Trulicity ® (dulaglutide)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Trulicity Summary of Product Characteristics (SmPC)

Trulicity® (dulaglutide): Medullary Thyroid Carcinoma and C-Cell Hyperplasia

One case of MTC was reported in Trulicity (dulaglutide) clinical trials. This patient had a markedly elevated serum calcitonin level at baseline.

Preclinical Studies

Rodent Studies

Glucagon-like peptide-1 receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. 1

In rats, when compared to controls, dulaglutide caused both a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors, including adenomas and carcinomas, compared to controls at ≥3-fold the MRHD based on AUC.1

A 6-month carcinogenicity study was conducted with dulaglutide administered SC twice weekly in rasH2 transgenic mice and did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at doses of

  • 0.3 mg/kg

  • 1.0 mg/kg, or

  • 3.0 mg/kg.1

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. There was no tumorigenic response in a 6- month carcinogenicity study in transgenic mice.2

Monkey Studies

Over the course of 12 months, monkeys treated with dulaglutide 8.15 mg/kg twice weekly, which was nearly 200-fold the MRHD based on AUC, demonstrated no proliferative changes in thyroid C-cells.3

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology and repeat-dose toxicity conducted with dulaglutide.2

Clinical Studies

In phase 2 and phase 3 clinical studies, treatment with dulaglutide 1.5 mg and dulaglutide 0.75 mg once-weekly did not increase mean serum calcitonin values compared with placebo.2

There was no increased reporting of potential C-cell hyperplasia defined by unstimulated calcitonin measurements in dulaglutide-treated patients compared with either placebo-comparator or active-comparator treated patients.2

One case of MTC was reported in a female patients exposed to dulaglutide for 6 months in a trial 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 baseline sample that confirmed a similarly high baseline value. The patient was subsequently discovered to be positive for a RET proto-oncogene mutation associated with MEN 2 or familial MTC. With these data, Lilly determined this patient to have pre-existing MTC.4,5

However, for rare diseases, like many cancers with long latency periods, the database is too small and duration of exposure too short to definitively conclude that there is no increased risk of malignancy. Eli Lilly and Company will continue to carefully assess for malignancies in ongoing studies and will continue to assess risk through postmarketing cases and exposure.2

References

1. Byrd 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

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Vahle 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

4. Sherman 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

5. Skrivanek 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

Glossary

AUC = area under the curve

Lilly = Eli Lilly and Company

MEN 2 = Multiple Endocrine Neoplasia syndrome type 2

MRHD = maximum recommended human dose

MTC = medullary thyroid carcinoma

RET = rearranged during transfection

SC = subcutaneous

Date of Last Review: August 12, 2020


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