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>

Association of SGLT2 inhibitors with lower incidence of death in type 2 diabetes mellitus and causes of death analysis

“…Increasing evidence has indicated that SGLT2i exerts protective effects on nephritis, nephrotic syndrome and nephrosis 25 , chronic liver disease 26 , and septicemia survival 27 . SGLT2i-use also demonstrated consistent heart and kidney protective effects in patients with obstructive sleep apnea 28 and chronic obstructive pulmonary disease 29 .…”

Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

“…SGLT2i have been shown to reduce incident obstructive sleep apnea in two SGLT2i CVOTs based on adverse event reporting (304,305). However, it is not clear that the data collected on incident obstructive sleep apnea in these trials were complete or that the benefit is mediated through changes in weight.…”

GLP-1 receptor agonists, SGLT-2 inhibitors, and obstructive sleep apnoea: can new allies face an old enemy?

“…In this way, SGLT2 inhibitors may decrease rostral-to-caudal fluid shifts in the recumbent sleep position, cardiac preload, and intrathoracic fluid retention; (iii) due to the modest increase in urinary frequency, manifested usually as nocturia, SGLT2 inhibitors could promote interrupted sleep cycles and suppress the duration of REM sleep (a higher risk period for OSA events); (iv) SGLT2 inhibitors can suppress circadian sympathetic nervous system activation and its related conditions (such as non-dipping pattern of hypertension, cardiac autonomic neuropathy, and stroke); (v) forced glucosuria after their administration can reduce the availability of glucose as an energy fuel. In this way other substrates are utilized, and less endogenous CO 2 production is expected, with less CO 2 to be removed by the respiratory tract; and (vi) modulation of arousal threshold, muscle compensation, and loop gain [78,[93][94][95][96][97][98].…”

“…A recent exploratory post-hoc analysis of the EMPA-REG OUTCOME trial demonstrated that about 6% of the population enrolled experienced OSA at baseline [100]. Patients with OSA were more likely to experience moderate to severe obesity (55.2% vs. 18.2%), had greater prevalence of CAD, longer duration of T2D, higher rates of insulin administration, and more prevalent use of antihypertensive therapies.…”