The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial

Abstract

Objective: To explore the effects of empagliflozin on the incidence of obstructive sleep apnea (OSA) and its effects on metabolic, cardiovascular (CV), and renal outcomes among participants with or without OSA in the EMPA-REG OUTCOME trial.

Research design and methods: Participants with diabetes and CV disease were randomized to empagliflozin (10 and 25 mg) or placebo daily in addition to standard of care. OSA was assessed by investigator report using Medical Dictionary for Regulatory Activities version 18.0, and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models.

Results: OSA was reported in 391 of 7,020 (5.6%) participants at baseline. Those with OSA were more likely to be male (83% vs. 71%) and to have moderate to severe obesity (BMI ≥35 kg/m2; 55% vs. 18%). Over a median of 3.1 years, empagliflozin had similar placebo-adjusted reductions in HbA1c, waist circumference, and systolic blood pressure, regardless of OSA status, but a larger effect on weight (adjusted mean ± SE difference at week 52: OSA vs. no OSA -2.9 ± 0.5 vs. -1.9 ± 0.1 kg). Incidence of 3-point major adverse CV events, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo group was 1.2- to 2.0-fold higher for those with baseline OSA compared with those without. Empagliflozin significantly reduced the risk for outcomes regardless of OSA status (P-interaction all >0.05). Fifty patients reported a new diagnosis of OSA through 7 days after medication discontinuation, and this occurred less often with empagliflozin treatment (hazard ratio 0.48 [95% CI 0.27, 0.83]).

Conclusions: In EMPA-REG OUTCOME, participants with OSA had greater comorbidity and higher frequency of CV and renal events. Empagliflozin had favorable effects on risk factors and CV and renal outcomes regardless of preexisting OSA and may also reduce the risk for new-onset OSA.

Trial registration: ClinicalTrials.gov NCT01131676.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Effects of empagliflozin treatment on body weight by OSA status at baseline. Model reflects a mixed-model repeated-measures analysis that included terms for baseline weight and baseline HbA1c as linear covariates and baseline eGFR category, geographical region, baseline BMI category, number of weeks reachable with a postrandomization weight measurement, treatment, visit, sleep apnea syndrome at baseline, treatment-by-visit interaction, visit-by-sleep apnea syndrome at baseline interaction, treatment-by-sleep apnea syndrome at baseline interaction, treatment-by-visit by sleep apnea syndrome at baseline interaction, baseline HbA1c-by-visit interaction, and baseline weight-by-visit interaction as fixed effects. P values indicated are for differences in change between empagliflozin and placebo at respective time points. *Adjusted mean (SE) changes from baseline by OSA status at baseline. BL, baseline; E, empagliflozin; P, placebo; W, week.

Figure 2

Effects of empagliflozin treatment on CV, HHF, mortality, and renal outcomes by OSA status at baseline (BL). Events and HRs (95% CIs) for empagliflozin treatment on 3P-MACE, CV death, HHF, all-cause mortality, incident and worsening nephropathy, and progression to macroalbuminuria both overall (indicated in bold) and by OSA status at BL. Cox model includes age, sex, region, BL eGFR, BL BMI, BL HbA1c, treatment, OSA at BL, and treatment-by-OSA at BL interaction. *P-interaction.

Figure 3

Kaplan-Meier estimates for time to first OSA event on treatment for patients without OSA at baseline. OSA events are based on investigator-reported events (MedDRA version 18.0) until treatment end plus an additional 7 days. HRs are based on a Cox regression model with terms for age, sex, baseline BMI categories, HbA1c categories, eGFR categories, geographical region, and treatment. Empagliflozin estimates correspond to pooled treatment groups. IR, incidence rate.