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

Abstract

<b>Objective: </b>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. <p><b>Research Design and Methods: </b>Participants with diabetes and CVD were randomized to empagliflozin (10/25mg), or placebo daily in addition to standard of care. OSA was assessed by investigator-reports using MedDRA-18.0 and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models.</p> <p><b>Results: </b>OSA was reported in 391/7020 (5.6%) at baseline. Those with OSA were more likely to be male (83 vs 71%) and have moderate-severe obesity (BMI ≥35 kg/m<sup>2</sup>; 55 vs 18%). Over a median 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/no OSA: -2.9±0.5/-1.9±0.1 kg). Incidence of 3P-MACE, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo-group was 1.2-2.0 fold higher for those with baseline OSA compared to 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 (HR 0.48 [95% CI 0.27, 0.83]). </p> <p><b>Conclusions: </b>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.<b></b></p>

Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state

“…Preliminary results of their administration in patients with OSAS and T2D suggested not only important metabolic benefits but also significant improvements in apnoea hypopnoea index (AHI), hypoxaemia during sleep, and excessive daytime sleepiness [132,133]. A recent exploratory post-hoc analysis of the EMPA-REG OUTCOME trial suggested that approximately 6% of participants had OSAS at baseline, and that patients with OSAS experienced higher overall all-cause mortality, as well as cardiovascular and kidney events, confirming the huge cardiorenal burden that characterize this population [134,135]. A trend towards enhanced empagliflozin activity upon weight loss (adjusted for baseline body weight) in patients with OSAS, compared to those without OSAS, was also found.…”

Comment on Neeland et al. The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2020;43:3007–3015

“…We read with great interest the leading article by Neeland et al (1) highlighting the beneficial effects of empagliflozin treatment on several metabolic end points among participants with type 2 diabetes and obstructive sleep apnea (OSA) in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). In addition, the authors observed a lower frequency of new-onset OSA, even when adjusting for baseline BMI.…”