Available online 24 June 2020 In Press, Corrected ProofWhat are Corrected Proof articles? Clinical and Translational Report In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19 Author links open overlay panelXiao-JingZhang12331Juan-JuanQin1231XuCheng1231LijunShen1231Yan-CiZhao1231YufengYuan4FangLei2Ming-MingChen12HuilinYang12LiangjieBai2XiaohuiSong2LijinLin12MengXia2FengZhou23JianghuaZhou12Zhi-GangShe12LihuaZhu12XinliangMa5…HongliangLi123432 https://doi.org/10.1016/j.cmet.2020.06.015Get rights and content Highlights • Statin treatment among 13,981 patients with COVID-19 was retrospectively studied • Statin use in this cohort was associated with a lower risk of all-cause mortality • Adding an ACE inhibitor or an ARB did not affect statin-associated outcome in the cohort • The benefit of statins among this cohort may be due to immunomodulatory benefits Summary Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic. Graphical Abstract Download : Download high-res image (213KB) Download : Download full-size image Keywords COVID-19 statin ACEi/ARB SARS-COV-2 mortality Context and Significance Statins, potent lipid-lowering agents with anti-inflammatory effects, have been suggested as a therapeutic option for COVID-19. However, these drugs may increase the expression of ACE2, the receptor for the virus that causes COVID-19, and thus may exacerbate pathology. Here, Zhang et al. report that among 13,981 cases of COVID-19, in-hospital use of statins compared to non-statin use is significantly associated with a lower risk of death and a less inflammatory response during the entire hospitalization period. These findings support the notion that the potential benefits of statin therapy for COVID-19 might outweigh the risks. And they call for further prospective studies and randomized controlled clinical trials to more definitively determine the overall clinical benefits of statin treatment for COVID-19-related pathologies. Introduction The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected the health and livelihood of millions of people worldwide at an unprecedented scale and speed. To date, there are no definitive treatments specifically targeted to SARS-CoV-2 infection for COVID-19 therapy or prevention. Moreover, the development of effective vaccines or new therapies for curing COVID-19 is time-consuming and likely well off in the future. Thus, repurposing existing approved drugs to mitigate the severity of COVID-19 has been viewed as a more cost-effective and time-sensitive strategy. Statins are first-line lipid-lowering therapies with well-tolerated side effects, are low in cost, and are broadly available worldwide, including in developing countries. The potent anti-inflammatory and immunomodulatory effects of statins suggest they could be beneficial to counter coronoviral infections, including for SARS-CoV-2 (Castiglione et al., 2020; Dashti-Khavidaki and Khalili, 2020; Fedson et al., 2020). Indeed, observational studies and randomized controlled trials (RCTs) have demonstrated a significant protective effect of statins on improving proinflammatory cytokine release and immune cell functions among individuals with viral and bacterial pneumonia (Fedson, 2013; Papazian et al., 2013; Pertzov et al., 2019; Sapey et al., 2017). A more recent report based on molecular docking analysis showed that statins might inhibit SARS-CoV-2 entry into host cells by directly binding the main protease of the coronavirus (Reiner et al., 2020). These data led to speculation regarding the potential therapeutic benefits of statins for the treatment of COVID-19 (Arabi et al., 2020; Bifulco and Gazzerro, 2020). However, concerns have been raised regarding whether individuals on statins are at a greater risk for SARS-CoV-2 infection and COVID-19 exacerbation, as this class of drugs has been shown to increase the expression of angiotensin-converting enzyme 2 (ACE2), the receptor for the virus, in lab animals (Hoffmann et al., 2020; Shin et al., 2017; Tikoo et al., 2015; Wang et al., 2020b). Thus, direct clinical evidence is urgently needed to answer the question as to whether statin use is detrimental or beneficial in hospitalized individuals with COVID-19. In the clinical setting, statins are often prescribed along with renin-angiotensin-aldosterone system (RAAS) blockers, in particular angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), for subjects with hypertension or cardiac pathologies (Ray et al., 2014). Remarkably, clinical applications of ACE inhibitors and ARBs for COVID-19 also share a similar dilemma as a statin treatment regarding the perceived contraindications of increasing ACE2 expression versus anti-inflammation and cardio-protection (South et al., 2020). Our recent research has shown that individuals with COVID-19 on ACE inhibitors or ARBs (ACEi/ARB) are at lower risk of 28-day all-cause mortality than those not treated with ACE inhibitors or ARBs (Zhang et al., 2020). Moreover, combination therapy of statins and ARBs showed encouraging results in improving the survival of Ebola-infected individuals (Fedson et al., 2015). However, the effects of such combination treatment in individuals with COVID-19 have not been studied. To address these important clinical questions, we conducted one of the largest retrospective cohort studies to date—one involving 13,981 clinically confirmed cases of COVID-19—to determine the association of in-hospital use of statins with clinical outcomes. In the subgroup analysis, we further investigated the additional effects of combining ACEi/ARB with statins on the clinical outcomes of COVID-19. The time-varying Cox model, marginal structure model (MSM), and propensity score-matching analysis consistently showed a lower risk of all-cause mortality of COVID-19 in individuals with statin use versus statin nonuse. Results and Discussion Baseline Characteristics in Participants with and without Statin Treatment A total of 13,981 cases of confirmed COVID-19 admitted in 21 hospitals from Hubei Province, China, were included in this analysis. Among them, 1,219 had in-hospital use of statins (statin group) and the remaining 12,762 had no statin treatment (non-statin group) (Figure 1). The participants that received statin treatment were older (66.0 versus 57.0 years of age, p < 0.001) and had higher prevalence of chronic medical conditions, including hypertension (81.5% versus 30.3%, p < 0.001), diabetes mellitus (DM) (34.0% versus 14.6%, p < 0.001), coronary heart disease (36.3% versus 5.7%, p < 0.001), cerebrovascular diseases (8.8% versus 2.3%, p < 0.001), and chronic kidney diseases (5.2% versus 3.1%, p < 0.001) than those without statin treatment (Table 1). Chest CT revealed bilateral pulmonary lesions were more common in the statin group compared with that in the non-statin group (89.5% versus 83.7%, p < 0.001) (Table 1). Larger proportions of subjects in the statin group showed increased neutrophil counts, procalcitonin levels, and D-dimer compared with the non-statin group (Table 1). In addition to these inflammatory markers, abnormal serum biochemistry, including increased ALT and AST levels and decreased estimated glomerular filtration rate (eGFR), indicated more prevalent organ impairments in the participants with statin therapy compared to non-statin use (Table 1). The frequencies of individuals with increased low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) levels were higher among the statin group versus the non-statin group at admission. In terms of the whole hospitalization period, lipid profiles were comparable between the two groups (Figure S1). Days from onset of symptom to hospitalization and the median follow-up days were longer in the individuals on statin treatment compared to the non-statin group (Table 1). The absolute values of the median and interquartile range (IQR) of each laboratory examination are shown in Table S1. The laboratory values, including for c-reactive protein (CRP), procalcitonin, D-dimer, LDL-c, TC, and creatine kinase (CK), had different reference ranges for hospitals, which are listed in Table S2.
