Early Glycemic Control and Magnitude of HbA_1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators.

Abstract

We investigated the association of early achieved HbA_1c level and magnitude of HbA_1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin. This was a population-based cohort study including all metformin initiators with HbA_1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA_1c achieved (<6.5% or higher) and by magnitude of HbA_1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA_1c and other confounding factors. We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA_1c achieved compared with a target HbA_1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA_1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA_1c change (Δ = 0). A large initial HbA_1c reduction and achievement of low HbA_1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.