias for a warned-of event. The Institute concludes that the human relevance is not established in either direction, and that the trials are too short and too small to establish it for a cancer with this latency and incidence.
The conclusion rests on 24 contributing studies, listed with their extracted data at §3 and summarised outcome by outcome at §4.
§1.5Limitations
§1.6Consultation
This review was released for public comment before ratification. Draft safety review: the rodent thyroid C-cell signal and its human relevance received 16 submissions. Amendments arising are recorded in the amendment log and are traceable to a numbered submission.