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To ensure a focused review of the relationship between GLP-1 therapies and hypothyroidism, a few clinical specifics would be helpful.
1. Is the patient with hypothyroidism currently receiving thyroid hormone replacement, and if so, what is the regimen?
2. Are you interested in the effects of GLP-1 receptor agonists on thyroid function, or in their safety/efficacy in patients with pre-existing hypothyroidism?
3. Does the patient have any history of thyroid cancer, nodules, or other thyroid pathology beyond hypothyroidism?
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I need to clarify GLP-1 efficacy in untreated hypothyroidism, explore mechanisms, compare to other populations, and review guidelines.

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I want to ensure all possible clinical, mechanistic, and safety aspects of GLP-1 use in untreated hypothyroidism are addressed.

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I need to clarify if any new evidence, clinical trials, or expert recommendations have emerged since the last review, and to ensure all mechanistic, safety, and practical clinical aspects are covered for GLP-1 use in untreated hypothyroidism.

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Clinical Evidence and Guideline Review

The current clinical evidence does not include randomized controlled trials, large cohort studies, or case reports directly evaluating the efficacy or safety of GLP-1 receptor agonists in patients with untreated hypothyroidism. The available literature focuses on the efficacy of GLP-1 receptor agonists in general populations, including those with type 2 diabetes and obesity, and on their effects on thyroid function, but does not specifically address untreated hypothyroid patients. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus report recommends GLP-1 receptor agonists for glycemic control, weight reduction, and cardiovascular risk mitigation in patients with type 2 diabetes and obesity, with robust reductions in HbA1c, significant weight loss, and favorable cardiovascular outcomes documented in multiple clinical trials and meta-analyses.[1-4] However, these guidelines do not address the efficacy or safety of GLP-1 receptor agonists in patients with untreated hypothyroidism.
The only thyroid-related contraindication specified in guidelines from the ADA, EASD, and the American Association of Clinical Endocrinology (AACE) is for patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, based on preclinical rodent data showing an increased risk of C-cell tumors.[1][5-8] There is no mention of untreated hypothyroidism as a contraindication or as a factor influencing GLP-1 receptor agonist efficacy or safety. Recent reviews and cohort studies consistently note the absence of guideline-directed recommendations for this scenario and emphasize the need for individualized care, routine thyroid function monitoring, and further research.[9-13]
The standard of care for overt hypothyroidism remains thyroid hormone replacement with levothyroxine, which restores euthyroidism and normalizes metabolic parameters. GLP-1 receptor agonists may be considered as adjunctive therapy for weight loss and glycemic control in patients with comorbid obesity or type 2 diabetes, but only after hypothyroidism is adequately treated.[5][9] There is no evidence to support the use of GLP-1 receptor agonists as a substitute for thyroid hormone replacement in untreated hypothyroidism, and their efficacy in this setting is unproven.

Mechanistic and Translational Insights

Pharmacokinetics and Pharmacodynamics

Untreated hypothyroidism is characterized by a deficiency of thyroid hormones, resulting in a hypometabolic state that affects multiple organ systems, including the gastrointestinal tract, liver, kidneys, and cardiovascular system. These systemic changes have the potential to alter both the pharmacokinetics and pharmacodynamics of GLP-1 receptor agonists. Delayed gastric emptying is a hallmark of hypothyroidism and may further compound the gastric motility effects of GLP-1 receptor agonists, which themselves slow gastric emptying as part of their mechanism of action.[14-16] This interaction could potentially alter the absorption kinetics of orally administered GLP-1 receptor agonists, such as oral semaglutide, and may also affect the absorption of concomitant oral medications, including levothyroxine if initiated concurrently.[14][17]
Hepatic metabolism and renal clearance are also reduced in hypothyroid states, which could theoretically prolong the half-life and increase systemic exposure to GLP-1 receptor agonists, especially those that are renally excreted (e.g., exenatide).[14] While the metabolism and excretion profiles of GLP-1 receptor agonists differ by agent, with some (e.g., liraglutide, semaglutide) being primarily metabolized by proteolytic degradation and others (e.g., exenatide) being renally cleared, the potential for altered pharmacokinetics in hypothyroid patients, particularly those with significant renal impairment, should be considered when selecting and dosing GLP-1 receptor agonists.[14]
The pharmacodynamic effects of GLP-1 receptor agonists include glucose-dependent stimulation of insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, and promotion of satiety leading to weight loss. Untreated hypothyroidism may influence these effects through several mechanisms, including increased insulin resistance and impaired glucose metabolism, which could theoretically blunt the glycemic efficacy of GLP-1 receptor agonists.[9][18]

Metabolic and Central Interactions

Thyroid hormones, particularly triiodothyronine (T3), exert significant regulatory effects on glucose metabolism, in part by modulating GLP-1 production. Mechanistic studies in murine models have demonstrated that hepatic thyroid hormone signaling via thyroid hormone receptor β is required for the regulation of GLP-1 production.[19] In hypothyroid mice, T3 administration increased GLP-1 secretion and improved glucose metabolism, effects that were attenuated by GLP-1 receptor antagonism. Mechanistically, T3 suppresses hepatic Cyp8b1 expression, leading to increased levels of bile acids that antagonize the farnesoid X receptor in the intestine, thereby enhancing GLP-1 production and insulin secretion.[19] In humans with normal thyroid function, plasma GLP-1 levels correlate with thyroid hormone status and FXR-antagonistic bile acid levels, suggesting that intact thyroid hormone signaling is necessary for optimal GLP-1 production and downstream metabolic effects.[19]
In the context of untreated hypothyroidism, where T3 and T4 levels are low, this hepatic-thyroid-GLP-1 axis is disrupted, resulting in a reduction in GLP-1 production, which may blunt the incretin effect and diminish the efficacy of GLP-1 receptor agonists in promoting insulin secretion and glycemic control. Thus, hypothyroidism may create a state of relative GLP-1 deficiency or resistance, potentially limiting the therapeutic benefits of GLP-1 receptor agonists.
GLP-1 signaling also interacts with the central regulation of the hypothalamic-pituitary-thyroid axis. GLP-1-producing neurons innervate thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus, and these neurons express GLP-1 receptors.[20] Peripheral administration of GLP-1 receptor agonists in mice inhibited TRH release from axon terminals in the median eminence and reduced circulating free T4 levels, without affecting TRH expression in the paraventricular nucleus.[20] These findings suggest that GLP-1 receptor agonists can influence thyroid hormone secretion via central mechanisms, but the overall impact on the hypothalamic-pituitary-thyroid axis in vivo appears limited, and the weight loss effects of GLP-1 receptor agonists are not mediated by changes in thyroid hormone levels.[20]

Efficacy and Safety Data

Efficacy in General and Thyroid Dysfunction Populations

GLP-1 receptor agonists, including liraglutide, semaglutide, and exenatide, have demonstrated robust efficacy in promoting weight loss, improving glycemic control, and reducing cardiovascular risk in both diabetic and non-diabetic populations. Large-scale observational studies and meta-analyses show significant reductions in body weight and improvements in cardiometabolic parameters in individuals with obesity, regardless of diabetes status.[3-4] For example, semaglutide has been associated with a mean weight reduction of 11.85 kg (95% CI: 13.19 to 10.51), while liraglutide (3 mg) showed moderate effects with a mean difference of 4.59 kg (95% CI: 5.13 to 4.06).[4] These studies, however, do not stratify outcomes by thyroid function status and do not address untreated hypothyroid patients.
A recent umbrella review confirms that GLP-1 receptor agonists are effective and generally well-tolerated in non-diabetic adults with overweight or obesity, with semaglutide and tirzepatide showing the greatest mean weight reductions, and liraglutide demonstrating moderate effects.[4] Similarly, a large global retrospective cohort study found that GLP-1 receptor agonist treatment in individuals with obesity (without type 2 diabetes) was associated with lower all-cause mortality (hazard ratio 0.23; 95% CI: 0.15-0.34) and reduced cardiovascular complications, with consistent effects across subgroups.[3] However, neither of these studies provides data specific to untreated hypothyroid patients.
A prospective study of exenatide in patients with type 2 diabetes and obesity found that GLP-1 receptor agonist therapy led to a reduction in serum TSH levels, which was correlated with weight loss, but did not affect free T4 levels.[21] The authors suggested that weight loss, rather than thyroid hormone replacement, may be the primary driver of TSH reduction in obese individuals with mildly elevated TSH. This finding implies that the metabolic benefits of GLP-1 receptor agonists are preserved in patients with subclinical hypothyroidism or mild TSH elevations, but the study did not include patients with overt, untreated hypothyroidism.[21]
There is a notable absence of direct evidence regarding the efficacy of GLP-1 receptor agonists in patients with untreated hypothyroidism. Mechanistically, untreated hypothyroidism is characterized by reduced basal metabolic rate, increased insulin resistance, and a tendency toward weight gain and dyslipidemia, which could theoretically attenuate the weight loss and glycemic benefits of GLP-1 receptor agonists.[9][18] However, there is no clinical trial evidence to confirm or refute this hypothesis.

Safety Profile and Adverse Events

GLP-1 receptor agonists are associated with a well-defined spectrum of adverse effects, most notably gastrointestinal symptoms such as nausea, vomiting, and diarrhea. These effects are typically dose-dependent and transient, and can be mitigated by gradual dose titration and patient education regarding dietary habits and satiety cues.[1][17][22] The ADA and EASD recommend slow up-titration and mindful eating strategies to minimize gastrointestinal intolerance, and emphasize that these agents promote satiety, which supports weight loss but may be misinterpreted as nausea by some patients.[1][17][22] The most serious contraindication is for individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, based on preclinical rodent data showing C-cell tumors, although this has not been substantiated in human studies.[1][5-8]
Other recognized risks include an increased incidence of gallbladder and biliary disease, modest elevations in heart rate, and rare complications of diabetic retinopathy, particularly in patients with rapid glycemic improvement.[1][7][23] The risk of hypoglycemia is low when GLP-1 receptor agonists are used as monotherapy, but increases when combined with insulin or sulfonylureas.[7][23] Pancreatitis and pancreatic cancer have been reported in postmarketing surveillance, but large clinical trials have not demonstrated a significant increase in risk.[2][23-25]
The relationship between GLP-1 receptor agonists and thyroid function has been the subject of recent reviews and cohort studies. Capuccio et al. highlight that the evidence regarding the impact of GLP-1 receptor agonists on thyroid disorders is inconclusive, with conflicting results across studies and a lack of long-term data.[9] Zhang et al. report that GLP-1 receptor agonist treatment in diabetic patients is associated with a modest decrease in free thyroxine levels within the normal range and a slight increase in thyroid nodule diameter and TI-RADS score over 12 months, but linear regression analysis did not show a significant association between GLP-1 receptor agonist use and post-treatment differences in thyroid function or nodule progression.[11] These findings suggest that GLP-1 receptor agonists are relatively safe with respect to thyroid disease, but the potential for minor changes in thyroid hormone levels and nodule characteristics warrants routine monitoring, especially in patients with pre-existing thyroid pathology.[9][11-12]
Kupnicka et al. discuss concerns about the long-term use of GLP-1 receptor agonists and the potential risk of thyroid neoplasms, particularly in high-risk patients, and recommend more frequent and detailed follow-up for those with thyroid disease.[10] However, the clinical significance of these risks remains uncertain, and no clear consensus has emerged regarding the need for routine thyroid cancer screening in patients treated with GLP-1 receptor agonists.[12]
Untreated hypothyroidism is characterized by delayed gastric emptying, reduced gastrointestinal motility, and impaired hepatic and renal clearance, which may theoretically interact with the pharmacokinetics and pharmacodynamics of GLP-1 receptor agonists.[14-16] Delayed gastric emptying may be exacerbated by GLP-1 receptor agonists, increasing the risk or severity of gastrointestinal symptoms, such as nausea, vomiting, and bloating, and may also affect the absorption of concomitant oral medications, including levothyroxine if initiated concurrently.[14][17][26] Higher TSH levels are independently associated with increased risk of gastrointestinal adverse events in patients receiving GLP-1 receptor agonists, and clinical guidelines recommend gradual dose escalation and patient education to mitigate these risks.[1][17][26]
Pharmacovigilance studies utilizing large databases such as EudraVigilance and the FDA Adverse Event Reporting System have characterized the safety profiles of GLP-1 receptor agonists, including liraglutide, semaglutide, and tirzepatide, in real-world settings.[27-29] These studies consistently report that gastrointestinal adverse events are the most frequently observed, with most cases being non-serious and transient. Disproportionality analyses have identified increased reporting odds ratios for gastrointestinal events, pancreatitis, gallbladder disorders, and, less commonly, thyroid tumors, but do not provide subgroup data for patients with untreated hypothyroidism.[27-30]

Clinical Recommendations and Implementation

Given the absence of direct clinical evidence and guideline recommendations for GLP-1 receptor agonist use in untreated hypothyroidism, clinical decision-making must rely on mechanistic rationale, expert opinion, and general principles of individualized care. The first-line treatment for overt hypothyroidism remains thyroid hormone replacement with levothyroxine, which restores euthyroidism and normalizes metabolic parameters.[5][9] GLP-1 receptor agonists may be considered as adjunctive therapy for weight loss and glycemic control in patients with comorbid obesity or type 2 diabetes, but only after hypothyroidism is adequately treated.[5][9]
For patients with untreated hypothyroidism who are candidates for GLP-1 receptor agonist therapy, the following stepwise clinical approach is recommended:
Thyroid function should be optimized prior to initiation of GLP-1 receptor agonist therapy. Levothyroxine should be initiated at a starting dose of 1.6 mcg/kg/day orally, adjusted based on age, comorbidities, and cardiac risk, with dose titration every 6-8 weeks to achieve a target TSH within the reference range (typically 0.4-4.0 mU/L).[5][9] Once euthyroidism is achieved, GLP-1 receptor agonist therapy may be considered for metabolic indications.
GLP-1 receptor agonists should be initiated at the lowest recommended dose and titrated gradually to minimize gastrointestinal intolerance. For semaglutide, the recommended starting dose is 0.25 mg subcutaneously once weekly for 4 weeks, followed by 0.5 mg, 1.0 mg, and 1.7 mg weekly every 4 weeks at each dose, until the maintenance dose of 2.4 mg is reached after 16 weeks.[17] For liraglutide, the recommended starting dose is 0.6 mg subcutaneously once daily for 7 days, followed by 1.2 mg, 1.8 mg, and 2.4 mg daily every 7 days at each dose until the maintenance dose of 3.0 mg is reached after 4 weeks.[17] Clinical judgment should be used to adjust the titration schedule based on individual patient response, tolerance, and adverse effects.[17]
Routine monitoring of thyroid function is advisable in patients with thyroid disease who are treated with GLP-1 receptor agonists, as recommended by expert opinion.[9-11] Thyroid function tests (TSH, free T4) should be assessed at baseline, every 6-8 weeks during titration of levothyroxine, and at regular intervals (e.g., every 3-6 months) during GLP-1 receptor agonist therapy. Monitoring for gastrointestinal symptoms, gallbladder disease, and other adverse events should be performed at each visit, with dose adjustments as needed to optimize tolerability.[1][17][22][26]
For patients with persistent hypothyroidism who require GLP-1 receptor agonist therapy for metabolic indications, clinicians should consider slower dose escalation, close monitoring for gastrointestinal symptoms, and routine assessment of thyroid function. The ADA and EASD recommend these strategies for all patients experiencing gastrointestinal intolerance to GLP-1 receptor agonists, and they are particularly relevant for those with untreated hypothyroidism.[1][17][22][26]
GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, as specified by the ADA, EASD, and AACE guidelines.[1][5-8] There is no evidence to support additional screening or contraindication solely based on hypothyroid status.[9-12]

Evidence Gaps and Future Directions

There is a clear and well-documented gap in direct clinical evidence regarding the efficacy and safety of GLP-1 receptor agonists in patients with untreated hypothyroidism. No randomized controlled trials, large cohort studies, case reports, or pharmacovigilance analyses have specifically addressed this population.[9-11][27-30] The available literature highlights the need for longer-term studies with larger sample sizes to clarify the safety and efficacy of GLP-1 receptor agonists in patients with thyroid dysfunction, and recommends routine thyroid function monitoring in diabetic patients treated with GLP-1 receptor agonists as a precautionary measure.[9-11]
Future research should prioritize prospective studies and randomized controlled trials that specifically enroll patients with untreated hypothyroidism to evaluate the efficacy, safety, and tolerability of GLP-1 receptor agonists in this population. Subgroup analyses of existing large-scale trials should be conducted to assess outcomes stratified by thyroid function status. Mechanistic studies should further elucidate the interaction between hypothyroidism and GLP-1 signaling, particularly regarding metabolic outcomes and gastrointestinal side effects.
Guideline development should incorporate emerging evidence to provide clear recommendations for the management of patients with coexisting hypothyroidism and metabolic disease who may be candidates for GLP-1 receptor agonist therapy. Until such data become available, standard clinical practice should prioritize thyroid hormone replacement in overt hypothyroidism, consider GLP-1 receptor agonists for metabolic indications only after euthyroidism is achieved, and monitor thyroid function routinely in patients receiving GLP-1 receptor agonist therapy.[5][9][17]
In summary, while GLP-1 receptor agonists are effective and generally safe in the broader population, their efficacy and safety in untreated hypothyroid patients remain uncertain due to a lack of direct evidence. Clinical judgment and individualized patient assessment are essential, with a low threshold for thyroid function optimization prior to GLP-1 receptor agonist initiation. Routine monitoring of thyroid function and gastrointestinal symptoms is advisable in all patients receiving GLP-1 receptor agonists, particularly those with known or suspected thyroid disease.[9-11][26]

1.
Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Davies MJ, Aroda VR, Collins BS, et al.

Diabetes Care. 2022;45(11):2753-2786. doi:10.2337/dci22-0034.

Gradual up-titration is recommended to mitigate gastrointestinal effects ( 164 , 168 , 169 ). Education should be provided when initiating GLP-1 RA therapy. GLP-1 RA promote a sense of satiety, facilitating reduction in food intake. It is important to help people distinguish between nausea, a negative sensation, and satiety, a positive sensation that supports weight loss. Mindful eating should be encouraged: eating slowly, stopping eating when full and not eating when not hungry. Smaller meals or snacks, decreasing intake of high-fat and spicy foods, moderating alcohol intake, and increasing water intake are also recommended. Slower or flexible dose escalations can be considered in the setting of gastrointestinal intolerance ( 168 , 169 ).
Data from CVOTs on other safety areas of interest (pancreatitis, pancreatic cancer, and medullary thyroid cancer) indicate that there is no increase in these risks with GLP-1 RA. GLP-1 RA are contraindicated in people at risk for the rare medullary thyroid cancer ( 164 ), that is, those with a history or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2, due to thyroid C-cell tumors seen in rodents treated with GLP-1 RA in preclinical studies. Increased retinopathy complications seen in the SUSTAIN 6 CVOT appear attributable to the magnitude and rapidity of HbA 1c reductions in individuals with pre-existing diabetic retinopathy and high glycemic levels, as has been seen in previous studies with insulin ( 170 , 171 ). GLP-1 RA are also associated with higher risks of gallbladder and biliary diseases ( 172 ).

2.
Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes: A Clinical Update of Safety and Efficacy.

Drab SR.

Current Diabetes Reviews. 2016;12(4):403-413. doi:10.2174/1573399812666151223093841.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer.

Methods: A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized.

Results: Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events.

Conclusion: GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer.

3.
Long-Term Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Individuals With Obesity and Without Type 2 Diabetes: A Global Retrospective Cohort Study.

Huang YN, Liao WL, Huang JY, et al.

Diabetes, Obesity & Metabolism. 2024;26(11):5222-5232. doi:10.1111/dom.15869.

Aim: We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D).

Materials And Methods: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event.

Results: After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions.

Conclusions: In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

4.
The Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists in Non-Diabetic Adults With Overweight/­Obesity: An Umbrella Review of Systematic Reviews and Meta-Analyses.

Zamanian N, Imani H, Talebi S, et al.

European Journal of Pharmacology. 2025;:177966. doi:10.1016/j.ejphar.2025.177966.

Aims: Obesity and overweight pose significant global health challenges necessitating effective pharmacological interventions. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged for their weight-reducing effects in non-diabetic individuals, but conflicting findings require comprehensive evaluation. This umbrella review synthesizes evidence to assess GLP-1 RAs' efficacy and safety in non-diabetic adults with overweight or obesity.

Materials And Methods: A systematic search identified systematic reviews/meta-analyses of randomized controlled trials (RCTs) investigating GLP-1 RAs in non-diabetic adults with overweight/obesity. Primary outcomes included weight/body mass index (BMI) changes, cardiometabolic parameters, and adverse events. Heterogeneity was assessed using I2 statistics; the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evaluated evidence quality.

Results: Fifteen systematic reviews and meta-analyses covering six GLP-1 RAs were included. Among these, tirzepatide demonstrated the greatest mean weight reduction (mean difference [MD]: -17.60 kg; 95% confidence interval [CI]: -32.15 to -2.95), followed by semaglutide (

Md: -11.85 kg; 95%

Ci: -13.19 to -10.51). Liraglutide (3 mg) showed moderate effects (

Md: -4.59 kg; 95%

Ci: -5.13 to -4.06). Semaglutide and liraglutide were also associated with significant reductions in BMI (

Md: -4.26 kg/m2 and -1.66 kg/m2, respectively). Gastrointestinal side effects were common but generally mild.

Conclusions: GLP-1 RAs appear to be effective and generally well-tolerated in non-diabetic adults with overweight or obesity. Although some reviews reported more favorable weight outcomes with semaglutide, no definitive conclusions regarding the superiority of individual agents can be drawn from this umbrella review. Further head-to-head trials and network meta-analyses are warranted to clarify their comparative efficacy.

Registration: PROSPERO registration no. CRD42024603661.

5.
American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

Blonde L, Umpierrez GE, Reddy SS, et al.

Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2022;28(10):923-1049. doi:10.1016/j.eprac.2022.08.002.

Practice Guideline

Additionally, liraglutide, semaglutide, and dulaglutide have demonstrated reduction in MACE in CVOTs.,, As a result, guidelines recommend use of GLP-1 RAs before initiation of insulin for most individuals with T2D (see Evidence Base 9: How should antihyperglycemic agents be prioritized in persons with T2D at high risk for or with established CVD?).
The most frequently experienced adverse effects with GLP-1 RAs are nausea, vomiting, and diarrhea, which may lead to discontinuation of the GLP-1 RA in 5% to 10% of persons, but usually these adverse symptoms diminish over time.
Although medullary thyroid carcinoma has not been shown to be caused by GLP-1 RAs in humans, all GLP-1 RAs except twice-daily exenatide and lixisenatide are contraindicated in persons with a personal or family history of medullary thyroid carcinoma and in persons with multiple endocrine neoplasia syndrome type 2. The FDA has stated that persons taking a GLP-1 RA do not need to be monitored for medullary thyroid carcinoma (eg, with calcitonin levels) (also see discussion of pharmacologic therapies for DM and cancer risk or prognosis under Q27. How should potential increased cancer risk be managed in persons with obesity/T2D?).

6.
Use of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes and Cardiovascular Disease: A Review.

Honigberg MC, Chang LS, McGuire DK, et al.

JAMA logoJAMA Cardiology. 2020;5(10):1182-1190. doi:10.1001/jamacardio.2020.1966.

GLP-1RAs, SGLT2 Inhibitors, or Both > Contraindications and Cautions

In general, GLP-1RAs are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 ( Box ), although these concerns are based exclusively on observations in rodent models with uncertain human clinical relevance, as reflected in US product labeling. Because GLP-1RAs delay gastric emptying, caution should be used in prescribing these agents to patients with gastroparesis, chronic nausea, or previous gastric surgical procedure. Complications of diabetic retinopathy were rare but more commonly seen in patients who received injectable semaglutide vs placebo (3.0% vs 1.8%) in SUSTAIN-6. This finding has been attributed to the rapid reduction in blood glucose in a patient population at higher risk for retinopathy complications, which has been observed with insulin therapy when poorly controlled hyperglycemia is rapidly rectified. The early worsening of retinopathy phenomenon is reflected in product labels for all insulin medications and for injectable semaglutide as well. This issue should be taken into account before semaglutide initiation among patients with proliferative diabetic retinopathy or for those with poor glucose control (eg, HbA 1c >10%), and a formal retinal examination should be performed before semaglutide initiation. A randomized clinical trial of the safety of injectable semaglutide in diabetic retinopathy is currently being conducted. GLP-1RA should not be used in pregnancy or breastfeeding.

Patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk

Patients with overweight or obese status

Patients with advanced diabetic kidney disease

Contraindications

GLP-1RA hypersensitivity

Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2

Pregnancy or breastfeeding

Extra vigilance

Gastroparesis or previous gastric surgical procedure

History of pancreatitis

Proliferative diabetic retinopathy

Adverse effects

7.
2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: A Report of the American College of Cardiology Solution Set Oversight Committee.

Das SR, Everett BM, Birtcher KK, et al.

Journal of the American College of Cardiology. 2020;76(9):1117-1145. doi:10.1016/j.jacc.2020.05.037.

Practice Guideline

The contraindications and potential safety concerns of GLP-1RAs are included in Table 4.
The most frequently reported side effects of GLP-1RAs are nausea and vomiting (). These gastrointestinal symptoms are usually transient for longer-acting GLP-1RAs and can be mitigated by escalating the dose gradually () and educating patients to reduce meal size. GLP-1RAs may also increase the risk of gallbladder disease, including acute cholecystitis (,). Caution should be used in patients with prior gastric surgery (,). GLP-1RAs can lead to modest elevations in heart rate, although the clinical relevance of these effects is unclear (,,). GLP-1RAs are unlikely to cause hypoglycemia on their own, but they may increase the risk of hypoglycemia when used in combination with insulin or insulin secretagogues–most commonly sulfonylureas (). Although postmarketing case reports have suggested possible associations between GLP-1RAs and acute pancreatitis, none of the large trials has demonstrated any increase in the risk of pancreatitis (); that being said, patients at high pancreatitis risk were generally excluded from the trials. These agents should be discontinued if pancreatitis occurs. The FDA and the European Medicines Agency have not identified a link between this class of drugs and either pancreatitis or pancreatic cancer (). In the SUSTAIN-6 trial, diabetic retinopathy complications were reported with injectable semaglutide, although it is unclear if this is a direct effect of the drug or due to other factors such as rapid improvement in blood glucose control. Therefore, patients should be advised to undergo appropriate, guideline-recommended eye examinations before starting therapy if an examination has not been completed within the last 12 months ().

8.
Lipid Management in Patients With Endocrine Disorders: An Endocrine Society Clinical Practice Guideline.

Newman CB, Blaha MJ, Boord JB, et al.

The Journal of Clinical Endocrinology and Metabolism. 2020;105(12):dgaa674. doi:10.1210/clinem/dgaa674.

Practice Guideline

Medication,Contraindications,Warnings,Common Adverse Reactions
Orlistat,"Chronic malabsorption, cholestasis, pregnancy","Reduced levels of fat-soluble vitamins, interaction with cyclosporine (reduced cyclosporine levels), severe liver injury, worsening of renal function in patients with chronic kidney disease, increased gastrointestinal side effects if high-fat diet","Steatorrhea, oily spotting, flatulence with discharge, fecal urgency, incontinence"
Phentermine/topiramate,"Use with monoamine oxidase inhibitors, hyperthyroidism, glaucoma, pregnancy","Increased heart rate, suicidal behavior, acute myopia and secondary angle closure glaucoma, mood and sleep disorders, cognitive impairment, metabolic acidosis, increased creatinine","Paresthesia, dizziness, insomnia, dysgeusia, constipation, dry mouth"
Naltrexone/ bupropion,"Uncontrolled hypertension, seizure disorders, anorexia, bulimia, abrupt discontinuation of alcohol, benzodiazepines, or barbiturates, pregnancy","Suicidal ideation and behavior, neuropsychiatric adverse events during smoking cessation, risk of seizure, increased blood pressure and heart rate, angle closure glaucoma in patients with untreated narrow angel, hepatitis, liver dysfunction","Nausea, constipation, vomiting, diarrhea, headache, dizziness, insomnia, dry mouth"
"Liraglutide, 3 mg","Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, pregnancy","Thyroid C cell tumors, acute pancreatitis, acute gallbladder disease, severe hypoglycemia when used with sulfonylurea or other glucose secretagogue, increased heart rate, impaired renal function, suicidal behavior or ideation","Nausea, vomiting, diarrhea, constipation, abdominal pain, headache, decreased appetite, fatigue, dizziness, increased lipase"

9.
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.

Capuccio S, Scilletta S, La Rocca F, et al.

Biomolecules. 2024;14(6):687. doi:10.3390/biom14060687.

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.

10.
GLP-1 Receptor Agonists: A Promising Therapy for Modern Lifestyle Diseases With Unforeseen Challenges.

Kupnicka P, Król M, Żychowska J, et al.

Pharmaceuticals (Basel, Switzerland). 2024;17(11):1470. doi:10.3390/ph17111470.

Modern lifestyle diseases remain a persistent challenge in healthcare. Currently, about 422 million people worldwide are affected by diabetes, while 1 in 8 people are living with obesity. The development of glucagon-like peptide 1 receptor agonists (GLP-1RAs) has marked a significant milestone in treating these conditions. Interest in GLP-1RAs has grown due to evidence that, beyond their established role in diabetes management, these drugs influence other metabolic disorders. This is attributed to the fact that GLP-1 receptors are found in various healthy human tissues. However, a potential cause for concern is the expression of GLP-1 receptors in certain cancers. This review focuses on the most recent findings concerning the actions of GLP-1RAs, detailing their documented impact on the thyroid gland and pancreas. It addresses concerns about the long-term use of GLP-1RAs in relation to the development of pancreatitis, pancreatic cancer, and thyroid neoplasms by exploring the mechanisms and long-term effects in different patient subgroups and including data not discussed previously. This review was conducted through an examination of the literature available in the MedLine (PubMed) database, covering publications from 1978 to 10 May 2024. The collected articles were selected based on their relevance to studies of GLP-1 agonists and their effects on the pancreas and thyroid and assessed to meet the established inclusion criteria. The revised papers suggest that prolonged use of GLP-1RA could contribute to the formation of thyroid tumors and may increase the risk of acute inflammatory conditions such as pancreatitis, particularly in high-risk patients. Therefore, physicians should advise patients on the need for more frequent and detailed follow-ups.

11.
Implications of GLP-1 Receptor Agonists on Thyroid Function and Thyroid Nodules: A Drug Target Mendelian Randomization and Cohort Study.

Zhang Z, Yang J, Gao L.

Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2025;:S1530-891X(25)00971-1. doi:10.1016/j.eprac.2025.07.013.

Objectives: GLP-1 receptor agonists are antidiabetic medications, with conflicting reports about their relationship with thyroid diseases. This study investigates their effects on thyroid function and nodules in patients with diabetes.

Methods: Mendelian randomization (MR) was conducted to examine the association between genetically proxied GLP-1 receptor agonist activity and thyroid diseases. This was followed by a cohort study involving 169 patients with diabetes, who were divided into a control group (Control group, W/O GLP-1 treatment) and a GLP-1 receptor agonist treatment group (GLP-1RAs group) based on their medication usage. Patients' thyroid function tests, thyroid nodule diameters and TI-RADS classifications were compared at baseline and after 12 months of treatment.

Results: Through MR, GLP-1 receptor agonists decrease fT4 levels within the normal range [OR (95% CI) = 0.9948 (0.9936-0.9961), P<0.001]. Cohort study showed that after treatment, the nodule diameter increased in both the Control group (0.69 vs. 0.77, p=0.004) and the GLP-1 group (0.68 vs. 0.71, p=0.019). In the GLP-1 group, the TI-RADS (2.60 vs. 2.69, p=0.007) levels increased, while the fT4 (1.26 vs. 1.17, p=0.005) levels decreased. However, linear regression did not show significant association between GLP-1 and post-treatment differences in thyroid function or thyroid nodule.

Conclusions: GLP-1 receptor agonists treatment of 12 months in patients with diabetes is considered relatively safe regarding thyroid disease although there is a potential risk for decreasing of fT4 levels and nodule growth/progression, with no clear evidence of superiority over other antidiabetic treatments.

12.
Approach to the Patient With Thyroid Nodules: Considering GLP-1 Receptor Agonists.

Kelly CA, Sipos JA.

The Journal of Clinical Endocrinology and Metabolism. 2025;110(6):e2080-e2087. doi:10.1210/clinem/dgae722.

Glucagon-like peptide 1 receptor agonists (GLP1RAs) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the US Food and Drug Administration recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RAs and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use.

13.
Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review.

Espinosa De Ycaza AE, Brito JP, McCoy RG, Shao H, Singh Ospina N.

Thyroid : Official Journal of the American Thyroid Association. 2024;34(4):403-418. doi:10.1089/thy.2023.0530.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer.

14.
A Comprehensive Review on the Pharmacokinetics and Drug-Drug Interactions of Approved GLP-1 Receptor Agonists and a Dual GLP-1/­GIP Receptor Agonist.

Min JS, Jo SJ, Lee S, et al.

Drug Design, Development and Therapy. 2025;19:3509-3537. doi:10.2147/DDDT.S506957.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

15.
Effects of GLP-1 and Other Gut Hormone Receptors on the Gastrointestinal Tract and Implications in Clinical Practice.

Camilleri M, Lupianez-Merly C.

The American Journal of Gastroenterology. 2024;119(6):1028-1037. doi:10.14309/ajg.0000000000002519.

Agonists targeting the receptors of incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute a potential barrier to their use, particularly at higher doses. Multiple studies reviewed in this article document the diverse effects of these drugs on the glucagon-like peptide-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery.

16.
Physiology and Pharmacology of Effects of GLP-1-based Therapies on Gastric, Biliary and Intestinal Motility.

Jalleh RJ, Marathe CS, Rayner CK, et al.

Endocrinology. 2024;166(1):bqae155. doi:10.1210/endocr/bqae155.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GLP-1- and glucose-dependent insulinotropic polypeptide receptor co-agonist tirzepatide (referred to here collectively as "GLP-1-based therapy") are incretin-based therapies being used increasingly in the management of both type 2 diabetes and obesity. They are now recognized to have beneficial effects beyond improved glycemic control and weight loss, including cardiovascular and renal protection. GLP-1-based therapy also slows gastric emptying, which has benefits (lowering postprandial glucose), but also potential risks (eg, hypoglycemia in individuals on insulin or sulphonylurea therapy). Their effects on the gallbladder may also be beneficial, contributing to reducing postprandial triglycerides, but they also potentially increase the risk of biliary disease. In this review, we summarize the effects of GLP-1 and incretin-based therapeutics on gastric, biliary and small intestinal function. An improved understanding of these effects will optimize the use of these drugs.

17.
AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

Grunvald E, Shah R, Hernaez R, et al.

Gastroenterology. 2022;163(5):1198-1225. doi:10.1053/j.gastro.2022.08.045.

Practice Guideline

To minimize risk of GI adverse effects, gradual dose titration is recommended for semaglutide and liraglutide. Semaglutide is started at 0.25 mg weekly for the first 4 weeks, followed by doses of 0.5 mg, 1.0 mg, and 1.7 mg weekly every 4 weeks at each dose, until the maintenance dose of 2.4 mg is reached after 16 weeks. For liraglutide, it is recommended to start with 0.6 mg daily for the first 7 days, followed by doses of 1.2 mg, 1.8 mg, and 2.4 mg daily every 7 days at each dose until the maintenance dose of 3.0 mg is reached after 4 weeks. Clinical judgment is recommended for adjusting the titration schedule as needed for an individual patient’s response, tolerance, and adverse effects. If more than 2 consecutive doses are missed, clinical judgment is required to decide on subsequent dosing. Based on our expert opinion, resuming at the same dose can be considered if a patient has tolerated the medication well. Otherwise, prescribers should consider lowering the next dose. Restarting the titration schedule should be considered if 3 or more consecutive doses are missed. Some patients may achieve a strong response at a submaximal dose and could continue that given dose long term.
Liraglutide and semaglutide should not be used with other GLP-1 RAs or with dipeptidyl peptidase-4 inhibitors. Because GLP-1 RAs can delay gastric emptying, it may impact the absorption of some oral medications that require rapid onset of action. Caution is advised when using GLP-1 RAs in combination with insulin or insulin secretagogues (eg, sulfonylureas).

18.
Thyroid Hormone and Diabetes Mellitus Interplay: Making Management of Comorbid Disorders Complicated.

Chauhan A, Patel SS.

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 2024;56(12):845-858. doi:10.1055/a-2374-8756.

Insulin and thyroid hormones play important roles in our body. Insulin helps regulate the glucose level while the thyroid hormones affect various cells and tissues, metabolizing protein, lipids, and glucose. Hyperthyroidism and thyrotoxicosis are potential hazards for type 2 diabetes mellitus. There is a high prevalence of hypothyroidism being more common compared to hyperthyroidism coexisting with diabetes mellitus. Thyroid hormones affect glucose metabolism through its action on peripheral tissues (gastrointestinal tract, liver, skeletal muscles, adipose tissue, and pancreas). High-level thyroid hormone causes hyperglycemia, upregulation of glucose transport, and reduction in glycogen storage. The reverse is observed during low levels of thyroid hormone along with insulin clearance. The net result of thyroid disorder is insulin resistance. Type 2 diabetes mellitus can downsize the regulation of thyroid stimulating hormones and impair the conversion of thyroxine to triiodothyronine in peripheral tissues. Furthermore, poorly managed type 2 diabetes mellitus may result in insulin resistance and hyperinsulinemia, contributing to the proliferation of thyroid tissue and an increase in nodule formation and goiter size. Although metformin proves advantageous for both type 2 diabetes mellitus and thyroid disorder patients, other antidiabetics like sulfonylureas, pioglitazone, and thiazolidinediones may have adverse effects on thyroid disorders. Moreover, antithyroid drugs such as methimazole can weaken glycemic control in individuals with diabetes. Thus, an interplay between both endocrinopathies is observed and individualized care and management of the disorder needs to be facilitated.

19.
Hepatic Thyroid Hormone Signalling Modulates Glucose Homeostasis Through the Regulation of GLP-1 Production via Bile Acid-Mediated FXR Antagonism.

Yan Y, Niu Z, Sun C, et al.

Nature Communications. 2022;13(1):6408. doi:10.1038/s41467-022-34258-w.

Thyroid hormones (TH) regulate systemic glucose metabolism through incompletely understood mechanisms. Here, we show that improved glucose metabolism in hypothyroid mice after T3 treatment is accompanied with increased glucagon-like peptide-1 (GLP-1) production and insulin secretion, while co-treatment with a GLP-1 receptor antagonist attenuates the effects of T3 on insulin and glucose levels. By using mice lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is required for both the regulation of GLP-1 production and the insulinotropic and glucose-lowering effects of T3. Moreover, administration of a liver-targeted TRβ-selective agonist increases GLP-1 and insulin levels and alleviates hyperglycemia in diet-induced obesity. Mechanistically, T3 suppresses Cyp8b1 expression, resulting in increased the levels of Farnesoid X receptor (FXR)-antagonistic bile acids, thereby potentiating GLP-1 production and insulin secretion by repressing intestinal FXR signalling. T3 correlates with both plasma GLP-1 and fecal FXR-antagonistic bile acid levels in people with normal thyroid function. Thus, our study reveals a role for hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.

20.
GLP-1 Receptor Signaling Has Different Effects on the Perikarya and Axons of the Hypophysiotropic Thyrotropin-Releasing Hormone Synthesizing Neurons in Male Mice.

Ruska Y, Peterfi Z, Szilvásy-Szabó A, et al.

Thyroid : Official Journal of the American Thyroid Association. 2024;34(2):252-260. doi:10.1089/thy.2023.0284.

Background: Glucagon-like peptide 1 (GLP-1) is involved in the regulation of energy and glucose homeostasis. As GLP-1 has similar effects on the energy homeostasis as the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons that regulate the hypothalamic-pituitary-thyroid (HPT) axis, we raised the possibility that the TRH neurons are involved in the mediation of the effects of GLP-1. Therefore, the relationship and interaction of the GLP-1 system and the TRH neurons of the hypothalamic paraventricular nucleus (PVN) were studied. Methods: To examine the anatomical and functional relationship of TRH neurons and the GLP-1 system in the PVN, immunocytochemistry, in situ hybridization, in vitro patch-clamp electrophysiology, metabolic phenotyping, and explant experiments were performed. Results: Our data demonstrate that the TRH neurons of the PVN are innervated by GLP-1 producing neurons and express the GLP-1 receptor (GLP-1R). However, not only do the GLP-1-innervated TRH neurons express GLP-1R but the receptor is also present in the axons of the hypophysiotropic TRH neurons in the blood-brain barrier free median eminence (ME) suggesting that peripherally derived GLP-1 may also influence the TRH neurons. In vitro, GLP-1 increased the firing rate of TRH neurons and depolarized them. In addition, GLP-1 directly stimulated the GABAergic input of a population of TRH neurons. Furthermore, GLP-1 inhibited the release of TRH from the hypophysiotropic axons in the ME. In vivo, peripheral GLP-1R agonist administration markedly inhibited the food intake and the energy expenditure, but had no effect on the TRH expression in the PVN and resulted in lower circulating free T4 levels. Conclusions: Our results indicate that GLP-1R activation has a direct stimulatory effect on TRH neurons in the PVN, but the activation of GLP-1R may also inhibit TRH neurons by facilitating their inhibitory inputs or by inhibiting the axon terminals of these cells in the ME. The innervation of TRH neurons by GLP-1 neurons suggests that TRH neurons might be influenced by both circulating GLP-1 and by GLP-1 neurons of the nucleus tractus solitarii. The lack of GLP-1R agonist-induced regulation of TRH neurons in vivo suggests that the HPT axis does not mediate the GLP-1R agonist-induced weight loss.

21.
The GLP-1 Receptor Agonist Exenatide Reduces Serum TSH by Its Effect on Body Weight in People With Type 2 Diabetes.

Tee SA, Tsatlidis V, Razvi S.

Clinical Endocrinology. 2023;99(4):401-408. doi:10.1111/cen.14901.

Objective: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in patients with type 2 diabetes and obesity leads to a significant reduction in serum thyrotropin (TSH) levels but it is unclear whether this is related to weight loss and improvement in sensitivity to thyroid hormones (TH). DESIGN,

Patients And Measurements: We prospectively analysed clinical and biochemical data in patients with type 2 diabetes and obesity who were commenced on the GLP-1 RA exenatide and followed them for 12 months. We assessed the relationship between changes in body weight and serum TSH and resistance to TH indices.

Results: In 112 patients (mean age: 53.5 years, 43.8% female, mean body mass index: 39.8 kg/m ), 12 months of exenatide treatment was associated with a mean (95% CI) percent body weight loss of 6.5% (5.0%-8.1%) and change in serum TSH of -0.25 mU/L (-0.43 to -0.06). There was a significant negative and nonlinear relationship between change in serum TSH and percent body weight loss: -0.25 mU/L with 5%, -0.4 mU/L with 10% and -0.5 mU/L with 15%, respectively, whereas a rise in serum TSH of 0.5 mU/L was associated with 5% weight gain. There were no changes observed in serum FT4 levels with weight loss but a significant reduction in resistance to TH indices was noted.

Conclusions: Exenatide therapy reduces serum TSH levels and improves central sensitivity to TH action over 12 months via its effect on weight loss. The effectiveness of weight loss strategies, rather than TH replacement, should be investigated in individuals with obesity and mildly raised serum TSH levels.

22.
Nutritional Priorities to Support GLP-1 Therapy for Obesity: A Joint Advisory From the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and the Obesity Society.

Mozaffarian D, Agarwal M, Aggarwal M, et al.

The American Journal of Clinical Nutrition. 2025;122(1):344-367. doi:10.1016/j.ajcnut.2025.04.023.

Underlying causes of these GI symptoms appear varied. GLP-1s delay gastric emptying, leading to bloating, fullness, and nausea . GLP-1s activate several brain regions responsible for weight regulation, appetite, and nausea . Occasionally, GLP-1s affect intestinal motility or secretions, contributing to diarrhea . Higher doses are more likely to provoke these adverse symptoms, indicating a dose-dependent relationship .
Less common side effects included dyspepsia, fatigue, headache, eructation (belching), hair loss, gastroesophageal reflux, dizziness, and gastritis (Table 2). Hypoglycemia can occur in individuals with type 2 diabetes, especially when they are consuming insulin or insulin secretagogues such as sulfonylureas [12,41]. Rare side effects include gallbladder disease, pancreatitis, acute kidney injury (typically related to hypovolemia), hypersensitivity reactions, and gastroparesis [12,41]. Ophthalmic complications have been rarely reported, which could relate to direct toxicity or rapid GLP-1-correction of hyperglycemia . Rare cases of suicidality have been reported, although preliminary evaluation using the FDA Adverse Reporting System, post hoc analysis of the STEP clinical trials, and 1 large cohort study have not confirmed any definitive link; the FDA and European Agencies are monitoring potential risk [, , ].

23.
Safety of Semaglutide.

Smits MM, Van Raalte DH.

Frontiers in Endocrinology. 2021;12:645563. doi:10.3389/fendo.2021.645563.

The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide is the most recently approved agent of this drug class, and the only GLP-1RA currently available as both subcutaneous and oral formulation. While GLP-1RAs effectively improve glycemic control and cause weight loss, potential safety concerns have arisen over the years. For semaglutide, such concerns have been addressed in the extensive phase 3 registration trials including cardiovascular outcome trials for both subcutaneous (

Sustain: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and oral (

Pioneer: Peptide InnOvatioN for the Early diabEtes tReatment) semaglutide and are being studied in further trials and registries, including real world data studies. In the current review we discuss the occurrence of adverse events associated with semaglutide focusing on hypoglycemia, gastrointestinal side effects, pancreatic safety (pancreatitis and pancreatic cancer), thyroid cancer, gallbladder events, cardiovascular aspects, acute kidney injury, diabetic retinopathy (DRP) complications and injection-site and allergic reactions and where available, we highlight potential underlying mechanisms. Furthermore, we discuss whether effects are specific for semaglutide or a class effect. We conclude that semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease (cholelithiasis). No unexpected safety issues have arisen to date, and the established safety profile for semaglutide is similar to that of other GLP-1RAs where definitive conclusions for pancreatic and thyroid cancer cannot be drawn at this point due to low incidence of these conditions. Due to its potent glucose-lowering effect, patients at risk for deterioration of existing DRP should be carefully monitored if treated with semaglutide, particularly if also treated with insulin. Given the beneficial metabolic and cardiovascular actions of semaglutide, and the low risk for severe adverse events, semaglutide has an overall favorable risk/benefit profile for patient with type 2 diabetes.

24.
A Review of Serious Adverse Events Linked With GLP-1 Agonists in Type 2 Diabetes Mellitus and Obesity Treatment.

Tobaiqy M.

Pharmacological Reports : PR. 2024;76(5):981-990. doi:10.1007/s43440-024-00629-x.

Glucagon-like peptide-1 (GLP-1) agonists play a crucial role in treating type 2 diabetes mellitus and obesity by providing glycemic control and aiding weight management. Despite their widespread use, concerns about serious adverse events have prompted extensive research. This review aims to describe the current understanding of serious adverse events associated with GLP-1 agonists. A comprehensive search of PubMed, Google Scholar and Embase databases was performed starting from 2010. Studies reporting evidence of an association between GLP-1 agonists and serious adverse events from 22 articles (5 case reports, 5 randomized controlled trials (RCTs), 9 real-world data cohort analyses, 2 meta-analyses and 1 systematic review and meta-analysis) were included and categorized by the type of adverse event. While some studies reported risks, including anaphylaxis, cardiovascular, gastrointestinal, psychiatric and thyroid-related events, others found no significant associations. The evidence remains mixed, necessitating further research to fully understand the safety profile of GLP-1 agonists and inform clinical practice.

25.
GLP-1R Agonist Therapy for Diabetes: Benefits and Potential Risks.

Samson SL, Garber A.

Current Opinion in Endocrinology, Diabetes, and Obesity. 2013;20(2):87-97. doi:10.1097/MED.0b013e32835edb32.

Purpose Of Review: Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined.

Recent Findings: GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety.

Summary: GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.

26.
Factors Associated With Gastrointestinal Side Effects After Liraglutide Treatment for Type 2 Diabetes.

Wu H, Lu Z, Chen R, et al.

Frontiers in Endocrinology. 2023;14:1098032. doi:10.3389/fendo.2023.1098032.

Aim: To identify risk factors predictive of or associated with gastrointestinal side effects (GISE) of liraglutide in patients with type 2 diabetes (T2DM). Methods: T2DM patients treated with liraglutide for the first time were obtained and grouped into patients without GSEA and patients with GSEA. Baseline variables, including age, sex, body mass index (BMI), glycemia profiles, alanine aminotransferase, serum creatinine, thyroid hormones, oral hypoglycemic drugs and history of gastrointestinal diseases, were tested for possible associations with GSEA outcome. Significant variables were entered into univariate and multivariate logistic regression (forward LR) analyses. Receiver operating characteristic (ROC) curves to determine clinically useful cutoff values. Results: A total of 254 patients (95 female) were included in this study. 74 cases (29.13%) reported GSEA and 11 cases (4.33%) discontinued treatment. The results of univariate analyses showed that sex, age, thyroid stimulating hormone (TSH), free triiodothyronine, α-glucosidase inhibitor (AGI), and concomitant gastrointestinal diseases were associated with GSEA occurrence (all p <0.05). In the final regression model, AGI use (adjusted OR=4.01, 95%

Ci: 1.90-8.45, p<0.001), gastrointestinal diseases (adjusted OR=3.29, 95%

Ci: 1.51-7.18, p=0.003), TSH (adjusted OR=1.79, 95%

Ci: 1.28-2.50, p=0.001) and male sex (adjusted OR=0.19, 95%

Ci: 0.10-0.37, p<0.001) were independently associated with GSEA. Furthermore, ROC curve analysis confirmed that TSH values of 1.33 and 2.30 in females and males, respectively, were useful thresholds for predicting GSEA. Conclusion: This study suggests that the combination of AGI, concomitant gastrointestinal diseases, female sex and higher TSH levels are independent risk factors of GSEA of liraglutide treatment in patients with T2DM. Further research is warranted to elucidate these interactions.

27.
Real-World Safety Comparison of Liraglutide and Semaglutide in Weight Management: Insights From European Pharmacovigilance Data.

Ruggiero R, Longo M, Mascolo A, et al.

European Journal of Pharmacology. 2025;:178004. doi:10.1016/j.ejphar.2025.178004.

Background: In recent years, the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), as liraglutide and semaglutide, for weight management has significantly risen. Even if these medications are effective, some concerns remain about their safety profiles, particularly regarding long-term adverse events (AEs). This study provides an evaluation of the safety profiles of liraglutide and semaglutide in a real-world setting.

Methods: A retrospective case-non-case study was conducted using data from the EudraVigilance database. All cases involving liraglutide or semaglutide used for weight management and collected in the database between January 2018 and December 2023 were analyzed. Disproportionality analysis was performed to assess the reporting odds ratios for events of interest (gastrointestinal events, pancreatitis, gallbladders disorders, psychiatric events, and gallbladder, pancreatic or thyroid tumors) reported at least three times.

Results: A total of 27,639 cases were identified. Most cases occurred in female patients aged 18-64 years. Most reported AEs were not-serious. Gastrointestinal events were the most common, with nausea, vomiting, and diarrhea leading the list. Two events were related to gallbladder tumors. Disproportionality analysis revealed that liraglutide was associated with a higher reporting frequency of pancreatitis, gallbladder disorders, and thyroid tumors, while semaglutide showed a greater likelihood of vomiting and abdominal pain. No significant differences were found for other common gastrointestinal events, pancreatic tumors, depression, or suicidal ideation.

Conclusions: Liraglutide and semaglutide showed distinct safety profiles when used for weight management. These findings highlight the importance of considering individual patient profiles and potential risks when prescribing these medications for weight management. Further real-world studies are needed to explore long-term safety and to clarify the potential association between GLP-1 RAs and malignancies.

28.
The Real-World Safety Profile of Tirzepatide: Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database.

Caruso I, Di Gioia L, Di Molfetta S, et al.

Journal of Endocrinological Investigation. 2024;47(11):2671-2678. doi:10.1007/s40618-024-02441-z.

Purpose: Randomized controlled trials with tirzepatide (TZP) displayed unprecedented glucose and body weight lowering efficacy in individuals with type 2 diabetes and/or obesity and a safety profile similar to that of glucagon-like peptide-1 receptor agonists (GLP-1RA), mainly characterized by gastrointestinal (GI) adverse events (AE). Concerns on diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were also addressed. We aimed to investigate whether the same safety issues emerged from the FDA Adverse Event Reporting System (FAERS) post-marketing surveillance database.

Methods: OpenVigil 2.1-MedDRA-v24 and AERSMine (data 2004Q1-2023Q3) were used to query the FAERS database. Reports of GI AE, diabetic retinopathy, pancreato-biliary disorders, and medullary thyroid cancer were investigated. The analysis was then filtered for age, gender, and designation as primary suspect. AE occurrence with TZP was compared to insulin, sodium-glucose cotransporter-2 inhibitors, metformin, and GLP-1RA.

Results: Disproportionate reporting of GI [i.e., nausea (ROR 4.01, 95% CI 3.85-4.19)] and pancreato-biliary disorders [i.e., pancreatitis (ROR 3.63, 95% CI 3.15-4.19)], diabetic retinopathy (ROR 4.14, 95% CI 2.34-7.30), and medullary thyroid cancer (ROR 13.67, 95% CI 4.35-42.96) was detected. TZP exhibited a similar risk of GI AE and medullary thyroid cancer and a lower risk of most pancreato-biliary AE and diabetic retinopathy vs. GLP-1RA.

Conclusions: TZP was associated with an increased risk of specific AE. However, its safety profile was similar to that of GLP-1RA, without increased risk of pancreato-biliary AE, diabetic retinopathy, and medullary thyroid cancer.

29.
Safety of Glucagon-Like Peptide-1 Receptor Agonists: A Real-World Study Based on the US FDA Adverse Event Reporting System Database.

Wu T, Zhang Y, Shi Y, et al.

Clinical Drug Investigation. 2022;42(11):965-975. doi:10.1007/s40261-022-01202-1.

Background And Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as adjunctive therapy to lifestyle intervention and metformin treatment in type 2 diabetes mellitus patients, as most GLP-1RAs have cardiovascular benefits; however, a number of adverse events (AEs) have been reported in postmarketing surveillance.

Objective: The aim of this study was to describe the AEs associated with GLP-1RA monotherapy and identify important medical event (IME) signals for GLP-1RAs.

Methods: Data from 1 April 2005 to 31 December 2021 from the US FDA Adverse Event Reporting System (FAERS) database were extracted to conduct disproportionality analysis and Bayesian analysis. AEs and IMEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). The reporting odds ratio (ROR) and information component (IC) were used to indicate the disproportionality.

Results: A total of 71,515 records involving GLP-1RA monotherapy were submitted to the database, of which 16,350 records were GLP-1RA/IME pairs. Significant disproportionality emerged in five SOCs: 'gastrointestinal disorders' (n = 13,104; lower end of the 95% confidence interval (CI) of the IC [IC] = 1.34), 'investigations' (n = 6889; IC = 0.64), 'metabolism and nutrition disorders' (n = 2943; IC = 0.44), 'neoplasms benign/malignant' (n = 1989; IC = 0.01), and 'hepatobiliary disorders' (n = 1497; IC = 0.38). The most common AEs were pancreatitis, nausea, and weight decrease. Unexpected significant AEs were detected, such as ileus, osteomyelitis, renal cell carcinoma, nephrolithiasis, and drug-induced liver injury.

Conclusion: The majority of AEs have been listed in the prescribing information or reported in previous studies, however we found significant disproportionality in some specific tumor- and liver-related AEs. Clinicians should pay more attention to the newly detected disproportionality that may be triggered by GLP-1RAs, especially in the vulnerable population after long-term use. Considering the limitations of the FAERS database, there is a need for additional pharmacoepidemiological approaches to validate the results of this study.

30.
Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

Feier CVI, Vonica RC, Faur AM, Streinu DR, Muntean C.

International Journal of Molecular Sciences. 2024;25(8):4346. doi:10.3390/ijms25084346.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.