Unexpected Impact of Roxadustat on Thyroid Function: New Insights into HIF-PH Inhibitors in Renal Anemia

Chronic kidney disease (CKD) causes renal anemia which is a frequent and serious complication that adversely affects patients’ quality of life and increases their mortality rates. Until recently, erythropoiesis-stimulating agents (ESAs) and dietary iron supplements have been the standard therapeutic approach to treating CKD-related anemia because they can raise hemoglobin levels and minimize the requirement for blood transfusions. Nevertheless, ESAs therapy may increase cardiovascular events risk especially if using higher targets of hemoglobin hence necessitating alternative interventions which are safer. In recent times, there has been a great interest in hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors as new drugs to manage anemia in CKD. They promote native synthesis of erythropoietin by stabilizing HIF enabling more physiological management of anaemia rather than exogenous ESA administration which may be fraught with untoward effects through its modulation possibly obviating adverse outcomes linked to exogenous ESA administration through more physical ways. Roxadustat, an HIF-PH inhibitor, is one of the promising therapeutic agents that have been introduced and its efficacy in anemia management has attracted special attention because of its unique molecular structure. The difference between roxadustat and other drugs in the same class is that it has triiodothyronine (T3) a thyroid hormone like molecular configuration. This similarity poses important questions about its effect on thyroid function, which plays a significant role in metabolic regulation and interacts with renal functions. Some preliminary studies and clinical observations indicate that roxadustat might interact with thyroid hormone receptors thereby influencing thyroid hormone levels but detailed investigations into this possibility remain to be conducted.

A collaborative group from the Kansai Electric Power Medical Research Institute, Kansai Electric Power Hospital, and Gifu University (Takuya Haraguchi, Yoshiyuki Hamamoto, Hitoshi Kuwata, Yuji Yamazaki, Susumu Nakatani, Takanori Hyo, Yuichiro Yamada, Daisuke Yabe, and Yutaka Seino ) reported for the first time globally that roxadustat, a new HIF-PH inhibitor drug for renal anemia, affects thyroid hormone test values (decrease in TSH and free T4), whereas another HIF-PH inhibitor, daprodustat, does not show significant effects. The new study published in the Journal of Clinical Endocrinology & Metabolism.  This method allowed the authors to directly assess the thyroid-related effects of every medication, therefore offering a clear comparison between one without such similarities (daprodustat) and a structurally thyroid hormone-like HIF-PH inhibitor (roxadustat). The main goal of this work was to close the information gap about the effect of roxadustat on thyroid function in renal anemic individuals.

It is critical to comprehend this area of roxadustat’s pharmacology as there are complex relationships between renal health and thyroid function. Elucidating the effects of roxadustat on the thyroid axis may be clinically significant because thyroid dysfunction can seriously complicate CKD management and its outcomes. The specific aims of this investigation will to assess if thyroxine synthesis inhibitors, such as rapamycin or tetracycline, either prevent or limit suppression by HIF-PH inhibitors that resemble thyroid hormones. By comparing, it will help establish whether there is an important difference between them regarding what happens in patient with CKD related renal anemia involving their structures due to similarity with thyroxines hence helping decision-making when prescribing drugs for managing such kind of people.

The authors found significant changes in thyroid function indicators in roxadustat treated subjects. Especially, TSH and FT4 levels statistically significantly dropped with the start of roxadustat medication. Particularly, FT4 declined from 0.93 ng/dL to 0.70 ng/dL and median TSH levels dropped from 2.481 μIU/mL pre-treatment to 0.659 μIU/mL post-treatment. These alterations imply that roxadustat suppresses thyroid function, which fits its structural and functional mimicry of thyroid hormones and may possibly interact with thyroid hormone receptors, especially THRβ. Conversely, patients treated with daprodustat did not experience significant changes in either TSH or FT4 levels. The stability of these thyroid function indicators in the daprodustat group emphasizes the uniqueness of roxadustat’s actions connected to its special chemical structure. This unusual effect not only emphasizes the possible thyroid hormone-like action of roxadustat but also gives comfort about the thyroid safety profile of daprodustat in clinical situations. Along with other clinical variables like hemoglobin levels, total cholesterol, and creatine kinase, the authors looked at relationships between changes in thyroid function and these studies revealed no appreciable correlations, suggesting that alterations in these parameters had no bearing on the noted declines in TSH and FT4 with roxadustat. This result is significant as it shows that roxadustat’s suppression of thyroid hormones does not produce usual hypothyroid symptoms or metabolic disturbances usually connected with low thyroid function, including changed cholesterol levels or decreased enzyme activities.

In conclusion, the new study by Dr. Takuya Haraguchi and colleagues  explained well the different influences of the HIF-PH inhibitors roxadustat and daprodustat on thyroid function, highlighting the importance of careful thyroid monitoring in CKD patients receiving roxadustat because it acts like a kind of hormone. A possible management approach for roxadustat, including close monitoring of hypothyroidism in those who had pre-existing thyroid dysfunction, might be needed. Conversely, daprodustat is considered to have better effects on thyroid health and could be more suitable for patients with complex endocrine diseases. These findings can also provide insights into future drug development as well as influence regulatory and prescribing guidelines thus leading to safer and more effective management approaches for renal anemia among CKD patients. The findings do not only give improved comprehension of mechanisms behind how drugs work but also highlights individualized treatment options that enable attainment of optimal results while minimizing adverse reactions.  In a statement to Medicine Innovates, the authors said “Roxadustat, due to its chemical structure, possesses a skeleton similar to the thyroid hormone T3 (triiodothyronine), and is thought to suppress TSH and reduce T3 and T4 levels. However, even when thyroid hormone levels were reduced, no hypothyroidism-like test data (such as elevated cholesterol or CK) were observed, suggesting the possibility that roxadustat possesses thyroid hormone-like effects. Therefore, caution is necessary when interpreting thyroid hormone test values in patients using roxadustat.”