Hemoglobin A1c-levels and subsequent risk of depression in individuals with and without diabetes

It has been suggested that long-term glycemic load as reflected in plasma levels of Glycosylated Hemoglobin, Type A1C (HbA1c) is associated with higher risk of depression, however results have been conflicting. We examined the potential association between HbA1c and risk of depression in a large population-based cohort without baseline diabetes (the Glostrup cohort) defined by either self-reported diabetes, registry diagnosis of diabetes or use of antidiabetic medication at baseline and in a national diabetes cohort (the Danish Adult Diabetes Database).A total of 16,124 middle-aged individuals from the Glostrup cohort and 93,544 patients registered in the Danish Adult Diabetes Database were followed from the first registered HbA1c measurement (1999-2014) for subsequent diagnosis of depression or use of antidepressant medication in nation-wide Danish registers. The association was analyzed using a Cox proportional hazards regression model with HbA1c on both a continuous scale using restricted cubic splines and categorized based on the groups found in the spline model. We adjusted for relevant sociodemographic and clinical variables including previous depression and tested for interaction of both gender, insulin use and diabetes type.During follow-up, 2694 (17%) in the Glostrup cohort and 29,234 (31%) in the diabetes cohort developed depression. In the Glostrup cohort, we found an indication of a positive linear association between HbA1c and depression in women, while no clear association was found in men. In patients with diabetes, we found a U-shaped association between HbA1c and depression in both men and women with the lowest risk estimates for HbA1c levels of 58 mmol/mol (7.5%) in men and of 60 mmol/mol (7.6%) in women. When HbA1c was categorized, men with the highest HbA1c-levels had significantly elevated risk of depression (HRHbA1c>9.4 1.16 (95%CI 1.10-1.23)) after multifactorial adjustment compared to the reference group with HbA1c of 42.1-56.2 mmol/mol (6.0-7.3%). Women in the lowest and highest category of HbA1c had significantly higher risk of depression HRHbA1c<6.0 1.15 (95% CI 1.09-1.22) and HRHbA1c>9.3 1.10 (95% CI 1.04-1.16), respectively, compared to the reference group with HbA1c 42.1-55.0 mmol/mol (7.2-9.3%). There was a significant interaction with gender, but no interaction for insulin use or diabetes type.In a population without baseline diabetes, higher HbA1c levels seemed associated with higher depression risk in women, whereas a U-shaped association was found in patients with known diabetes.