Drug Therapy for Unexplained Dyspnea in Post–COVID-19 Fatigue Syndrome: Empagliflozin and Sildenafil

A primary complaint of chronic dyspnea, often associated with exercise intolerance, is commonly attributed to a cardiac or respiratory system condition. Other frequent explanations include obesity, sleep apnea, malignancy, and anemia. Deconditioning, metabolic disorders, oxidative/mitochondrial myopathy, and neuromuscular pathology complete the differential diagnosis in patients reporting continuous or intermittent breathlessness lasting more than 1 month.1 The etiology is discoverable after a reasonable search conducted by primary care physicians in approximately 85% of the patients evaluated for chronic dyspnea/exercise intolerance. The remaining 15% of the patients are often referred to cardiologists or pulmonologists and undergo a variety of imaging and functional tests. These patients have symptoms out of proportion with the results of prior testing and lack of response to standard treatment for pre-existent or newly diagnosed conditions such as asthma or heart failure. The investigations with the highest diagnostic yield include the invasive cardiopulmonary exercise test (CPET), which allows a breath-to-breath assessment of cardiac function; ventilation and pulmonary gas exchange, coupled with direct measurement of pulmonary and radial artery pressure; and blood gas parameters at rest and during exercise.1 In a large cohort of patients with unexplained dyspnea (n = 530) evaluated at the Brigham and Women's Hospital in Boston with invasive CPET and careful review of previous testing, the most common causes were oxidative myopathy (24.5%), dysautonomia or preload failure (21.1%), heart failure with preserved ejection fraction (HFpEF) apparent only with exercise (17.7%), and pulmonary arterial hypertension (PAH) present during exercise (16.6%).1 Evidence-based effective pharmacological interventions exist only for HFpEF2 and PAH.3 PAH is often present in HFpEF as a passive consequence of increased left atrial and pulmonary capillary pressures and impaired lung diffusing capacity.4 Unexplained dyspnea and exertional intolerance are common in patients with post–coronavirus disease 2019 (COVID-19) fatigue syndrome and contribute, together with persistent fatigue, “brain fog,” memory loss, executive function deficits, and depressive psychopathology, to a significant decrease in quality of life and to occupational disability.5–7 A recent systematic review which assessed 9 studies and a total of 1816 survivors of hospital admission for acute COVID-19 infection identified fatigue in 52% and dyspnea in 37% of the patients examined 3 weeks–3 months after hospital discharge.8 Across the studies, the prevalence of dyspnea was not uniformly greater among patients who had required admission to an intensive care unit but was around 50% in persons with a pre–COVID-19 history of asthma or chronic obstructive pulmonary disease. A careful study of a small sample of patients with unexplained dyspnea post–COVID-19 who underwent CPET 9 months after the acute illness found excessive ventilatory response to exercise and circulatory impairment in most of the cases.9 Another small sample study compared unexplained dyspnea cases with versus without post–COVID-19 syndrome matched by age, sex, and subjective severity of breathlessness and found no significant CPET differences between groups.10 A reasonable approach to the diagnosis of unexplained dyspnea after a thorough internal medicine and pulmonary evaluation should focus on treatable condition, that is, HFpEF and PAH. Therefore, the diagnostic workup must include at last CPET to confirm the functional impairment and a rest/exercise echocardiogram11 to determine the presence of HFpEF and PAH. Measuring the plasma level of the N-terminal proB–type natriuretic peptide will provide additional support for the diagnosis of HFpEF.11 Clinical examination may be unrevealing because the pulmonary congestion in HFpEF is often subclinical.12 Empagliflozin, a sodium–glucose cotransporter 2 inhibitor (SGLT-2), marketed as an antidiabetic drug, which enhances renal glucose excretion, has been recently shown to improve the outcome of HFpEF in persons with and without diabetes.2 The study compared 2997 patients treated with 10 mg once daily off empagliflozin with 2991 patients receiving placebo. The participants had class II–IV heart failure with ejection fraction >40%. The empagliflozin group had a significantly lower rate of hospitalizations for heart failure over a median of 26 months of treatment (6.9 vs. 8.7 events/100 patient-years). By contrast, the effectiveness of other drugs tried for HFpEF, such as candesartan, spironolactone, and sacubitril–valsartan, had only marginal significance when compared with placebo.2 In pairwise comparisons, SGLT-2 inhibitors were shown to be superior to other antidiabetic drug classes, such as glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors and metformin, in improving left ventricular dysfunction.13 For the treatment of post–COVID-19 symptoms, it is important to note that emerging evidence indicates that SGLT-2 inhibitors have anti-inflammatory14 effects including M2 macrophage polarization and decreased proinflammatory cytokines.15 Empagliflozin is lipid soluble and may reach a serum/brain ratio of up to 0.5 and have been shown to inhibit acetylcholinesterase, reduce the oxidative stress, and modulate favorably neurotransmission and plasticity of neurons,15 with a demonstrable neuroprotective effect.16 Sildenafil blocks phosphodiesterase 5 and promotes vasodilation in the lungs. The drug has been used by patients with PAH for the past 2 decades. A systematic review of trials involving 545 patients indicated that a 12-week course improved exercise tolerance on the 6-minute walk distance time and health-related quality of life.3 Long-term treatment of up to 3 years was generally well tolerated and the patients maintained the progress regarding functional status.17 The drug crosses the blood–brain barrier, and animal experimental models have provided evidence of increased cerebral blood flow and of alleviate ischemia-induced neuroinflammation.18 The pleiotropic features of empagliflozin and sildenafil should encourage clinical trials of these drugs in post–COVID-19 patients with persistent dyspnea/exercise intolerance.