Tirzepatide-Associated Transition from Hypothyroidism to Graves’ Disease
Magdi Essa Abdullah Bakheet *, Sami Kenz1, Shaimaa Samir2, Naeema Alshihhi3, Mamoun Mukhtar4
1,2,3,4. UAE – SKMCA – Ajman – Rashid Center for Diabetes and Research (RCDR)
*Correspondence to: Dr. Magdi Essa Abdullah Bakheet, UAE – SKMCA – Ajman – Rashid Center for Diabetes and Research (RCDR)
Copyright
© 2026 Dr. Magdi Essa Abdullah Bakheet. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 24 June 2026
Published: 01 July 2026
DOI: https://doi.org/10.5281/zenodo.21064784
Abstract
We report the case of a 57-year-old woman with long-standing primary hypothyroidism secondary to autoimmune thyroid disease, with a history of subtotal thyroidectomy for a thyroid nodule. She had been maintained on a stable dose of levothyroxine for several years.
Following initiation of Tirzepatide for weight management, her thyroxine requirement progressively declined over a three-month period and was ultimately discontinued. Subsequently, she developed clinical and biochemical thyrotoxicosis. Further evaluation revealed positive thyroid autoantibodies, including TSH receptor antibodies, along with features consistent with Graves’ orbitopathy, confirming a diagnosis of Graves’ disease. She is currently clinically stable and biochemically controlled on a low dose of Carbimazole. To our knowledge, this represents the first reported case of thyrotoxicosis due to Graves’ disease potentially associated with tirzepatide use. While previous reports have described reduced levothyroxine requirements with tirzepatide—likely related to weight loss—we hypothesize a possible additional effect of this drug class on autoimmune pathways involved in thyroid disease. This potential association remains speculative and warrants further investigation.
Keywords
Autoimmune thyroid disease
Abbreviations
Introduction
Autoimmune thyroid disorders are commonly encountered in clinical practice and encompass a spectrum ranging from hyperthyroidism due to Graves’ disease to hypothyroidism caused by Hashimoto’s thyroiditis. Typically, patients remain at one end of this spectrum, and spontaneous transition between hypothyroid and hyperthyroid states is uncommon [1].
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become a cornerstone in the management of type 2 diabetes mellitus, owing to their efficacy in glycemic control and established cardiovascular benefits [2]. More recently, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists have demonstrated superior efficacy in weight reduction. Tirzepatide, the first-in-class dual agonist, has been approved for weight management and is increasingly utilized worldwide [3].
Consistent with other agents in this class, prescribing information for tirzepatide includes warnings regarding thyroid C-cell tumors, and its use is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma [4]. With its expanding use, emerging clinical observations suggest that tirzepatide may influence levothyroxine requirements in patients with hypothyroidism. Several reports have documented reduced levothyroxine requirements following initiation of tirzepatide, an effect largely attributed to weight loss and altered pharmacokinetics [5,6].
Here, we report what is, to our knowledge, the first case of a patient with long-standing hypothyroidism who developed overt thyrotoxicosis due to Graves’ disease following initiation of tirzepatide for weight management.
Case Presentation
A 57-year-old woman with a background of type 2 diabetes mellitus, hypertension, dyslipidemia, and obesity presented for routine endocrine follow-up. Her diabetes was well controlled on oral therapy, with a consistently maintained HbA1c below 7%.
Her past surgical history was notable for a partial thyroidectomy performed in 2008 for a goiter; however, details of the histopathology were unavailable. Prior to surgery, she had been diagnosed with autoimmune hypothyroidism and commenced on levothyroxine therapy.
Her regular medications included metformin 1000 mg twice daily, candesartan 16 mg once daily, bisoprolol 5 mg once daily, atorvastatin 40 mg once daily, and levothyroxine 100 µg once daily. Her levothyroxine dose had remained stable for at least three years prior to presentation, with no recent adjustments required.
The patient expressed a long-standing desire for weight reduction and had previously attempted multiple lifestyle interventions with limited success. In August 2022, she was initiated on Dulaglutide as an adjunct to lifestyle modification, primarily for weight management. Over the subsequent 12 months, she achieved a weight loss of 7 kg.
In September 2023, at her request, dulaglutide was discontinued and replaced with Tirzepatide, initiated at 2.5 mg weekly and titrated to 5 mg weekly. Following this change, she experienced a further weight reduction of 10 kg over a three-month period (Figure 1)The patient subsequently reported new-onset symptoms of excessive sweating and palpitations. Clinical examination revealed a pulse rate of 96 beats per minute and blood pressure of 132/70 mmHg. Ophthalmic assessment demonstrated exophthalmos and lid lag, consistent with thyroid eye disease. Neck examination showed a well-healed thyroidectomy scar, with a small, smooth, non-tender goiter palpable in the residual thyroid tissue, without discrete nodules or cervical lymphadenopathy.
Initially, the patient attributed her abnormal thyroid function to a recently initiated herbal remedy, the nature of which could not be verified. In view of biochemical thyrotoxicosis, her levothyroxine dose was progressively reduced based on serial thyroid function tests. By February 2024, levothyroxine was discontinued entirely. Despite this, her thyroid-stimulating hormone (TSH) remained suppressed, with persistently elevated free triiodothyronine (fT3) and free thyroxine (fT4) levels, and she remained significantly symptomatic.
Further evaluation with an autoimmune panel revealed negative anti-thyroid peroxidase antibodies but strongly positive TSH receptor antibodies (TRAb), confirming a diagnosis of Graves’ disease with associated orbitopathy.
She was commenced on Carbimazole at a dose of 20 mg daily, with marked symptomatic improvement. By July 2024, her TSH began to recover (0.12 mIU/L), and thyroid hormone levels normalized. Her carbimazole dose was gradually tapered, and she is currently maintained on a low dose of 5 mg daily, remaining both clinically and biochemically euthyroid.
However, her ophthalmopathy persisted, with ongoing diplopia and exophthalmos representing her main clinical concern. She remains under ophthalmology care. Orbital magnetic resonance imaging (MRI) demonstrated bilateral proptosis with enlargement of the extraocular muscles, consistent with thyroid-associated ophthalmopathy, Patient refused to use steroids to treat her Graves ophthalmopathy. She received a course of Teprotumumab, a monoclonal antibody approved for the treatment of thyroid eye disease, with partial response. She is scheduled for a second course of therapy.
Follow-up orbital MRI after teprotumumab showed mildly reduced exophthalmos. There was persistent inflammation of the left superior rectus muscle (measuring 12 mm), while the right inferior rectus demonstrated reduced inflammation with early lipomatosis. Other extraocular muscles showed mild improvement. Mild crowding of the orbital apex (left greater than right) was noted, with normal optic nerves.
Repeat thyroid ultrasound demonstrated post-lobectomy changes in the right lobe without nodules. The left lobe was enlarged, multinodular, and hypervascular. A dominant 25 mm solid, isoechoic, lobulated nodule (TI-RADS 4) was identified, along with additional nodules classified as TI-RADS 2 and 3, overall suggestive of a toxic multinodular goiter pattern. Fine-needle aspiration (FNA) of the dominant TI-RADS 4 nodule revealed benign cytology.
Discussion
Autoimmune thyroid disease exists along a dynamic spectrum, ranging from hypothyroidism due to Hashimoto’s thyroiditis to hyperthyroidism caused by Graves’ disease. Although transition between these two states is uncommon, it is a recognized clinical phenomenon [1]. In this case, the close temporal relationship between initiation of Tirzepatide therapy and the onset of hyperthyroidism makes this observation particularly noteworthy.
The effects of GLP-1–based therapies on thyroid function in patients with hypothyroidism are increasingly being recognized. The most widely accepted explanation for reduced levothyroxine requirements in this context is significant weight loss, which leads to a reduction in lean body mass and consequently alters the volume of distribution of thyroid hormone. This may result in relatively higher circulating levels of thyroxine for a previously stable dose [5,6]. Such a mechanism has been proposed in cases of iatrogenic thyrotoxicosis, including reports of tirzepatide-associated atrial fibrillation attributed to rapid weight loss [7].
However, the clinical course in our patient extends beyond simple dose-related thyrotoxicosis. Despite complete discontinuation of levothyroxine, she remained biochemically thyrotoxic and developed classical features of thyroid eye disease, with strongly positive TSH receptor antibodies. These findings confirm a new diagnosis of Graves’ disease and suggest an underlying pathogenic process distinct from, or in addition to, pharmacokinetic changes related to weight loss.
This raises the important question of whether tirzepatide may have contributed to triggering this autoimmune shift. The mechanisms underlying transition from Hashimoto’s thyroiditis to Graves’ disease are not fully understood but are thought to involve a shift in the balance of autoimmune activity—from destructive, thyroid peroxidase antibody–mediated processes to stimulatory TSH receptor antibody–driven activity [1]. It is plausible that the profound metabolic and immunological changes associated with rapid weight loss, or a potential direct immunomodulatory effect of dual GIP/GLP-1 receptor agonism, may create conditions that favor this transition. Notably, GLP-1 receptors have been identified on immune cells, although their role in modulating human autoimmune disease remains incompletely defined and requires further investigation.
The literature suggests that GLP-1R activation may have an impact on thyroid hormone Levels and, more generally, on thyroid function parameters, although the exact mechanism and outcomes are still being elucidated. However, several studies reported contrasting findings, with a decrease in thyroid-stimulating hormone (TSH) levels as a result of GLP-1R activation [8–10].
GLP-1 RAs may have a direct central inhibitory effect, as GLP-1Rs are expressed in the paraventricular nucleus (PVN) of the hypothalamus where thyrotropin-releasing hormone (TRH)-producing neurons are located. This suggests that GLP-1 RAs may directly affect the activity of TRH-producing neurons in the hypothalamus [11].
The impact of GLP-1 on the hypothalamus–pituitary–thyroid (HPT) axis involves complex interactions. While the precise mechanism is not fully understood, the literature suggests that GLP-1Rs may modulate thyroid hormone production and secretion through their effects on various metabolic pathways, such as the central regulation of appetite and energy balance.
Additionally, the reduction in serum TSH levels is unlikely to be due to a direct effect on the thyroid gland itself because GLP-1Rs are primarily expressed in the C cells of the thyroid, which are not responsible for thyroid hormone synthesis [12]. The variation in serum TSH levels could be linked to weight loss. Indeed, obesity is associated with an increase in serum TSH levels [13,14]
We acknowledge several limitations. Most notably, we were unable to definitively confirm the initial diagnosis of autoimmune hypothyroidism due to the absence of historical biochemical data and surgical histopathology. Nonetheless, the patient’s long-standing requirement for levothyroxine following partial thyroidectomy strongly supports this diagnosis. Furthermore, as a single case report, this observation demonstrates association rather than causation, and the possibility of coincidental occurrence cannot be excluded.
Conclusion
We report a case of a patient with long-standing hypothyroidism who developed overt Graves’ disease with associated orbitopathy shortly after initiation of Tirzepatide. While previous reports have described reduced levothyroxine requirements with tirzepatide—most likely attributable to weight loss—this case raises the possibility of a novel association with the development of stimulatory TSH receptor–mediated autoimmunity
Although a direct causal relationship cannot be established, this observation highlights a potentially important and previously unrecognized clinical phenomenon. Increased awareness among clinicians is warranted, and further studies are needed to explore the potential immunomodulatory effects of incretin-based therapies and for better understanding the role of GLP-1 RAs on thyroid function and to delineate the underlying mechanisms of this complex interaction is evident.
Learning Points
Autoimmune thyroid disease can rarely transition from hypothyroidism due to Hashimoto’s thyroiditis to hyperthyroidism caused by Graves’ disease, reflecting a shift in underlying autoimmune mechanisms.
Tirzepatide and other incretin-based therapies may reduce levothyroxine requirements, most commonly as a result of significant weight loss and altered pharmacokinetics.
Persistent thyrotoxicosis after discontinuation of levothyroxine should prompt evaluation for endogenous causes, including Graves’ disease, rather than assuming medication-related over-replacement.
The development of thyroid eye disease and positive TSH receptor antibodies confirms autoimmune hyperthyroidism and necessitates appropriate antithyroid treatment.
This case highlights a potential, yet unproven, association between tirzepatide and the emergence of stimulatory thyroid autoimmunity, warranting further clinical awareness and research.
References