Popular Diabetes Drugs Show No Effect on Thyroid Hormone or Inflammation Markers

Sodium-glucose cotransporter-2 inhibitors, the blockbuster diabetes pills better known as SGLT-2 inhibitors, have built a reputation for doing far more than lowering blood sugar. They protect the heart and kidneys, trim weight, and are increasingly prescribed to millions of people with type 2 diabetes worldwide. Yet as their use has surged, a subtle question has lingered among endocrinologists: could these drugs, which act on transporters found in unexpected tissues, quietly influence the thyroid gland or the body’s inflammatory state? A new retrospective study from Türkiye now offers one of the most direct answers to date, and the finding is essentially a reassuring null result.

Researchers at Ankara Etlik City Hospital compared 224 patients with type 2 diabetes who had been taking either empagliflozin or dapagliflozin for at least six months against 106 age- and sex-matched patients with type 2 diabetes who had never used the drug class. The study, published in BMC Endocrine Disorders, tracked two principal outcomes: thyroid-stimulating hormone, or TSH, the pituitary messenger that regulates thyroid function, and the systemic immune-inflammation index, known as SII, a simple blood-derived marker calculated from platelet, neutrophil, and lymphocyte counts that is increasingly used as a low-cost gauge of systemic inflammation. Crucially, the investigators excluded anyone with known thyroid disease, thyroid autoantibody positivity, active inflammatory or autoimmune conditions, advanced organ failure, or ongoing immunomodulatory therapy, ensuring that the comparison was as clean as retrospective data allow.

The headline numbers tell a story of remarkable similarity across the groups. Median TSH was 1.6 micro-international units per milliliter in the empagliflozin group, 1.8 in the dapagliflozin group, and 1.9 in the control group, a difference that failed to reach statistical significance with a p-value of 0.338. The SII told the same tale: medians of 481, 531, and 468.5 respectively, with a p-value of 0.509. In plain terms, people on SGLT-2 inhibitors had thyroid function markers and inflammatory indices that were statistically indistinguishable from their peers on other diabetes regimens.

What lends this result weight is the study’s statistical diligence, which goes beyond the simple group comparison. The team ran correlation analyses, multivariate linear regression, multicollinearity diagnostics using variance inflation factors, and even a post-hoc power calculation, an unusually transparent step for a retrospective design. The power analysis showed the study had 80 percent ability to detect a Cohen’s f effect size of 0.17 or larger, yet the observed effect sizes for TSH and SII were dramatically smaller, at f of 0.02 and approximately 0.00 respectively. In other words, the study was adequately powered to find a meaningful signal, and the signal simply was not there, suggesting that if any true effect of SGLT-2 inhibitors on these markers exists, it is likely too small to matter clinically.

The regression analysis did, however, surface an unexpected protagonist. When the researchers modeled log-transformed TSH as the outcome, female sex emerged as an independent predictor, with a standardized coefficient of 0.161 and a p-value of 0.015, a finding consistent with the well-documented observation that thyroid parameters differ by sex. More intriguingly, estimated glomerular filtration rate, or eGFR, the standard measure of kidney function, independently predicted TSH levels with a coefficient of minus 0.0043 and a p-value of 0.037, meaning that as kidney function declined, TSH tended to rise regardless of which diabetes medications a patient was taking. SGLT-2 inhibitor use itself, along with SII, neutrophil-to-lymphocyte ratio, age, metformin use, and diabetes duration, all fell away as non-significant in the final model.

This renal-thyroid connection is more than a statistical footnote. The hypothalamic-pituitary-thyroid axis and the kidneys are intertwined in ways that clinicians sometimes underestimate. Declining renal clearance alters the metabolism and excretion of thyroid hormones, chronic kidney disease can produce a state resembling non-thyroidal illness, and conversely, hypothyroidism can impair renal hemodynamics. The finding that eGFR independently tracks with TSH in a population deliberately screened free of thyroid disease suggests that kidney function deserves closer attention when interpreting thyroid tests in patients with type 2 diabetes, a group in which diabetic nephropathy is common. The authors argue that this axis warrants further study independent of any drug exposure.

The mechanistic backdrop explains why the question was worth asking in the first place. SGLT-2 transporters are expressed not only in the kidney’s proximal tubule but also in extrarenal tissues, and some animal and small human studies had hinted at crosstalk between glucose-lowering agents and thyroid physiology. Meanwhile, the systemic immune-inflammation index and its cousin, the neutrophil-to-lymphocyte ratio, have become fashionable proxies for the chronic low-grade inflammation that underlies both insulin resistance and diabetic complications. Because SGLT-2 inhibitors appear to dampen inflammatory pathways in some experimental models, researchers suspected the drugs might measurably shift these indices in patients. The Turkish dataset, one of the largest head-to-head comparisons to date, found no evidence of such a shift; notably, SII and NLR were themselves strongly correlated in the sample, with a correlation coefficient of 0.467 and a p-value below 0.001, confirming that the inflammatory markers were behaving as expected even if the drugs did not move them.

For the millions of people taking empagliflozin or dapagliflozin, the practical message is one of reassurance. The study population, 330 adults in total, had used the drugs for at least six months, a duration long enough for any steady-state effect on thyroid physiology or immune-cell dynamics to manifest. The absence of significant differences in TSH or SII means there is currently no basis for routine thyroid monitoring specifically triggered by SGLT-2 inhibitor initiation in patients without preexisting thyroid conditions, and no signal that the drugs are provoking systemic inflammation. At the same time, the authors are careful to frame the result within the limits of its design: it was a single-center, retrospective, observational study, and it relied on TSH rather than the full panel of free thyroxine and triiodothyronine measurements that would capture the complete thyroid picture. Subclinical shifts in peripheral hormone conversion, for example, could theoretically escape a TSH-only lens.

Those caveats point directly at the research agenda the authors propose. Prospective, multicenter studies incorporating free thyroxine and triiodothyronine measurements, longer follow-up, and perhaps more granular inflammatory biomarkers such as interleukin-6 or C-reactive protein would settle the question with greater authority. Until then, this study stands as a well-powered negative result, a category of evidence that science needs more of. It trims the list of things clinicians must worry about with one of the most widely prescribed drug classes in modern medicine, while quietly spotlighting renal function as a variable that genuinely shapes thyroid readings. In a field saturated with hyped drug effects, a rigorous demonstration that nothing is happening can be its own kind of headline news.

The choice of the systemic immune-inflammation index as an outcome reflects a broader shift in diabetes research toward hematological composite markers. Because the index is derived from routine complete blood counts rather than specialized assays, it can be computed cheaply and repeatedly in ordinary clinical settings, which explains its growing popularity as a surrogate for the inflammatory burden associated with insulin resistance, atherosclerosis, and microvascular complications. Its strong correlation with the neutrophil-to-lymphocyte ratio in this cohort, with a correlation coefficient of 0.467, indicates that both markers captured overlapping aspects of the same underlying inflammatory physiology, lending internal coherence to the null finding.

The thyroid measurements were performed using electrochemiluminescence immunoassay, a widely adopted platform for thyrotropin detection that offers high analytical sensitivity at the low concentrations relevant to suppression and subclinical disease. This matters for interpretation, because a null result obtained with a precise assay is more convincing than one obtained with older, noisier methods. The reliance on a single TSH measurement per patient, however, means that within-person biological variation, which can be substantial for thyrotropin, was not accounted for, a limitation inherent to the retrospective design.

The composition of the cohort also deserves note. Patients taking empagliflozin outnumbered those on dapagliflozin by 139 to 85, and both active groups were pooled for some analyses rather than analyzed as separate exposures, since the two agents share the same mechanism of glucose excretion through urinary inhibition of the sodium-glucose cotransporter. Metformin use was deliberately included as a covariate because the drug is nearly ubiquitous in type 2 diabetes and has itself been anecdotally linked to thyroid parameters, yet it showed no independent association with thyrotropin in the final regression model.

The sex difference in thyrotropin, with female sex independently predicting higher values, aligns with decades of epidemiological data showing that thyroid dysfunction and mildly elevated thyrotropin are more prevalent in women, particularly with advancing age. Its emergence in a cohort screened free of thyroid disease suggests that even within the normal reference range, physiological sex-based variation persists and should be considered when clinicians interpret borderline results.

Finally, the ethics approval from the Ankara Etlik City Hospital committee and the waiver of individual consent, justified by anonymized extraction from the hospital information system, illustrate the standard governance pathway for retrospective chart-based endocrine research in Türkiye. The open-access publication under a Creative Commons license ensures that this carefully powered negative result is freely available to the clinicians and researchers best positioned to build on it.

Subject of Research: Effects of long-term SGLT-2 inhibitor use on thyroid-stimulating hormone and systemic immune-inflammation index in patients with type 2 diabetes

Article Title: Effects of SGLT-2 inhibitors on thyroid-stimulating hormone and systemic immune-inflammation index in type 2 diabetes: a retrospective study

Article References: Bayram, S. M., Demirci, H., Üçgül, E., Canlar, Ş., Cinel, M., Menekşe, B., Kuşabbi, İ. A., & Çakal, E. (2026). Effects of SGLT-2 inhibitors on thyroid-stimulating hormone and systemic immune-inflammation index in type 2 diabetes: a retrospective study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02483-9

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02483-9

Keywords: SGLT-2 inhibitors, empagliflozin, dapagliflozin, type 2 diabetes, TSH, systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, thyroid function, estimated glomerular filtration rate, retrospective study, endocrinology, inflammation