Association of SGLT-2 Inhibitors with Thyroid Dysfunction: A Drug-Target Mendelian Randomization Study

Abstract

Abstract Context: Diabetes and thyroid dysfunction are prevalent endocrine disorders. Diabetes substantially increases the incidence of thyroid dysfunction, and the concurrent presence of diabetes and thyroid dysfunction further heightens the risk of adverse events associated with diabetes. However, no studies have been conducted to investigate the impact of novel antidiabetic medications, particularly sodium-glucose co-transporter 2 (SGLT-2) inhibitors, on thyroid dysfunction. Objective: This study aims to estimate the causal associations of SGLT-2 inhibitors with thyroid dysfunction. Methods: We extracted single-nucleotide polymorphisms associated with SLC5A2 gene expression and glycated hemoglobin A1c levels from a genome-wide association study predominantly conducted in individuals of European descent. These genetic variants were utilized as tools to simulate the effects of SGLT-2 inhibitors. Subsequently, we conducted drug-targeted mendelian randomization (MR) studies to assess the impact of SGLT-2 inhibitors on thyroid dysfunction and captured the results demonstrating this effect. Results:The inverse variance-weighted method served as the primary analysis technique in the MR study. Treatment with SGLT-2 inhibitors, predicted through genetic analysis, is strongly linked to a higher risk of thyroid disease (OR: 4.63, 95%CI: 2.94-7.28, p=3.23E-11), especially hypothyroidism (OR: 8.99, 95%CI: 5.31-15.25, p=3.46E-16). Furthermore, SGLT-2 inhibitors treatment substantially raises the occurrence of hyperthyroidism (OR: 1.01, 95%CI: 1-1.03, p=0.02). Conversely, immune dysfunction plays a significant role in the development of both hyperthyroidism and hypothyroidism, and SGLT-2 inhibitors treatment significantly increases the incidence of these related diseases (OR: 3.94, 95%CI: 2.74-5.67, p=1.63E-13). Conclusions: Our study found that the use of SGLT-2 inhibitors significantly increases the incidence of thyroid dysfunction.