USE OF SGLT2 INHIBITORS IN PATIENTS WITH TYPE 2 DIABETES AND THEIR IMPACT ON THYROID FUNCTION

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 8 USE OF SGLT2 INHIBITORS IN PATIENTS WITH TYPE 2 DIABETES AND THEIR IMPACT ON THYROID FUNCTION Sh.Sh. Mukhtarova¹, G.A. Karimova², D.D. Khudoyberdiyeva³ Tashkent State Medical University¹,²,³ https://doi.org/10.5281/zenodo.17906521 Abstract. Diabetes mellitus is the most common endocrine disease worldwide and represents a serious public health challenge in modern society. According to the World Health Organization (WHO), in 2021 diabetes was the direct cause of 1.6 million deaths, and 47% of all diabetes-related deaths occurred in individuals under 70 years of age. Objective. To study and review the scientific literature over recent years regarding the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and the effect of treatment on thyroid function. A review of current scientific literature was conducted using databases such as PubMed, Scopus, and Web of Science. Searches were performed using the English keywords “sodium-glucose cotransporter type 2 inhibitors” and “Diabetes mellitus,” which allowed the identification of relevant studies on the treatment of type 2 diabetes (T2DM) with SGLT2 inhibitors and their effects on the heart, kidneys, and thyroid function over the last five years. Keywords: diabetes mellitus, sodium-glucose cotransporter 2 inhibitors, thyroid gland. Introduction Diabetes mellitus ranks first among all endocrine pathologies worldwide and is considered a current “epidemic.” According to the International Diabetes Federation, the number of adults (aged 18–79) with diabetes in 2017 was 425 million, and it is projected to rise to 630 million by 2045 (IDF, 8th edition, 2017). SGLT2 inhibitors block glucose reabsorption in the proximal renal tubules, leading to the excretion of a portion of filtered glucose in the urine. This allows for lowering glycated hemoglobin (HbA1c) levels without increasing the risk of hypoglycemia (especially compared to insulin secretagogues), which is important for many patients [3,4]. In addition to glycemic control, these drugs have demonstrated multiple benefits: weight reduction, decreased blood pressure, and positive effects on kidney and heart function (reducing hospitalizations for heart failure, slowing the progression of diabetic kidney disease), making them an important component of modern T2DM therapy [2]. Materials and Methods. A review of recent scientific literature was conducted using databases such as PubMed, Scopus, and Web of Science. The search used the English keywords “sodium-glucose cotransporter type 2 inhibitors” and “Diabetes mellitus,” enabling identification of recent studies on SGLT2 inhibitor therapy in T2DM and its effects on heart, kidney, and thyroid function over the last five years. In a multicenter retrospective study, patients with type 2 diabetes (T2DM) were divided into two groups: one receiving an SGLT2 inhibitor and one without. It was found that in the SGLT2 inhibitor group, free T3 (fT3) and the fT3:fT4 ratio were higher, while free T4 (fT4) was lower compared to the group without SGLT2 inhibitors. Thyroid-stimulating hormone (TSH) did not differ significantly [6,7]. It is possible that SGLT2 inhibitors influence peripheral conversion of T4→T3 or iodothyronine metabolism. As a result, thyroid hormone metabolism may change, which is important to consider, especially in cases of subclinical thyroid dysfunction. SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 9 The prescription of SGLT2 inhibitors in T2DM is highly relevant: they provide not only glycemic control but also significant organ-protective effects (heart, kidneys). The effect on thyroid function is currently under investigation, but several studies have already reported changes in thyroid function parameters, associations with reduced thyroid cancer risk, improvements in comorbid conditions related to these organs, and other outcomes. According to research analysis, thyroid function disorders occupy second place among endocrine diseases after diabetes. Over the past five years, studies have shown a relationship between these pathologies. On one hand, thyroid hormones participate in the regulation of carbohydrate metabolism and pancreatic function, while on the other hand, T2DM affects thyroid functional status to varying degrees [7,8]. The high prevalence of T2DM necessitates targeted treatment and glycemic control, adhering to the latest recommendations for therapy and the use of new-generation drugs [4,5,7,8]. Currently, drugs of a new class for treating T2DM are the gliflozins - SGLT2 inhibitors. Their mechanism of action is based on inhibiting glucose reabsorption in the proximal tubules of nephrons, thereby increasing glucose excretion in the urine. This effect is considered glucose-dependent. Consequently, SGLT2 inhibitor therapy is associated with a reduced risk of hypoglycemia. In Uzbekistan, SGLT2 inhibitors registered include dapagliflozin, empagliflozin, and canagliflozin. Drugs such as Forxiga (dapagliflozin) and Jardiance (empagliflozin) are used for the treatment of T2DM, as well as chronic heart failure and chronic kidney disease [9]. These drugs are widely used for the treatment of T2DM and its complications, including at early stages of the disease, based on their cardioand nephroprotective properties. As mentioned, SGLT2 inhibitors increase glucose excretion in urine and lead to mild osmotic diuresis. This effect induces a range of systemic effects, including modulation of cardiovascular risk factors. Numerous studies and specifically designed experiments have already confirmed the cardioprotective and nephroprotective properties of SGLT2 inhibitors. The use of gliflozins in patients with atherosclerotic cardiovascular disease (ASCVD) reduces the risk of the three-component composite endpoint (3-Point Major Adverse Cardiovascular Events – 3P-MACE): non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. According to study results, SGLT2 inhibitors reduce the frequency of hospitalizations due to heart failure (HF). It should be emphasized that this effect was observed in all cardiovascular safety studies of gliflozin treatment for type 2 diabetes, both in patients with established ASCVD and those with multiple risk factors. Based on these data, it can be concluded that gliflozins have a class effect on heart failure regardless of previous ASCVD [11,12,13]. Thyroid dysfunction (TD) and diabetes mellitus are frequently coexisting, among the most common chronic endocrine disorders. Thyroid hormones play a role in glucose homeostasis through various mechanisms. SGLT2 inhibitors are a new class of drugs used in diabetes treatment. Their effects on thyroid hormone levels and thyroid gland function have been investigated in several recent studies. In a study by Mojgan Sanjari et al., the effects of empagliflozin on thyroid function tests were assessed. A study conducted at Kerman University of Medical Sciences investigated 44 patients with prediabetes and type 2 diabetes, aged 18–65 years (2022–2023). Patients had HbA1c levels 0.5–1% above therapeutic targets and were not receiving hypoglycemic drugs. All patients received empagliflozin 10 mg once daily for 3 months. Changes in serum TSH, total T4, and total T3 levels were evaluated before therapy and after 3 months of treatment. Results: The mean age of patients was 54.77 years. After three months of empagliflozin therapy, there was a statistically significant reduction in fasting glucose and HbA1c levels (p<0.05). Additionally, a significant increase in T3 levels and the T3/T4 ratio was observed SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 10 (p=0.001). Meanwhile, T4 and TSH concentrations did not change significantly (p>0.05). Furthermore, the increase in T3 was associated with changes in body weight and triglyceride levels following empagliflozin treatment. These results suggest that empagliflozin may increase T3 levels and the T3/T4 ratio but does not affect total T4 or TSH [13,14]. In another study, Narmeen Bastawy et al. investigated the potential therapeutic effect of SGLT2 inhibitors (dapagliflozin) on cardiopulmonary injury associated with hyperthyroidism in rats. In this experiment, sodium levothyroxine hydrate (LT4) and dapagliflozin (DAPA) were used. A total of 24 adult male Wistar rats were included (Table 1) [13]. The animals were divided into the following groups: Table 1. Group Solution / Drug Dose Duration Control group Physiological saline 1 ml/kg/day, orally 4 weeks DAPA group Dapagliflozin dissolved in physiological saline 1 mg/kg/day, orally 4 weeks T4 group Levothyroxine 0.3 mg/kg/day, intraperitoneally 4 weeks T4 + DAPA group Levothyroxine 1 mg/kg/day, orally 2 weeks T4 + DAPA group Combination of levothyroxine and dapagliflozin 1 mg/kg/day, orally 2 weeks After 4 weeks of therapy, changes in body weight, thyroid hormone levels, ECG results, the effect of dapagliflozin on blood biochemical markers, oxidative/antioxidant biomarkers, and the effect of DAPA on DNA fragmentation in hyperthyroid rats were assessed. Results: The study demonstrated that the imbalance between oxidative and antioxidant systems, accompanied by activation of pro-inflammatory and pro-apoptotic markers, is a primary cause of cardiopulmonary damage induced by hyperthyroidism. Combined treatment with dapagliflozin (DAPA) and levothyroxine (LT4) effectively regulated inflammatory and apoptotic processes by reducing TNF-α and caspase-3 expression, mitigating genotoxic effects, and restoring redox balance in heart and lung tissues. Additionally, dapagliflozin exhibited sympatholytic effects, which was confirmed by improvements in ECG parameters associated with hyperthyroidism, reflecting restored cardiac function. Thus, dapagliflozin may be considered a promising therapeutic candidate with potential cardiopulmonary protective effects in hyperthyroidism. However, further clinical and molecular studies are required to confirm these effects [12,13]. A review of the literature revealed conflicting results from Chinese researchers Chao Fu, Dongbo Liu, Qiu Liu, and Xuedong Wang. They analyzed single nucleotide polymorphisms (SNPs) associated with SLC5A2 gene expression and glycated hemoglobin (HbA1c) levels, based on genome-wide association study (GWAS) data, primarily from individuals of European ancestry [3]. These genetic variants were used as instruments to model the effects of SGLT2 inhibitors. Subsequently, Mendelian randomization (MR) studies were conducted to evaluate the impact of SGLT2 inhibitors on thyroid dysfunction, and the results showed a measurable effect. Results: The primary method in the MR study was the inverse-variance weighted approach. Genetically predicted exposure to SGLT2 inhibitor therapy was significantly associated with an increased risk of thyroid disease (OR = 4.63; 95% CI: 2.94–7.28; p = 3.23E−11), SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 11 particularly hypothyroidism (OR = 8.99; 95% CI: 5.31–15.25; p = 3.46E−16). Additionally, SGLT2 inhibitor therapy was associated with a modestly increased risk of hyperthyroidism (OR = 1.01; 95% CI: 1.00–1.03; p = 0.02). Immune dysfunction also plays an important role in the pathogenesis of both hyperand hypothyroidism, and SGLT2 inhibitor use significantly increased the frequency of these comorbidities (OR = 3.94; 95% CI: 2.74–5.67; p = 1.63E−13). These data indicate that SGLT2 inhibitor use may be associated with a substantially increased risk of thyroid dysfunction, including both hypoand hyperthyroidism [10,11]. In another study by Chinese researcher Xuefeng Chen, the effects of SGLT2 inhibitors were analyzed in normoglycemic patients with heart failure (HF). In this experiment, 24 male New Zealand white rabbits were randomly divided into 4 groups: -Sham group (control), - HF group (heart failure) -Perindopril group -Dapagliflozin (DAPA) group The model of normoglycemic CHF was created by aortic constriction for 12 weeks. Starting from week 13, the animals were administered the drugs: DAPA (1 mg/kg/day) or perindopril (0.5 mg/kg/day) orally for 10 weeks. Control groups received saline. After 10 weeks, the structure and function of the heart were evaluated using echocardiography and plasma NTproBNP levels. The results showed that dapagliflozin improved myocardial structure and function in normoglycemic rabbits with CHF and reduced the severity of myocardial fibrosis [11,12]. In the analysis of studies by Fan Zhang and other researchers, the role of the transforming growth factor-β (TGF-β) signaling pathway in fibrogenesis was investigated, which is considered one of the effects of SGLT2 inhibitors [13,14,15]. Several preclinical studies by foreign authors (in animals and cell cultures) have shown that SGLT2 inhibitors contribute to reducing fibrotic processes in various organs – kidneys, heart, and peritoneum [13]. Conclusion: Based on the literature analysis of local and foreign sources, the data indicate a possible causal relationship between the use of SGLT2 inhibitors and their effect on thyroid function. As mentioned, dapagliflozin can be considered a promising therapeutic candidate with potential cardiopulmonary protective effects in hyperthyroidism. Mendelian randomization studies showed that the use of drugs in this group may increase the risk of both hypothyroidism and hyperthyroidism, likely related to their effects on immune mechanisms and the oxidativeantioxidant balance. The obtained data emphasize the need for more thorough investigation of the potential influence of SGLT2 inhibitors on endocrine regulation and metabolic processes. REFERENCES 1. Bastawy, N., et al. (2024). SGLT2 inhibitor as a potential therapeutic approach in hyperthyroidism-induced cardiopulmonary injury in rats. Pflugers Archiv: European Journal of Physiology, 476(7), 1125–1143. https://doi.org/10.1007/s00424-024-02967-4 2. Cosentino, F., et al. (2020). 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal, 41(2), 255–323. https://doi.org/10.1093/eurheartj/ehz486 3. Chao Fu, Dongbo Liu, Qiu Liu, Xuedong Wang. (2023). Association of SGLT-2 inhibitors with thyroid dysfunction: A drug-target Mendelian randomization study. Research Square. https://doi.org/10.21203/rs.3.rs-3332941/v1 SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 12 4. Okada, S., et al. (2023). The ratio of free triiodothyronine to free thyroxine is regulated differently in patients with type 2 diabetes mellitus treated and not treated with SGLT2 inhibitors. Diabetes & Metabolic Syndrome, 17(1), 102704. https://doi.org/10.1016/j.dsx.2022.102704 5. Sanjari, M., et al. (2025). Effect of Empagliflozin on Serum Levels of Thyroid Hormones Among Prediabetic and Diabetic Patients. International Journal of Endocrinology, 2025, 9920286. https://doi.org/10.1155/ije/9920286 6. Sanjari, M., et al. (2025). Effect of Empagliflozin on Serum Levels of Thyroid Hormones Among Prediabetic and Diabetic Patients. International Journal of Endocrinology, 2025, 9920286. https://doi.org/10.1155/ije/9920286 7. Murray, C. J. L., & GBD 2021 Collaborators (2024). Findings from the Global Burden of Disease Study 2021. Lancet, 403(10440), 2259–2262. https://doi.org/10.1016/S01406736(24)00769-4 8. Mim, J. J., et al. (2024). A comprehensive review on the biomedical frontiers of nanowire applications. Heliyon, 10(8), e29244. https://doi.org/10.1016/j.heliyon.2024.e29244 9. Yang Z, et al. (2022). The Correlation between Thyroid Hormone Levels and the Kidney Disease Progression Risk in Patients with Type 2 Diabetes. Diabetes Metab Syndr Obes, 15, 59–67. https://doi.org/10.2147/DMSO.S347862 10. Yalçın, N., et al. (2025). Impact of SGLT2 Inhibitors on Cardiovascular Risk Scores, Metabolic Parameters, and Laboratory Profiles in Type 2 Diabetes. Life, 15(5), 722. https://doi.org/10.3390/life15050722 11. Xu, B., et al. (2022). The current role of SGLT2 inhibitors in type 2 diabetes mellitus management. Cardiovascular Diabetology, 21(1), 83. https://doi.org/10.1186/s12933-02201512-w 12. NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biology, 2, 267–272. https://doi.org/10.1016/j.redox.2014.01.012 13. NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biology, 2, 267–272. https://doi.org/10.1016/j.redox.2014.01.002 14. Petunina, N. A., et al. (2020). Role of SGLT2 inhibitors in type 2 diabetes management in clinical practice. Effective Pharmacotherapy, 16(12), 16–24. https://doi.org/10.33978/23073586-2020-16-12-16-24 15. Shestakova, M. V., & Galstyan, G. R. (2020). Latest news on type 2 diabetes management: The role of SGLT2 inhibitors. III All-Russian Conference with international participation. Effective Pharmacotherapy. Endocrinology, 16(2). https://umedp.ru/articles/