Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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 Delta=-4, HR 0.98 (0.80-1.20) for Delta=-3, HR 0.92 (0.78-1.08) for Delta=-2, and HR 0.99 (0.89-1.10) for Delta=-1 compared with no HbA(1c) change (Delta=0). CONCLUSIONS 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.