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Trulicity ® (dulaglutide)
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Does Trulicity® (dulaglutide) cause Medullary Thyroid Carcinoma and C-Cell Hyperplasia?
Dulaglutide causes thyroid C-cell tumors in rats. The human relevance of these findings has not been determined, and the risk in humans is unknown. One case each of MTC and C-cell hyperplasia has been reported in dulaglutide clinical trials.
Content Overview
Preclinical Studies
Rodent Studies
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have induced thyroid C-cell hyperplasia and neoplasia in rodents at clinically relevant exposures.1
Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology and repeat-dose toxicity conducted with dulaglutide.2
In a 2-year carcinogenicity study in rats, dulaglutide caused statistically significant, dose-related increases in the incidence of thyroid C-cell tumors (adenomas and carcinomas combined) at ≥3 times the human clinical exposure following once weekly administration of 4.5 mg dulaglutide. The human relevance of these findings is currently unknown.2
Monkey Studies
Over the course of 12 months, treatment of monkeys with dulaglutide 8.15 mg/kg twice weekly, which was nearly 200-fold the maximum recommended human dose (MRHD) of dulaglutide 4.5 mg once weekly based on area under the curve (AUC), did not demonstrate proliferative changes in thyroid C cells.3
Clinical Studies in Adults
It is unknown whether dulaglutide causes thyroid C-cell tumors in humans, including MTC, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.2
Medullary Thyroid Carcinoma
One case of MTC was reported in an adult female patient exposed to dulaglutide for 6 months in a trial (AWARD-5) that predated the initiation of serum calcitonin monitoring.4,5
A high serum calcitonin value at the patient's termination visit prompted an analysis of a preserved baseline sample that confirmed a similarly high baseline value. The patient was subsequently discovered to be positive for a REarranged during Transfection (RET) proto-oncogene mutation, which is known to be associated with MEN 2 or familial MTC. With these data, Eli Lilly and Company (Lilly) determined this patient to have preexisting MTC.4
C-Cell Hyperplasia
In the REWIND cardiovascular outcomes trial (CVOT) of dulaglutide, where the median follow-up period was 5.4 years, one case of C-cell hyperplasia with elevated serum calcitonin levels following treatment was reported.2
Serum Calcitonin Levels
In the phase 2 and phase 3 registration trials in adults, treatment with dulaglutide 0.75 mg and 1.5 mg once weekly did not significantly increase mean serum calcitonin values compared with placebo.2
In REWIND, there were no significant differences between dulaglutide 1.5 mg and placebo in serum calcitonin changes from baseline.2
In AWARD-11, which compared dulaglutide 1.5 mg with dulaglutide 3.0 mg and 4.5 mg doses, there were no significant mean changes from baseline in serum calcitonin for any of the 3 dulaglutide dose groups.2
Clinical Study in Pediatrics
AWARD-PEDS was a phase 3, randomized, placebo-controlled study that assessed the efficacy and safety of dulaglutide 0.75 mg and 1.5 mg in pediatric patients, ages 10 to less than 18 years old, with inadequately controlled type 2 diabetes despite diet and exercise, with or without metformin and/or basal insulin.6
No treatment-emergent adverse events (TEAEs) related to malignancy or thyroid neoplasms were reported during the study.2
No clinically meaningful differences were observed among treatment groups in mean changes from baseline through week 26 or week 52 in serum calcitonin.2
Ongoing Thyroid Safety Surveillance
For rare diseases, like many cancers with long latency periods, clinical trials are too small and duration of exposure too short to definitively conclude that there is no increased risk of malignancy. Lilly will continue to carefully assess for malignancies in ongoing studies and will continue to assess risk through postmarketing cases and exposure.2
Multipharmaceutical Company MTC Registry
Lilly is currently collaborating with several other pharmaceutical companies to monitor MTC incidence associated with GLP-1 RA use in the postmarketing setting in the United States. The study is entitled An Active Surveillance Program for Cases of Medullary Thyroid Carcinoma (MTC), and further information can be found at this link.7
Postmarketing (Spontaneous) Adverse Event Reports
Postmarketing spontaneous adverse event (AE) data do not represent the incidence of an AE in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an AE.2
Spontaneous reporting has limited use due to
- lack of control population
- under-reporting or reporting bias, and
- missing or incomplete information regarding patient's medical history or concomitant medications.2
The Lilly spontaneous AE database may also include reports of AEs for products that may be available from Lilly and from other manufacturers. Although verification of product manufacturer is sought, this verification is not always obtainable. The default for these cases is to include them in the database.2
Thyroid Malignancy Preferred Terms
Based on the estimated exposure of 13,908,000 patients through September 18, 2022, the following Medical Dictionary for Regulatory Activities (MedDRA) preferred terms have been Very Rarely Reported in the Lilly spontaneous adverse event database for dulaglutide. These preferred terms include
- medullary thyroid cancer
- papillary thyroid cancer
- thyroid cancer
- thyroid cancer metastatic
- thyroid neoplasm, and
- anaplastic thyroid cancer.2
Very Rarely Reported is defined as an adverse event that has been reported at an estimated rate of <0.01% according to the reporting system information.2
Diabetes Care Article on Thyroid Cancer Risk With GLP-1 RA Treatment
On November 10, 2022, Diabetes Care published a paper, “GLP-1 Receptor Agonists and the Risk of Thyroid Cancer.” This publication concerned findings from an analysis of GLP-1 RA use and thyroid cancer among patients treated for type 2 diabetes in France.9
Using a relatively large sample from a nationally representative database, this publication presents a quantitative measure of the association indicating an elevated risk of thyroid cancer and MTC for GLP-1 RAs. The authors found that GLP-1 RAs, in particular after 1 to 3 years of treatment, moderately increased risk of all thyroid cancer and MTC. The findings do not provide conclusive evidence for a causal association between GLP-1 RA exposure and thyroid cancer, including MTC, and should be verified with additional studies due to important limitations, such as possible detection bias overestimating incidence of thyroid cancer and MTC. Clinicians and patients should continue to balance benefit and harm.9
References
1Byrd RA, Sorden SD, Ryan T, et al. Chronic toxicity and carcinogenicity studies of the long-acting GLP-1 receptor agonist dulaglutide in rodents. Endocrinology. 2015;156(7):2417-2428. http://dx.doi.org/10.1210/en.2014-1722
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Vahle JL, Byrd RA, Blackbourne JL, et al. Effects of dulaglutide on thyroid C cells and serum calcitonin in male monkeys. Endocrinology. 2015;156(7):2409-2416. http://dx.doi.org/10.1210/en.2014-1717
4Sherman SI, Kloos RT, Tuttle RM, et al. No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer. Diabet Med. 2018;35(3):381-385. http://dx.doi.org/10.1111/dme.13437
5Skrivanek Z, Gaydos BL, Chien JY, et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab. 2014;16(8):748-756. https://doi.org/10.1111/dom.12305
6Arslanian SA, Hannon T, Zeitler P, et al; AWARD-PEDS Investigators. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes. N Engl J Med. 2022;387(5):433-443. https://doi.org/10.1056/NEJMoa2204601
7An active surveillance program for cases of medullary thyroid carcinoma (MTC). Clinicaltrials.gov identifier: NCT01511393. Updated October 6, 2022. Accessed January 20, 2023. https://clinicaltrials.gov/ct2/show/NCT01511393
8Dulaglutide and potential risks of pancreatic cancer and thyroid cancer: a non-interventional PASS. EU PAS register number: EUPAS32646. Updated September 19, 2022. Accessed February 9, 2023. https://www.encepp.eu/encepp/viewResource.htm?id=45048
9Bezin J, Gouverneur A, Pénichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2023;46(2):384-390. https://doi.org/10.2337/dc22-1148
Date of Last Review: 13 January 2023