Improvement in Cardiovascular Outcomes With Empagliflozin Is Independent of Glycemic Control
Authors: Silvio E. Inzucchi, Mikhail Kosiborod, David Fitchett, Christoph Wanner, Uwe Hehnke, Stefan Kaspers, Jyothis T. George, Bernard Zinman
Journal: Circulation (2018)

Key Words: blood glucose ◼ sodiumglucose transporter 2 ◼ treatment outcome ◼ type 2 diabetes mellitus C ardiovascular disease (CVD) is the leading cause of death in type 2 diabetes mellitus (T2DM). 1 However, control of the major metabolic derangement of T2DM, hyperglycemia, as denoted by hemoglobin A1c (HbA1c), does not substantively impact its cardiovascular complications. 2 In the EMPA-REG OUT-COME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) involving 7020 patients with T2DM and established CVD, the SGLT2 inhibitor empagliflozin reduced the risk of 3-point major adverse cardiovascular events (composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) by 14%. 3 This effect was driven by a 38% reduction in cardiovascular death. 3Empagliflozin also reduced heart failure (HF) hospitalization by 35%. 3 Until EMPA-REG OUTCOME, such cardiovascular benefits had not been demonstrated by any glucose-lowering agent, and the data led to a label indication for empagliflozin to reduce cardiovascular mortality.We have previously reported no heterogeneity in the cardiovascular effects of empagliflozin in subgroups by HbA1c < versus ≥8.5% at baseline. 3,4Building on this, we analyzed the risks of cardiovascular death, HF hospitalization, and the composite of HF hospitalization or cardiovascular death (1) in subgroups stratified by baseline HbA1c (<7%; 7% to <8%; 8% to <9%; ≥9%) and (2) after adjustment for HbA1c control (defined as <7.5%; yes/no) during the trial as a time-dependent factor.In the EMPA-REG OUTCOME trial, background glucose-lowering therapy was to remain unchanged for the first 12 weeks.We therefore also analyzed the risks of cardiovascular death, HF hospitalization, and HF hospitalization or cardiovascular death after week 12 in subgroups stratified by reduction in HbA1c from baseline to week 12 using 3 thresholds: (1) 0.5% (used by the American Diabetes Association and the European Association for the Study of Diabetes to categorize glucose-lowering efficacy as low versus intermediate); (2) 0.3% (the U.S. Food and Drug Administration definition for a minimal clinically meaningful reduction), and (3) the median reduction across all patients (0.4%).In subgroup analyses, P values were derived from tests of heterogeneity of treatment group differences without adjustment for multiple testing.An independent ethics committee or institutional review board approved the clinical protocol at each participating center.All patients provided written informed consent.The reductions in risks of cardiovascular death, HF hospitalization, and HF hospitalization or cardiovascular death with empagliflozin versus placebo were consistent across categories of baseline HbA1c (Figure).In analyses adjusted for HbA1c control at baseline and during the trial, the relative reductions were similar to those in the main analyses (Figure).At week 12, the median HbA1c reduction was 0.4% (placebo, 0.1%; empagliflozin, 0.6%).The benefits of empagliflozin on these outcomes were evident regardless of whether the reduction in HbA1c reached thresholds of 0.5%, 0.3%, or the median (Figure).