Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels

Stefania Capuccio 1,†, Sabrina Scilletta 1,†, Francesca La Rocca 1, Nicoletta Miano 1, Maurizio Di Marco 1, Giosiana Bosco 1, Francesco Di Giacomo Barbagallo 1, Roberto Scicali 1, Salvatore Piro 1, Antonino Di Pino 1,*

Editors: Mohsin Saleet Jafri1, Carola Yvette Förster1, Tarun W Dasari1

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PMCID: PMC11202033  PMID: 38927090

Abstract

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management.

Keywords: GLP-1 receptor agonists, thyroid cancer, hypothyroidism, hyperthyroidism, TSH, diabetes

1. Introduction

The remarkable growth in the use of Glucagon-Like Peptide-1 receptor agonists (GLP-1 RAs) in recent years has drawn attention to a class of drugs that have proven to be highly effective in managing type 2 diabetes mellitus (T2DM) and mitigating the effects of its numerous complications. 

These drugs, acting as agonists of Glucagon-like Peptide-1 receptor (GLP-1R), are recognized for promoting insulin secretion, suppressing glucagon release, and delaying gastric emptying [1]. However, while the beneficial effects of GLP-1 RAs on glycemic control, weight loss, and blood pressure reduction are extensively documented, a crucial aspect requiring further investigation is their impact on thyroid function. This interest becomes particularly significant in the context of the intricate interactions involving thyroid hormones (TH) and their interconnection with metabolic pathways, considering the essential role of TH in regulating cellular metabolism. Thyroid diseases frequently emerge in metabolic conditions such as T2DM and obesity, highlighting a complex connection between thyroid dysfunction and metabolic disorders. This association is particularly evident in patients with type 1 and T2DM since epidemiological studies show a significant increase in the prevalence of thyroid dysfunction in these populations, suggesting that the management of metabolic diseases could directly impact thyroid health [2]. 

Studies in animal models have revealed that the use of GLP-1 RAs causes abnormal alterations in thyroid C cells, with a gradual formation of hyperplasia and adenomas [3]. Despite initial reports of a potential increased risk of thyroid cancer in patients treated with GLP-1 RAs, long-term results from clinical studies have alleviated such concerns. The contradiction in these data leaves the discussion open concerning the effect of GLP-1 RAs on the thyroid, emphasizing the need for a systematic investigation. 

Considering the frequent occurrence of thyroid disorders in metabolic diseases such as T2DM and obesity, this scientific review aims to explore in-depth and critically assess the link between the use of GLP-1 RAs and the onset of thyroid disorders. This approach will be implemented through meticulous and detailed analysis of the literature, with the goal of contributing to a more comprehensive understanding of this complex interaction and providing clarity on the safety of GLP-1 RAs in patients with thyroid dysfunction. Additionally, it aims to evaluate the necessity to conduct periodic thyroid function screenings in diabetic patients using GLP-1 agonists.

2. Relationship between Type 2 Diabetes Mellitus and Thyroid Function

Thyroid dysfunction and diabetes mellitus are conditions frequently seen in clinical practice and often coexist. Compared with those patients without diabetes, both hyperthyroidism and hypothyroidism are more common in patients with T2DM [4]. 

The prevalence of thyroid dysfunction is significantly higher among patients with T2DM compared with the general population [5]; Perros et al. have reported an overall prevalence of thyroid disease of 13.4% on a total of 1310 adult diabetic patients [6]. A similar prevalence of thyroid dysfunction was found in other studies conducted on Greek (12.3%) [7], Saudi Arabian (16%) [8], Brazilian (14.7%) [9], and Jordanian diabetic populations (12.5%) [10]. Finally, a systematic review reported the association between subclinical hypothyroidism and T2DM with an estimated prevalence of 10.2% [11].

Increased interest has recently focused on the relationship between thyroid function and metabolic diseases. The pathogenetic reasons underlying this interplay are not yet fully understood, but various hypotheses have been formulated. Thyroid hormones influence the regulation of glucose and lipid metabolism, targeting several organs such as the liver, skeletal muscle, pancreas, adipose tissue, and central nervous system [12].

Furthermore, some observational studies suggest an association between T2DM and thyroid cancer, especially in women. Yeo et al. [13] performed a systematic review and meta-analysis to investigate this association, showing that patients with diabetes were at increased risk of cancer by approximately 20%. Insulin resistance, dysglycemia, high body mass index (BMI), and hypertension were shown to significantly increase the incidence of thyroid cancer. Hyperinsulinemia can reduce cell apoptosis and induce cell proliferation through insulin and the insulin-like growth factor-1 (IGF-1) pathway [14]. It has been observed that insulin receptors are overexpressed in most thyroid tumors as an early step in thyroid carcinogenesis [15]. Moreover, in several studies, hyperinsulinemia and insulin resistance were significantly associated with the carcinogenesis and aggressiveness of thyroid cancer [16,17,18].

3. Overview of GLP-1 Receptor Agonists

3.1. Mechanism of Action

Therapies acting on GLP-1R exert their effect on glucose control through multiple mechanisms based on the incretin effect that delineates the occurrence wherein oral glucose evokes a greater insulin secretion compared with intravenous glucose despite inducing similar levels of glycemia in healthy individuals. This phenomenon is orchestrated by the enteroendocrine hormones GLP-1 and Gastric Inhibitory Peptide (GIP), both of which concomitantly facilitate insulin secretion (Figure 1). This effect exhibits a consistent impairment in individuals diagnosed with T2DM [19]. GLP-1 and GIP are “incretin” hormones that are released during a meal, after the ingestion and absorption of glucose, protein, and fat, and provide one of the physiologic connections between eating and insulin release [20,21].

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