Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies
Authors: Alwan Heba , Villoz Fanny , Feller Martin , Dullaart Robin P F , Bakker Stephan J L , Peeters Robin P , Kavousi Maryam , Bauer Douglas C , Cappola Anne R , Yeap Bu B , Walsh John P , Brown Suzanne J , Ceresini Graziano , Ferrucci Luigi , Gussekloo Jacobijn , Trompet Stella , Iacoviello Massimo , Moon Jae Hoon , Razvi Salman , Bensenor Isabela M , Azizi Fereidoun , Amouzegar Atieh , Valdés Sergio , Colomo Natalia , Wareham Nick J , Jukema J Wouter , Westendorp Rudi G J , Kim Ki Woong , Rodondi Nicolas , Del Giovane Cinzia 
Published: September 2022

Abstract

Objective
Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes.

Methods
We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up.

Results
Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88–1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82–1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87–1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88–1.29). The results were robust in all sub-group and sensitivity analyses.

Conclusions
This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes.

Significance statement
Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.