Empagliflozin Outcome on Obstructive Sleep Apnea, Cardiovascular, and Renal Events

The unique benefits of using empagliflozin need to be considered when determining treatments for type 2 patients, including those with obstructive sleep apnea. 

Obstructive sleep apnea (OSA) is a significant sleep disorder prevalent in patients with obesity, and it is known to occur in patients with type 2 diabetes. Reduction in airflow occurs when the upper airway collapses. This study aimed to evaluate the impact of empagliflozin on obstructive sleep apnea, cardiovascular events, and renal factors in type 2 diabetes patients. As stated by the authors, there is no randomized controlled trial for SGLT2 inhibitors evaluating OSA outcomes. Previous studies included a small, open-label, single-arm study conducted in Japanese participants with moderate to severe OSA, obesity, and diabetes, which found improvement in metabolic parameters with fewer oxygen desaturation events using low dose dapagliflozin for 24 weeks. Another study investigated the combination of extended-release phentermine/topiramate on patients with moderate to severe OSA, not using CPAP therapy. This study evaluated the participants for 28 weeks and showed a reduction in weight by 10% and an improved change in the apnea-hypopnea index (AHI) at 15 events. A study of liraglutide 3.0 mg in moderate to severe patients with OSA, not using CPAP therapy, following 32 weeks, reduced weight by 4%, and found a significant reduction in AHI at six events. 

This study’s objective was to determine the effects of empagliflozin on OSA events and results on metabolic, cardiovascular, and renal outcomes, as seen in patients with or without OSA in a randomized controlled trial of participants with type 2 diabetes. This study had three arms: empagliflozin 10 mg, empagliflozin 2.5 mg, or placebo once daily.  Participants in the study were followed for 3.1 years. The main study’s primary outcome was the composite outcome of 3P-MACE, which is death resulting from cardiovascular events (CVD), nonfatal myocardial infarction, or nonfatal stroke, with secondary effects of hospitalized heart failure (HHF), all-cause death, and incident or worsening of nephropathy.   

The treatment groups’ baseline characteristics and effects on CVD risks, HHF, mortality, and renal outcomes used a Cox proportional hazards model.  Kaplan-Meier was used to estimate time to the first OSA event, as seen in patients without OSA at baseline.  Sensitivity analysis was performed documenting all OSA events. Hazard ratios (HR) were used to compare time to first events of OSA based upon a Cox regression.   

The study included 7,020 participants. Three hundred ninety-one of the participants reported OSA at baseline. Males were more likely to have OSA than females at 83% vs. 71% and moderate to severe obesity with a BMI ≥ 35 kg/m2 at 55% vs. 18%.  Reductions in A1c, waist circumference, and systolic blood pressure, were assessedno matter if OSA status was present at baseline. There was a significant reduction in weight loss seen between OSA vs. no OSA at -2.9 ± 0.5 vs. -1.9 ± 0.1 kg.  The results for 3P-MACE found there was a 1.2-2.0-fold higher risk for patients with baseline OSA, compared to patients without OSA. Empagliflozin reduced the risk for outcomes measured regardless of OSA status with p-values all > 0.05 showing statistically significant findings. On the other hand, the study reported fifty patients reporting a new OSA diagnosis after 7-day medication discontinuation with a hazard ratio of 0.48 (95% CI 0.27-0.83).  A patient treated with empagliflozin was 52% less likely to report new OSA than patients treated with placebo.  

To conclude, empagliflozin showed positive effects on cardiovascular events, reduction in A1C, and weight loss. 6% of patients who have OSA at baseline show that they experienced higher overall CV and renal event rates during the study. Empagliflozin showed an improvement in different cardiometabolic risk factors. The authors stated they found empagliflozin to provide a significant reduction of risk for CV, HHF, mortality outcomes, and the incidents or worsening nephropathy irrespective of OSA status.  Empagliflozin reduced the incidence of new-onset of OSA compared to patients without OSA at baseline. The study limitations included: patients and investigators defined OSA diagnoses; no prior sleep studies obtained; lower population; no measurement of AHI; no reports of patients’ treatments for OSA during the study; CPAP vs. other therapies. The study could not distinguish between empagliflozin impact on OSA versus central sleep apnea (CSA).  Future studies are needed to confirm this study outcome as the authors state the findings as a hypothesis, with more assessments required on SGLT2 inhibition in OSA.   

Practice Pearls 

• Empagliflozin demonstrates positive outcomes on the effects of cardiometabolic risk factors and reduces the risk for 3P-MACE, HHF, mortality, and renal outcomes in patients with and without OSA at baseline. 
• The benefit of reducing OSA’s new-onset risk when using empagliflozin in type 2 diabetes patients is a promising outcome. 
• Patients with OSA might have greater chances of comorbidity and a higher rate of CV and renal events.  

Ian J. Neeland, Bjorn Eliasson, The Impact of Empagliflozin on Obstructive Sleep Apnea, Cardiovascular, and Renal Outcomes: Analysis of the EMPA-REG OUTCOME Trial.  

Tarshay Boyd, PharmD. Candidate, LECOM School of Pharmacy