Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial

Abstract

Background: Glucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin's cardiovascular death reductions.

Methods: In total, 7,020 patients with type 2 diabetes and established cardiovascular 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 cardiovascular 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 cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615.

Conclusions: HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin's reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676.

Keywords: Cardiovascular death; Empagliflozin; Glucose variability; Type 2 diabetes.

Conflict of interest statement

AC: Advisory Board membership: Abbott, Astra Zeneca, Eli Lilly, Janssen, Mundipharma, Novo Nordisk, OM Pharma. Lectures: Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, Mundipharma, Novo Nordisk, Roche Diagnostics. Research Grants: Astra Zeneca, Eli Lilly, Mitsubishi, Novartis. AN has received honoraria from Novo Nordisk, Medtronic, AstraZeneca, Eli Lilly and Boheringer and research support from Novo Nordisk, Sanofi-Aventis, Pikdare, Shionogi, SOBI. APO, IZ, SK and JG are employees of Boehringer Ingelheim.

Figures

Fig. 1

Association of HbA1c variability at week 28 (a) and 52 (b) and subsequent CV deaths (Landmark analysis) in the treatment groups separately. Only patients still at risk for CV death at week 28 (week 52, resp.) and with at least 2 post-baseline HbA1C measurements up to week 28 (week 52, resp.) included. HRs are for a 1-unit (%) increase in HbA1c variability. CV cardiovascular, HbA1c glycated hemoglobin, LM landmark. Cox models include: age, sex, Hba1c, BMI, eGFR, geographic region, treatment, change in HbA1c from baseline to week 12, HbA1c variability up to week 28 (week 52, resp.) and its interaction with treatment. *HbA1c variability*treatment interaction