Once-Weekly Exenatide Treatment Does Not Increase Risk for Medullary Thyroid Carcinoma

Treatment with once-weekly exenatide 2 mg does not increase serum calcitonin concentrations or the risk for medullary thyroid carcinoma.

Treatment with once-weekly exenatide 2 mg does not increase serum calcitonin concentrations or the risk for medullary thyroid carcinoma (MTC), according to a post hoc analysis of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial published in Diabetes Care.

Animal studies have reported that glucagon-like peptide-1 receptor agonists liraglutide and exenatide are associated with an increase in serum calcitonin levels, a well-known biomarker for MTC. In response, regulatory agencies required assessment of the potential effect of these treatments on calcitonin levels, C-cell hyperplasia, and the risk for malignancy during cardiovascular outcome trials.

Data from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed no increase in calcitonin concentrations or incidence of MTC with liraglutide. Using data from EXSCEL, the researchers assessed the clinical effect of monitoring serum calcitonin levels and incidence of MTC in patients receiving once-weekly exenatide 2 mg.

During the EXSCEL study, serum calcitonin concentrations were measured at baseline, annually throughout follow-up, and at the final study visit. If calcitonin levels were elevated at baseline (>40 ng/L) or during follow-up (≥50 ng/L), the study medication was stopped immediately.

The analysis included 12,831 participants with available baseline calcitonin concentration and at least 1 additional measurement during follow-up. Increased calcitonin concentration at baseline was found in 52 patients (30 in the exenatide group and 22 in the placebo group). During follow-up, an additional 23 patients (15 in the exenatide group and 8 in the placebo group) were found to have elevated calcitonin concentrations.

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The investigators reported that 3 participants were diagnosed with MTC, including 2 patients treated with exenatide and 1 patient in the placebo group. In all cases, calcitonin levels were markedly elevated at baseline (>400 ng/L).

Of the 75 patients with increased calcitonin concentration at baseline or during follow-up, 70 participants had available follow-up data. Most patients (37 patients, 53%) had some investigation (eg, a diagnostic test or procedure) for the increased calcitonin concentration. Thyroid ultrasound was the most common investigation (32 patients, 87%), and 75% of cases reported benign findings with no need for further investigation.

A small minority was referred for fine needle aspiration (9 patients, 24%), with no need for additional interventions in 5 cases and surgical intervention in 4 (11%). Of these 4 patients, 3 were eventually diagnosed with confirmed MTC and underwent total thyroidectomy.

The researchers acknowledged several limitations to this study, including the relatively short follow-up (3.2 years), retrospective nature of calcitonin follow-up data, and lack of predefined strategy for follow-up and management of elevated calcitonin concentrations.

The investigators stressed that all 3 MTC cases were identified on the basis of calcitonin concentration at baseline, and that regular calcitonin monitoring during exenatide treatment did not identify additional MTC cases. “Calcitonin screening is not recommended in clinical care except in the evaluation of nodular thyroid disease, if a family history of MTC exists, or if multiple endocrine neoplasia type 2 is suspected,” concluded the researchers.

EXSCEL was sponsored and funded by Amylin Pharmaceuticals, Inc.

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Bethel MA, Patel RA, Thompson VP, et al. Changes in serum calcitonin concentrations, incidence of medullary thyroid carcinoma, and impact of routine calcitonin concentration monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) [published online April 22, 2019]. Diabetes Care. doi:10.2337/dc18-2028