IJCS | Volume 33, Nº4, July and August 2020

415 diabetes and some type II diabetes). In this scenario, a recent positioning of the Brazilian Societies of Diabetes, Endocrinology and Metabology, and Cardiology defined safety recommendations for the use of these drugs. In summary, the document does not recommend the use of SGLT2 inhibitors in patients with type I diabetes; suggests suspension in patients with type 2 diabetes, prone or not to ketosis, who are simultaneously using insulin, in case of symptomatic infection by the Coronavirus; does not recommend SGLT2 inhibitors for patients without diabetes or with pre-diabetes to reduce cardiovascular risk, and also does not recommend the use of SGLT2 inhibitors in hospitalized patients due to the increased risk of dehydration. 26 The content of these recommendations is based on the principle of patient safety in the COVID-19 pandemic scenario. Therefore, it does not seem relevant to discuss the potential withdrawal of the benefits of SGLT2 inhibitors to such patients with diabetes and HFpEF in the medium and long term. Cardiovascular Disease and Prognosis in COVID-19 Preliminary data from the COVID-19 case series suggested that hypertension correlates withworse results (23.2%) compared to other metabolic disorders. It was postulated that this observation was correlated with the use of ACE inhibitors or angiotensin receptor blockers (ARB) instead of hypertension itself. This supposed correlation was rapidly disseminated among medical communities, which encouraged the hasty withdrawl of the use of these drugs in patients with COVID-19. 14 This worsening seems to be related to the endocytosis of SARS-CoV2, which is mediated by the ACE-2 receptor and is fundamental in the viral life cycle. There are conflicting data on the effect of inhibitors of the renin-angiotensin-aldosterone system, including ACE inhibitors and ARB, on ACE2 activity in various human tissues and the resulting susceptibility to SARS‑CoV2 infection. All available data are insufficient to recommend discontinuation of ACE inhibitors or ARBs in individuals with an existing indication for therapy with these drugs, and the mainmedical societies strongly recommended continuation of treatment. An open randomized study is underway to examine the effect of prophylactic withdrawal from ACE inhibitors or ARBs in individuals with COVID-19. 14 Although the ACE-2 receptor may allow SARS‑CoV2 to enter cells, its free circulation forms could then inactivate the virus, interrupting coupling to membrane ACE-2 receptors and the consequent entry into pulmonary endothelial cells. However, the circulating plasma level of ACE-2 may be insufficient to protect the ACE-2 receptors connected to the SARS-CoV2 coupling membrane. In addition to circulating soluble ACE-2, it was observed that mineralocorticoid receptor antagonists such as spironolactone, with a well-studied safety and risk profile, increase the expression of soluble ECA-2 in the plasma by 3 to 5 times. 27-29 Three recent studies, with a large number of patients, evaluated the risk of using ACE inhibitors or ARBs in patients with COVID-19. A study that evaluated a potential harmful effect of ACE inhibitors and ARBs in 8910 patients hospitalized with COVID-19 showed that there was no potential harmful association between the use of ACE inhibitors or ARBs with hospital death in this clinical context. 30 Another study that evaluated 6272 patients with severe SARS-CoV-2 infection, where the use of ACE inhibitors and ARBs was more frequent in patients with Covid-19 than in the control group, showed no association between the use of ACE inhibitors or ARBs with a severe or fatal COVID-19 course. 31 Finally, Reynolds HR et al., 32 evaluating in 12 594 patients the relationship between treatment with ACE inhibitors, ARBs, beta-blockers, calcium channel blockers, and thiazide diuretics and the potential risk of these drugs in patients withCOVID-19 showed that there was no substantial increase in relation to the association of these 5 common classes of antihypertensive drugs with the risk of developing severe conditions in patients who tested positive for COVID-19. 32 The benefits of spironolactone in patients with HFpEF were assessed in the TOPCAT study, which showed a reduction in the number of hospital admissions for HF. 33 In patients with hypertension, spironolactone is widely used, being indicated as the fourth medication in the treatment of resistant arterial hypertension. 34 More recently, a hypothesis has suggested that inhibition of the angiotensin 1 receptor (AT1R) may provide benefits to patients with COVID-19. AT1R antagonists are widely used in hypertensive patients and increase the cardiac expression of ACE2 in rats and the urinary concentration of ACE2. Therefore, a higher expression of ACE2 after chronic therapy with angiotensin receptor blockers can protect patients with COVID-19 from acute lung injury. In this scenario, the role of neprilisin (NEP) and its sacubitrile Mesquita et al. HFpEF and COVID-19 Int J Cardiovasc Sci. 2020; 33(4):412-418 Viewpoint