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• W1626487600 abstract "The United States Food and Drug Administration (FDA)-approved product information (PI) statement for liraglutide (Victoza; NovoNordiskPrinceton, NJ, USA) begins with a boxed warning section stating that there may be “risk of thyroid C-cell tumors” with the use of this agent.1 This has engendered concern and it is appropriate to ask what is the strength of the evidence that liraglutide may affect the parafollicular cells of the thyroid in humans. The PI states that: In trials with on-treatment serum calcitonin measurements out to 5–6 months, 1.9% of patients treated with Victoza 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range (5.0 ng/L for women and 8.4 ng/L for men) compared to 0.8–1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% (respectively).1 Furthermore, the PI states that “In the clinical trials, there have been four reported cases of thyroid C-cell hyperplasia among Victoza-treated patients and one case in a comparator-treated patient (1.3 vs 0.6 cases per 1000 patient-years)”, with one case reported subsequently in a patient receiving liraglutide and one case of medullary carcinoma of the thyroid (MCT) in a comparator patient; four of the five liraglutide-treated patients with C-cell hyperplasia had elevated baseline as well as on-treatment calcitonin levels.1 There is evidence in rodents of a relationship between glucagon-like peptide (GLP)-1 and calcitonin. It has been demonstrated that GLP-1 receptors are present in rodent C-cells2 and GLP-1 stimulates C-cell secretion of both calcitonin and calcitonin gene-related peptide.3 Mice not expressing GLP-1 have reduced thyroid calcitonin mRNA, osteoporosis, bone fragility, and increased osteoclasts due not to a direct effect of GLP-1 on bone cells, but rather to calcitonin deficiency,4 suggesting that the GLP-1–calcitonin axis plays an important part in calcium homeostasis in these species. However, despite this relationship in rodents, thyroid GLP-1 receptors are not demonstrable in humans, and the strong dose–response effect of GLP-1 and the GLP-1 receptor activators liraglutide and exenatide in increasing calcitonin release from rat C-cell lines has not been demonstrated in human thyroid C-cells.5 Elevated levels of serum gastrin have long been recognized to increase circulating calcitonin concentrations, leading to the use of pentagastrin as a stimulatory test for the diagnosis of MCT.6 However, fasting and pentagastrin-stimulated calcitonin levels are increased in people treated either with histamine H2 receptor blockers (H2RB) or with proton pump inhibitors (PPI),7 with six of 10 healthy men receiving omeprazole 20 mg twice daily for 4 days having basal calcitonin >10 ng/L.8 Given the association between liraglutide (and other GLP-1 receptor activators) and gastrointestinal symptoms,1 the question may then be asked as to whether those people receiving the 1.8 mg/day dose simply were using more gastric acid-suppressing medication, leading to the higher calcitonin levels. Parks and Rosebraugh9 from the US FDA recently argued in the pages of the New England Journal of Medicine that the alarming boxed warning of the liraglutide PI should, in essence, be superseded by the “low risk to humans” of the modest increases in calcitonin levels seen in the clinical trials. Indeed, depending on the calcitonin assay used, 3–10% of people have baseline calcitonin levels >10 ng/L, with levels higher in men as well as among older and heavier people and those smoking cigarettes,10 all of which are risk factors for diabetes. Furthermore, the calcitonin elevations described in the liraglutide PI appear to be well below the level >50 ng/L, for which surgery is recommended, or 20–50 ng/L, for which pentagastrin stimulation is suggested, in people with thyroid nodules.11 Parks and Rosebraugh9 do qualify their assurance with the proviso that additional animal studies need to be performed and that a registry for MCT is being established. However, it is likely that any effort to screen for MCT in people treated with liraglutide would lead to the finding of many incidental thyroid nodules, causing perhaps unnecessary investigations. Although the liraglutide PI recommends that a personal or family history of MCT or of multiple endocrine neoplasia Type 2 is a contraindication for liraglutide treatment, it should be recognized that eliciting such a history accurately will often be quite difficult. At the present time, then, the routine measurement of calcitonin and performance of thyroid sonograms is not recommended. Careful history and physical examination pertaining to the thyroid should be performed prior to initiation of a GLP-1 receptor agonist, and thyroid examinations should be performed regularly during treatment, with sonography only for recognized clinical indications, typically the finding of a palpable nodule. If a thyroid nodule is found in a person treated with such agents, fasting calcitonin concentrations could reasonably be determined, with recognition of (and an attempt to exclude) the myriad additional factors that may be associated with elevated levels, including thyroiditis, hypercalcemia, renal insufficiency, cigarette use, and circumstances elevating gastrin levels, such as atrophic gastritis, H2RB, and PPI.12" @default.
• W1626487600 created "2016-06-24" @default.
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• W1626487600 date "2010-11-21" @default.
• W1626487600 modified "2023-10-16" @default.
• W1626487600 title "Liraglutide and calcitonin" @default.
• W1626487600 cites W1970021046 @default.
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• W1626487600 doi "https://doi.org/10.1111/j.1753-0407.2010.00079.x" @default.
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