Associations between HbA1c Reduction and Change in Depressive Symptoms following Glucose-lowering Treatment in Adults: A Systematic Review of Intervention Studies

Introduction: Hyperglycemia constitutes a likely pathway linking diabetes and depressive symptoms; lowering glycemic levels may help reduce diabetes-comorbid depressive symptoms. Since randomized controlled trials can help understand temporal associations, we systematically reviewed the evidence regarding the potential association of hemoglobin HbA1c lowering interventions with depressive symptoms. Methods: PubMed, PsycINFO, CINAHL, and EMBASE databases were searched for randomized controlled trials evaluating HbA1c-lowering interventions and including assessment of depressive symptoms published between 01/2000-09/2020. Study quality was evaluated using the Cochrane Risk of Bias tool. PROSPERO reg-istration: CRD42020215541. Results: We retrieved 1,642 studies of which twelve met our inclusion criteria. Nine studies had high and three unclear risks of bias. Baseline depressive symptom scores suggest elevated depressive symptoms in five stud-ies. Baseline HbA1c was <8.0% (<64 mmol/mol) in two, 8.0-9.0% (64-75 mmol/mol) in eight, and ≥10.0% (≥86 mmol/mol) in two studies. Five studies found greater HbA1c reduction in the treatment group; three of these found greater depressive symptom reduction in the treatment group. Of four studies analyzing whether the change in HbA1c was associated with the change in depressive symptoms, none found a significant association. The main limitation of these studies was relatively low levels of depressive symptoms at baseline, limiting the ability to show a lowering in depressive symptoms after HbA1c reduction. Conclusions: We found insufficient available data to estimate the association between HbA1c reduction and depressive symptom change following glucose-lowering treatment. Our findings point to an important gap in the diabetes treatment literature. Future clinical trials testing interventions to improve glycemic outcomes might consider measuring depressive symptoms as an outcome to enable analyses of this association.