Association between free triiodothyronine and diabetic retinopathy: Insights from a longitudinal cohort study and mendelian randomization

Xiaotong Feng^1,2Hongling Zhao^1,2Yongsong Xu^1,2Xianhua Li^1,2Haodi Cao^1,2Yingxiang Wang¹Dong Zhao^1,2Jing Ke^1,2*

• ¹Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China
• ²Laboratory for Clinical Medicine, Capital Medical University, Beijing, China

Background: Growing evidence indicates that thyroid function plays a critical pathophysiological role in diabetic microvascular complications. Nevertheless, the specific association between thyroid hormones, particularly free triiodothyronine (fT3), and diabetic retinopathy (DR) remains controversial. Methods: After applying the inclusion and exclusion criteria, 3703 patients were included in the baseline analysis. Multivariate logistic regression models were employed to assess the cross-sectional association between baseline fT3 levels and both the prevalence of DR. Subsequently, 1476 patients who underwent follow-up fundus photography were eligible for the retrospective cohort study. This secondary analysis examined the relationship between baseline fT3 quartiles and the risk of DR onset or progression. Additionally, two-sample mendelian randomization (MR) analysis was performed to analyze the causal effect of circulating fT3 on non-proliferative DR (NPDR) and proliferative DR (PDR). Results: In the cross-sectional analysis, higher fT3 levels were inversely associated with DR after multivariable adjustment, including NPDR (OR = 0.61, 95% CI: 0.50-0.74) and PDR (OR = 0.24, 95% CI: 0.13-0.44). In the longitudinal cohort, patients with moderate fT3 levels (Q2–Q3) had a lower risk of DR onset or progression versus the lowest quartile (Q1). This protective association remained significant in those with suboptimal glycemic control (HbA1c ≥7%) or longer diabetes duration (≥ 10 years), with risk reductions of 43% (Q2) and 37% (Q3) in the former, and 44% (Q2) and 49% (Q3) in the latter. Notably, among older patients (≥ 55 years), the benefit extended across Q2-Q4. Finally, the MR analysis suggested a potential protective effect of higher fT3 levels on NPDR (MR Egger, OR = 0.131, 95% CI: 0.023-0.755, P = 0.044). Conclusion: In conclusion, our study demonstrated an inverse association between fT3 levels and the risk of both NPDR and PDR. Moderate fT3 levels were associated with a lower risk of DR onset or progression, particularly among patients with suboptimal glycemic control (HbA1c ≥7%) or longer diabetes duration (≥ 10 years). In older patients (≥ 55years), even relatively higher fT3 levels may be protective. MR analysis suggested a potential protective effect of elevated fT3 levels on the risk of NPDR, which was significant only in the MR Egger model.