The intersection of weight management and thyroid health is a complex area, particularly concerning the use of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in individuals with hypothyroidism. While these medications have gained popularity for their effectiveness in managing type 2 diabetes mellitus (T2DM) and promoting weight loss, their potential impact on thyroid function warrants careful consideration. This article examines the current understanding of the relationship between GLP-1 RAs, weight loss, and thyroid disorders, providing a comprehensive overview for a broad audience.
The Rise of GLP-1 Receptor Agonists
In recent years, GLP-1 RAs have become increasingly prevalent in the treatment of T2DM, owing to their ability to effectively manage blood sugar levels and mitigate the complications associated with the disease. These drugs function by mimicking the effects of the naturally occurring hormone Glucagon-like Peptide-1 (GLP-1), which plays a crucial role in regulating insulin secretion, suppressing glucagon release, and slowing down gastric emptying.
GLP-1 RAs 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. This effect exhibits a consistent impairment in individuals diagnosed with T2DM. 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.
Beyond their impact on pancreatic and gastric function, GLP-1 is capable of influencing the brain to induce satiety and reduce food intake. The mechanisms by which GLP-1 RAs induce weight loss are multifaceted and are linked to GLP-1R activation in both central and peripheral enteric neurons, slowing gastric emptying and intestinal transit, as well as suppressing appetite at the hypothalamus level, collectively influencing a mechanism known as the “ileal brake”. A complex gut-brain relationship is evident, as satiety is influenced by GLP-1R activation present in both the central nervous system while the intestine is further modulated by vagal cholinergic signals.
Currently, liraglutide and semaglutide are the only two pharmacological agents among GLP-1 RAs indicated, in conjunction with a low-calorie diet and regular physical activity, for the management of body weight in adults with a BMI exceeding 30 kg/m2 or falling within the range of 27 to <30 kg/m2, in the presence of at least one weight-related co-morbidity. These co-morbidities may include dysglycemia, hypertension, dyslipidemia, or obstructive sleep apnea.
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Thyroid Dysfunction and Diabetes: A Common Co-occurrence
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. The prevalence of thyroid dysfunction is significantly higher among patients with T2DM compared with the general population.
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. Furthermore, some observational studies suggest an association between T2DM and thyroid cancer, especially in women.
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. It has been observed that insulin receptors are overexpressed in most thyroid tumors as an early step in thyroid carcinogenesis. Moreover, in several studies, hyperinsulinemia and insulin resistance were significantly associated with the carcinogenesis and aggressiveness of thyroid cancer.
GLP-1 RAs and Thyroid Function: What Does the Research Say?
The increasing use of GLP-1 RAs has prompted investigations into their potential effects on thyroid function. 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. 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.
Other studies have demonstrated the presence of GLP-1R in hepatocytes, in thyroid cells, and in thyroid C cells. However, despite the studies conducted, the function of the receptors on these cells is not yet fully understood.
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For example, He et al. conducted a study examining the expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), and GLP-1R in normal thyroid tissue, papillary thyroid carcinoma (PTC) tissues, and PTC cells as well as the potential role of insulin analogs and GLP-1 RAs in cell proliferation and energy metabolism. All three receptors were detected in both PTC tissues and PTC cell lines, as well as in normal thyroid cells. GLP-1R was found to be overexpressed in human PTC tissues/cells, and the expression of IGF-1R and GLP-1R was more pronounced in PTC compared to normal thyroid cells. Researchers investigated cell proliferation, levels of phosphoinositide 3-kinase/AKT serine/threonine kinase (Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) signaling pathway members, and metabolic activity of cell lines exposed to GLP-1 RAs, concluding that GLP-1 RAs may not influence cell proliferation or energy metabolism in PTC cells. Thus, there is currently no need to avoid the use of these antidiabetic agents in patients with PTC.
Another study by Boess et al. investigated primary cultures of rat and human thyroid cells to assess the expression and function of GLP-1R in C cells. In this study, GLP-1R expression was observed in primary rat C cells but was not detected in primary human C cells. Stimulation with GLP-1 RAs resulted in a modest increase in calcitonin release and expression in primary rat thyroid cultures; however, no functional response to GLP-1 RAs was observed in human thyroid cultures. This lack of functional response of human cultures to GLP-1 RAs suggests that human C cells have very low levels or completely lack functional GLP-1R. Conversely, using primary rat thyroid cells in culture, mRNA expression, and a functional response were observed after stimulation with GLP-1 RAs. These results further support that GLP-1 RAs-induced responses in C cells in rodents may not be relevant to humans. However, it cannot be ruled out that the lack of response to GLP-1 RAs in human primary thyroid cultures is due to the low percentage of C cells and very low calcitonin release, which is not detectable with the methods used in this study.
GLP-1 RAs, Weight Loss, and TSH Levels: A Closer Look
Recent research has explored the relationship between GLP-1 RAs, weight loss, and thyroid-stimulating hormone (TSH) levels in patients with hypothyroidism. One study found that patients with a history of hypothyroidism who were prescribed a GLP-1 medication and lost more than 5 pounds experienced a reduction in their TSH levels. Conversely, those who gained weight did not exhibit statistically significant changes in TSH levels.
According to the study findings, patients who were prescribed semaglutide and lost over 5 pounds saw the greatest reduction of their TSH levels (-0.55 mU/L). Within this subgroup, exenatide demonstrated the smallest reduction in TSH (-0.36 mU/L). Semaglutide had different effects in the “lost 0 to 5 pound” group and weight gain group, demonstrating TSH changes of -0.27 mU/L and 0.04, respectively. Additionally, exenatide was the only GLP-1 medication that resulted in a decrease in TSH levels (-0.05 mU/L) in the weight gain group, but the investigators noted that this group saw no statistically significant changes in their levels.
These findings suggest a potential interaction between GLP-1 medications and thyroid function, possibly due to the influence of these medications on metabolic pathways, which can alter thyroid hormone production.
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Semaglutide and Weight Loss in Hypothyroidism: A Promising Avenue
While no specific studies have focused on the use of semaglutide for weight loss in individuals with hypothyroidism, existing research has consistently demonstrated its effectiveness in promoting weight loss in patients with or without diabetes. Semaglutide, a GLP-1 RA, works by reducing appetite and caloric intake, leading to a lower body mass index.
A 2021 study involving over 1300 participants who received a weekly subcutaneous injection of 2.4 mg of semaglutide in addition to lifestyle modifications revealed that half of the participants experienced an average weight loss of 15% or more from their starting weight. At the end of 68 weeks, participants equated an average 35-pound weight loss from their initial body weight. Even more impressive, about 86% of participants had a weight reduction of 5% or more from their baseline body weight by the end of the study.
A 2020 study comparing weekly semaglutide to daily subcutaneous liraglutide showed a more significant overall weight loss in those that received semaglutide. While the doses were different, these results were echoed in a recent study. The authors of the 2020 study noted liraglutide is a daily subcutaneous injection, whereas semaglutide is weekly, which may have impacted adherence to liraglutide.
Considerations for Patients with Hypothyroidism
Given the potential interplay between GLP-1 RAs and thyroid function, it is crucial for individuals with hypothyroidism to exercise caution and consult with their healthcare providers before initiating treatment with these medications. Regular monitoring of thyroid function is essential, and adjustments to thyroid medication may be necessary to maintain optimal thyroid hormone levels.
Precautions for Patients with Hypothyroidism Taking Phentermine
People taking other medications like levothyroxine need to be especially careful when taking phentermine. Because phentermine alters hormones like norepinephrine, it can strain your adrenal glands. The adrenal glands make norepinephrine and also work closely with the thyroid. Therefore, if you have an underactive thyroid, you will want to ensure your thyroid levels are normal with a complete thyroid blood test. Also, some people may develop a tolerance to phentermine and may no longer have appetite suppression. These people will likely need to stop the medication if they become desensitized to the effects of phentermine.
Healthy Weight Loss Strategies for Individuals with Thyroid Conditions
Weight management with hypothyroidism requires different steps, including:
- Taking the correct dose of thyroid medication
- Getting regular thyroid testing and follow-up with your thyroid doctor
- Daily physical activity with moderate-intensity exercise at least three times per week
- Healthy, well-balanced meals that are full of anti-inflammatory foods
- Getting plenty of sleep each night
- Reducing stress
FDA Warnings and Potential Risks
It is important to be aware of the FDA's boxed warning for semaglutide medications, which cites a potential risk of thyroid tumors and cancer, particularly medullary thyroid cancer (MTC). The warning advises patients with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN2) to avoid semaglutide medications.
Other possible side effects of semaglutide include:
- Pancreatitis
- Hypoglycemia
- Gall bladder issues
- Vision changes
- Increased heart rate
- Depression/suicidal thoughts
In July, the FDA issued a new boxed warning for these popular weight loss drugs in response to reports of people overdosing and taking as much as 20 times more than the intended dose. The FDA also warns about the potential of developing ileus, a blockage that keeps food or liquid from passing through the colon.
Balancing Risks and Benefits
For individuals managing T2DM and struggling with weight loss, the benefits of GLP-1 RAs may outweigh the potential risks. These medications can improve blood glucose control, reduce cardiovascular risks, lower blood pressure, and alleviate sleep apnea. However, people who are already on thyroid medications will need more frequent monitoring of their thyroid levels and possible adjustments of medications because of absorption changes in the stomach and weight loss.
The Importance of Further Research
Current evidence regarding the interaction between GLP-1 RAs and thyroid dysfunction remains inconclusive, with conflicting results across studies. As these drugs are relatively recent, longer-term studies with larger sample sizes are needed to draw clearer conclusions and establish definitive guidelines for their use in patients with thyroid disorders.
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