Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk

Abstract

Background and purpose: In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), empagliflozin added to standard of care in patients with type 2 diabetes mellitus and high cardiovascular risk reduced the risk of 3-point major adverse cardiovascular events, driven by a reduction in cardiovascular mortality, with no significant difference between empagliflozin and placebo in risk of myocardial infarction or stroke. In a modified intent-to-treat analysis, the hazard ratio for stroke was 1.18 (95% confidence interval, 0.89-1.56; P=0.26). We further investigated cerebrovascular events.

Methods: Patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo; 7020 patients were treated. Median observation time was 3.1 years.

Results: The numeric difference in stroke between empagliflozin and placebo in the modified intent-to-treat analysis was primarily because of 18 patients in the empagliflozin group with a first event >90 days after last intake of study drug (versus 3 on placebo). In a sensitivity analysis based on events during treatment or ≤90 days after last dose of drug, the hazard ratio for stroke with empagliflozin versus placebo was 1.08 (95% confidence interval, 0.81-1.45; P=0.60). There were no differences in risk of recurrent, fatal, or disabling strokes, or transient ischemic attack, with empagliflozin versus placebo. Patients with the largest increases in hematocrit or largest decreases in systolic blood pressure did not have an increased risk of stroke.

Conclusions: In patients with type 2 diabetes mellitus and high cardiovascular risk, there was no significant difference in the risk of cerebrovascular events with empagliflozin versus placebo.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Keywords: blood pressure; cardiovascular diseases; hematocrit; stroke; type 2 diabetes mellitus.

© 2017 The Authors.

Figures

Figure 1.

Time to first fatal or nonfatal stroke. A, Modified intent-to-treat analyses in the treated set; events observed from randomization to the end of the study in treated set (patients treated with ≥1 dose of study drug). B, Sensitivity analysis in treated set plus 90 days; events observed during treatment or ≤90 days after a patient’s last intake of trial medication in treated set (patients treated with ≥1 dose of study drug). Cumulative incidence function. Hazard ratios (HR) are based on Cox regression analyses. CI indicates confidence interval.

Figure 2.

Time to first stroke, transient ischemic attack, and composite outcomes in modified intent-to-treat analyses. Cox regression analyses. Events from randomization to the end of the study in treated set (patients treated with ≥1 dose of study drug). Analyses were prespecified for time to first fatal or nonfatal stroke, time to first nonfatal stroke, and time to first transient ischemic attack. CI indicates confidence interval; and HR, hazard ratio.

Figure 3.

Time to first stroke in subgroups defined by baseline characteristics. Post hoc Cox regression analyses. Events of fatal or nonfatal stroke observed from randomization to end of study in treated set (patients treated with ≥1 dose of study drug). Race: Black and Other not included in Cox regression as P value is for homogeneity of the treatment group difference among subgroups (test for group by covariate interaction) with no adjustment for multiple tests. P=0.054 for age. The size of the oval is proportional to the number of patients in the subgroup. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate (according to Modification of Diet in Renal Disease formula); HbA1c, glycated hemoglobin; HR, hazard ratio; and SBP, systolic blood pressure. *Plus Australia and New Zealand.