Risk of All-Cause Mortality in Levothyroxine-Treated Hypothyroid Patients: A Nationwide Korean Cohort Study

Background Although hypothyroidism is associated with various comorbidities, its relationship with increased all-cause mortality remains controversial. The aim of this nationwide retrospective cohort study was to investigate whether hypothyroid patients treated with levothyroxine had increased mortality compared to controls. Methods Hypothyroid subjects were identified through the Korean National Health Insurance Service Claims database between 2008 and 2017. Hypothyroidism in this study was defined as overt hypothyroidism treated with long-term prescription of levothyroxine (>6 months). After 1:3 age-, sex- and index year-matching, 501,882 patients with newly diagnosed hypothyroidism and 1,505,646 controls without hypothyroidism were included. Results During a mean follow-up of 6 years, 25,954 (5.2%) hypothyroid patients and 59,105 (3.9%) controls died. Hypothyroidism was significantly associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI] 1.12-1.16) even with levothyroxine treatment. When stratified by age, sex, and cardiovascular disease risk, independent associations between hypothyroidism and mortality remained significant in all subgroups. The risk of mortality was higher in the < 65 age group (HR: 1.25, 95% CI: 1.22-1.29), men (HR: 1.28, 95% CI: 1.25-1.31), and the high cardiovascular disease risk group (HR: 1.31, 95% CI: 1.29-1.34). The mortality rate of hypothyroid patients was highest within 1 year of treatment and decreased with time. Conclusion This nationwide, population-based cohort study showed that all-cause mortality was significantly higher in levothyroxine-treated hypothyroid patients than in non-hypothyroid controls. This association remained significant regardless of age, sex, and cardiovascular disease risk.