Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study

Aims: While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the impact of glucose lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and its observational follow-up study (ACCORDION) to investigate the impact of intensive glucose control on multiple events and further identify any subgroup effects. Materials and methods: A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease (CVD) events including non-fatal myocardial infarction, non-fatal stroke, hospitalization from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results were confirmed in sensitivity analyses using alternative models. Results: The median duration of follow-up was 7.7 years. Of the 5,128 participants in the intensive and 5,123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) experienced a single event; 189 (3.7%) and 214 (4.2%) two events; 52 (1.0%) and 40 (0.8%) three events; and 1 (0.02%) and 1 (0.02%) four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (-0.3, 0.3) per 100 person-years comparing intensive vs standard intervention, although with nonsignificantly lower event rates in younger patients with HbA1c<7% and higher event rates in older patients with HbA1c≥9%. Discussion: Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routine in cardiovascular outcome trials, particularly when investigating long-term treatment effects. CLINICAL TRIAL REG: no. NCT00000620, clinicaltrials.gov. This article is protected by copyright. All rights reserved.