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Changes in Serum Calcitonin Concentrations, Incidence Of EMERGING THERAPIES: DRUGS AND REGIMENS Diabetes Care Volume 42, June 2019 1075 M. Angelyn Bethel,1 Rishi A. Patel,1 Changes in Serum Calcitonin Vivian P. Thompson,2 Peter Merrill,2 Shelby D. Reed,2 Yanhong Li,2 Concentrations, Incidence of Sara Ahmadi,3 Brian G. Katona,4 Stephanie M. Gustavson,4 Peter Ohman,4 Medullary Thyroid Carcinoma, Nayyar Iqbal,4 Robert F. Gagel,5 Adrian F. Hernandez,2,3 John B. Buse,6 and and Impact of Routine Calcitonin Rury R. Holman,1 Concentration Monitoring in the for the EXSCEL Study Group EXenatide Study of Cardiovascular Event Lowering (EXSCEL) Diabetes Care 2019;42:1075–1080 | https://doi.org/10.2337/dc18-2028 OBJECTIVE Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. RESEARCH DESIGN AND METHODS 1 EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or Diabetes Trials Unit, University of Oxford, Ox- ford, U.K. placebo. Serum calcitonin was measured at baseline (with trial medication 2Duke Clinical Research Institute, Duke University discontinued if >40 ng/L) and annually thereafter (with trial medication discon- School of Medicine, Durham, NC tinued if ‡50 ng/L). Median calcitonin concentrations were calculated at each time 3Departmentof Medicine,Duke UniversitySchool point, and thyroid malignancies were collected prospectively. Data regarding of Medicine, Durham, NC 4AstraZeneca Research and Development, Gai- follow-up after an elevated calcitonin were collected retrospectively. thersburg, MD 5MD Anderson Cancer Center, University of RESULTS Texas, Houston, TX At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, 6Department of Medicine, University of North and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had Carolina School of Medicine, Chapel Hill, NC calcitonin ‡50 ng/L in the intention-to-treat population. Median calcitonin con- Corresponding author: Rury R. Holman, rury [email protected] centrations were similar between treatment groups at baseline with no increase fi Received 25 September 2018 and accepted 27 over time. Con rmed MTC occurred in three participants (2 exenatide and 1 February 2019 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, Clinical trial reg. no. NCT01144338, clinicaltrials and 655 ng/L). .gov This article contains Supplementary Data online CONCLUSIONS at http://care.diabetesjournals.org/lookup/suppl/ During a median 3.2 years’ follow-up, no change in serum calcitonin was seen with doi:10.2337/dc18-2028/-/DC1. exenatide therapy. The three confirmed cases of MTC all occurred in participants © 2019 by the American Diabetes Association. with markedly elevated baseline calcitonin levels, measured prior to trial med- Readers may use this article as long as the work fi is properly cited, the use is educational and not ication administration. Regular calcitonin monitoring identi ed no additional cases fi fi for pro t, and the work is not altered. More infor- of MTC, suggesting no bene t of routine calcitonin monitoring during exenatide mation is available at http://www.diabetesjournals treatment. .org/content/license. 1076 Calcitonin Monitoring During Exenatide Therapy Diabetes Care Volume 42, June 2019 Glucagon-like peptide 1 receptor ago- protocol was approved by the ethics Investigators and participants were nists (GLP-1 RAs) are effective glucose- committee at each participating site, blinded to serum calcitonin concentra- lowering treatments for type 2 diabetes and all participants provided written in- tion values unless a protocol-defined that present a low risk of hypoglycemia, a formed consent for trial participation. elevation was detected. If a serum cal- potential for weight loss, and, for some Briefly, 14,752 adults with type 2 diabe- citonin concentration was elevated ei- agents, reduced risk of major adverse tes who either had experienced a prior ther at baseline (.40 ng/L) or during cardiovascular events (1,2). Preclinical cardiovascular event (10,782 [73.1%]) or follow-up ($ 50 ng/L), site investigators rodent studies of the GLP-1 RAs liraglu- were at any level of risk for a primary were given the numeric result, directed tide and exenatide demonstrated a dose- cardiovascular event (3,970 [26.9%]) to discontinue study medication imme- dependent increase in serum calcitonin were randomized 1:1 to receive once- diately, and asked to alert the partici- levels, a biomarker for thyroid C-cell dis- weekly exenatide 2 mg or placebo, in pant’s usual care provider to consider eases such as medullary thyroid car- addition to usual care, and followed up additional follow-up investigations. Dur- cinoma (MTC), raising concern about over a median of 3.2 years. The trial ing the trial, unblinded serum calcitonin potential off-target effects on the thyroid inclusion and exclusion criteria are listed concentrations were reviewed at regular gland (3). Liraglutide use was associated in Supplementary Data. The primary out- intervals by the Data and Safety Moni- with development of C-cell carcinomas in come was defined as the first occurrence toring Board, which included a thyroid rats (already predisposed to spontaneous of a three-component major adverse car- cancer specialist (R.F.G.). development of C-cell lesions with age) diovascular event outcome (death from Data on all malignancies, including and in female mice exposed to very high cardiovascular causes, nonfatal myocar- MTC, were collected prospectively doses (;45 times that used in human dial infarction, or nonfatal stroke) in throughout the trial, and all malignancies studies) (4,5).Incontrast, preclinical stud- a time-to-event analysis. Protocol-specified were adjudicated using prespecified cri- ies with exenatide demonstrated in- exclusion criteria related to calcitonin and teria (Supplementary Data) by an indepen- creased incidence of C-cell adenomas thyroid tumors included a baseline serum dent committee, blinded to treatment (not carcinomas) in female rats at expo- calcitonin concentration .40 ng/L or assignment. sures 130 times the clinical dose and no a personal or family history of MTC or Impact of Routine Serum Calcitonin C-cell pathology in mice (6). Neither lir- multiple endocrine neoplasia type 2. Ran- Concentration Monitoring aglutide nor exenatide was associated domization and administration of trial Site investigators were asked to complete with C-cell pathology in primates (3,6). medicationwerepermittedpriortoknow- an ancillary calcitonin case report form Because of these species differences in ing the baseline calcitonin value. If an (Supplementary Data) for all participants C-cell response, the relevance to humans elevated baseline calcitonin value (.40 who had an elevated serum calcitonin of the preclinical carcinogenicity data ng/L) was discovered, trial medication was concentration at baseline (.40 ng/L) or was unclear at the time that large-scale discontinued immediately, with the par- during follow-up ($50 ng/L) retrospec- cardiovascular outcomes trials (CVOTs) ticipant continuing to be followed until tively between July 2016 and May 2017. with GLP-1 RAs were initiated. As a result, trial cessation. Additionally, the develop- Thisform capturedadditionalinformation regulatory agencies mandated regular ment of a serum calcitonin concentration about the participants such as referral to serum calcitonin concentration monitor- $50 ng/L during postrandomization ne- specialists, investigations, and procedures ing during GLP-1 RA CVOTs for safety cessitated immediate discontinuation of performed. Repeat calcitonin measure- reasons to assess the potential impact on trial medication and notification of the ments were performed outside of the calcitonin levels over time and to eval- participant’s usual care provider, with the trial following referral to usual care pro- uate risks for C-cell hyperplasia or ma- participant continuing to be followed viders or thyroid specialists. Whether or lignancy. We report the results for the until trial cessation. not a repeat measurement was per- calcitonin data collected during the EX- formed in the local health care setting enatide Study of Cardiovascular Event Evaluation was captured on the ancillary calcitonin Lowering (EXSCEL), as well as the inci- Safety Outcomes case report form, but the results of any dence of MTC during the trial, and the Serum calcitonin concentrations were such measurements were not collected impact of routine serum calcitonin con- measured at baseline, annually through- robustly, as it was not mandatory for site centration monitoring in patients with out follow-up, and at the final study investigators to record them. type2diabetes treated with once-weekly follow-up visit. Samples, which were exenatide 2 mg. not required to be taken while fasting, Statistical Analysis were analyzed at local laboratories until Baseline characteristics were summarized RESEARCH DESIGN AND METHODS July 2010, after which they were all for participants with and without a ser- Trial Design analyzed at a central laboratory (Quin- um calcitonin concentration elevation at The design and primary results of EXSCEL tiles Laboratories Ltd.) using a Siemens any time during the trial as median (25th
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