Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial

Abstract

Background: Type 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676).

Methods: Overall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled blood pressure (BP; systolic blood pressure (SBP) ≥140 and/or diastolic blood pressure ≥90 mm Hg) or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on cardiovascular (CV) death, heart failure (HF) hospitalization, 3-point major adverse cardiac events, all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis.

Results: 1,579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 vs. placebo was -4.5 (95% confidence interval, -5.9 to -3.1) mm Hg (P < 0.001) in prHT and -3.7 (-4.5, -2.9) mm Hg (P < 0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mm Hg) with empagliflozin than with placebo. Patients with prHT had 1.5- to 2-fold greater risk of HF hospitalization, incident/worsening nephropathy, and CV death compared with those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P > 0.1 for all outcomes).

Conclusions: Empagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D.

Keywords: blood pressure; empagliflozin; hypertension; resistant hypertension; type 2 diabetes.

© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.

Figures

Figure 1.

Change from baseline in systolic blood pressure over time in patients (a) with presumed resistant hypertension and (b) no presumed resistant hypertension at baseline including all data up until individual trial termination: mixed effect repeated measurement model results. *MMRM model on the overall population including subject as random effect and, among others, treatment, visit, and presumed resistant hypertension at baseline as well as their corresponding 2- and 3-way interactions as fixed effects (for details on other fixed effects and linear covariates, see Statistical analysis section). Abbreviations: MMRM, mixed effect model repeat measurement; rHT, resistant hypertension.

Figure 2.

Proportion of patients (a) with presumed resistant hypertension and (b) without presumed resistant hypertension who achieved systolic blood pressure <130 mm Hg during the trial in empagliflozin and placebo groups.

Figure 3.

Treatment effects of empagliflozin vs. placebo on outcomes in patients with or without presumed resistant hypertension. *Based on a Cox regression model with terms for age sex, baseline BMI category, baseline HbA1c category, baseline eGFR category, geographical region, treatment, presumed resistant hypertension, and treatment by presumed resistant hypertension interaction. †Excludes fatal stroke. Abbreviations: 3P-MACE, 3-point major adverse cardiac event; BMI, baseline body mass index; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HHF, heart failure hospitalization; rHT, resistant hypertension.