Long-Term HbA1c Variability and Cardiovascular Death: Insights from the EMPA-REG OUTCOME Trial

Abstract

Background: Glucose variability has been associated with cardiovascular (CV) outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and CV death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of CV death by 38%. We explore post-hoc the association between HbA1c variability and CV death, and the potential mediating effects of HbA1c variability on empagliflozin’s CV death reductions.Methods: In total, 7,020 patients with type 2 diabetes and established CV disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between CV death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment.Results: HbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for CV death in both treatment arms with no interaction with treatment.Conclusions: HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of CV death. Empagliflozin’s reduction in CV death did not appear to be mediated by reductions in HbA1c variability.ClinicalTrials.gov number, NCT01131676. Registered May 27 2010. https://clinicaltrials.gov/ct2/show/NCT01131676

Implications of Fasting Plasma Glucose Variability on the Risk of Incident Peripheral Artery Disease in a Population without Diabetes: A Nationwide Population-Based Cohort Study

“…prospective cohort studies in the Asia Paci c region indicated that the FPG levels was a critical risk factor for cardiovascular disease, and that there were signi cant potential bene ts to reducing fasting glucose levels to at least 4.9 mmol/l in participants with/without diabetes [23] Additionally, reducing glycemic variability is an emerging glycemic target, and has been suggested as a critical predictor of cardiovascular complications. Several observational studies [7] and post-hoc analysis of trials, including the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial [9], the Veterans Affairs Diabetes Trial (VADT) [24], the Trial Comparing Cardiovascular Safety of Insulin Degludec vs. Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) [25], the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial [26], and the Empagli ozin Cardiovascular Outcome Event (EMPA-REG OUTCOME) trial [27] demonstrated a positive association between visit-to-visit glycemic variability and the risk of micro/macrovascular disease in participants with type 2 diabetes. Furthermore, long-term glycemic variability has also been suggested to affect cardiovascular disease and mortality even in individuals without diabetes.…”