Outpatient atorvastatin use and severe COVID‐19 outcomes: A population‐based study

Recei ed: 27 Feb ua y 2023 | Accep ed: 5 July 2023 DOI: 10.1002/jm .28971 RESEARCH ARTICLE Ou pa ien a o as a in use and se e e COVID‐19 ou comes: A popula ion‐based s udy I ene Visos‐Va ela 1 |Ma uxa Zapa a‐Cacha ei o 1,2,3 | Samuel Pin os‐Rod íguez 1 |Rosendo Buga ín‐González 4 | F ancisco Ja ie González‐Ba cala 5,6 |Ma ia T. He dei o 7 | Ma ía Piñei o‐Lamas 3 |Adol o Figuei as 1,2,3 |Ángel Salgado‐Ba ei a 1,2,3 1 Depa men o P e en i e Medicine and Public Heal h, Uni e si y o San iago de Compos ela, San iago de Compos ela, Spain 2 Ins i u e o Heal h Resea ch o San iago de Compos ela (IDIS), San iago de Compos ela, Spain 3 Conso ium o Biomedical Resea ch in Epidemiology & Public Heal h (CIBER en Epidemiología y Salud Pública‐CIBERESP), San iago de Compos ela, Spain 4 Mon o e de Lemos Heal h Cen e , Heal h A ea o Lugo, A Ma iña and Mon o e de Lemos, SERGAS, Mon o e de Lemos, Lugo, Spain 5 Spanish Biomedical Resea ch Ne wo king Cen e‐CIBERES, San iago de Compos ela, Spain 6 Pneumoloxy Depa men , San iago de Compos ela Uni e si y Hospi al Complex, San iago de Compos ela, Spain 7 Depa men o Medical Sciences, iBiMED‐ Ins i u e o Biomedicine, Uni e si y o A ei o, A ei o, Po ugal Co espondence Ma uxa Zapa a‐Cacha ei o, Depa men o P e en i e Medicine and Public Heal h, C/San F ancisco s/n, Uni e si y o San iago de Compos ela, 15786 San iago de Compos ela, A Co uña, Spain. Email: [email p o ec ed] Funding in o ma ion Ins i u o de Salud Ca los III; Ca los III Ins i u e o Heal h, G an /Awa d Numbe : COV20/ 00470; Eu opean Regional De elopmen Fund Abs ac E idence o he e ec o s a ins on pa ien s wi h co ona i us disease (2019) COVID‐19 is inconsis en . The aim o his s udy was o e alua e he associa ion be ween ch onic use o s a ins—bo h o e all and by ac i e ing edien —and se e e ou comes o COVID‐19 ( isk o hospi aliza ion and mo ali y), p og ession o se e e ou comes, and suscep ibili y o he i us. We conduc ed a popula ion‐ based case–con ol s udy wi h da a om elec onic eco ds o assess he isk o (1) hospi aliza ion: cases we e pa ien s admi ed due o COVID‐19 and con ols we e subjec s wi hou COVID‐19; (2) mo ali y: cases we e hospi alized pa ien s who died due o COVID‐19 and con ols we e subjec s wi hou COVID‐19; (3) p og ession: cases we e hospi alized COVID‐19 subjec s and con ols we e nonhospi alized COVID‐19 pa ien s; and (4) suscep ibili y: cases we e pa ien s wi h COVID‐19 (bo h hospi alized and nonhospi alized) and con ols we e subjec s wi hou COVID‐19. We collec ed da a on 2821 hospi alized cases, 26 996 nonhospi alized cases, and 52 318 con ols. Ch onic use o a o as a in was associa ed wi h a dec eased isk o hospi aliza ion (adjus ed odds a ios [aOR] = 0.83; 95% con idence in e al [CI]: 0.74–0.92) and mo ali y (aOR = 0.70; 95% CI: 0.53–0.93), a ibu able in pa o a lowe isk o suscep ibili y o he i us (aOR = 0.91; 95% CI: 0.86–0.96). Sim as a in was associa ed wi h a educed isk o mo ali y (aOR = 0.59; 95% CI: 0.40–0.87). The wide deg ee o he e ogenei y obse ed in he es ima ed odds a ios (ORs) o he di e en s a ins sugges s ha he e is no class e ec . The esul s o his eal‐wo ld s udy sugges ha ch onic use o a o as a in (and o a lesse deg ee, o sim as a in) is associa ed wi h a dec ease in isk o se e e COVID‐19 ou comes. KEYWORDS a o as a in, COVID‐19, hospi aliza ion, mo ali y, ou pa ien , s a ins J Med Vi ol. 2023;95:e28971. wileyonlinelib a y.com/jou nal/jm | 1o 10 h ps://doi.o g/10.1002/jm .28971 This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion‐NonComme cial‐NoDe i s License, which pe mi s use and dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non‐comme cial and no modi ica ions o adap a ions a e made. © 2023 The Au ho s. Jou nal o Medical Vi ology published by Wiley Pe iodicals LLC. 1|INTRODUCTION In ecen decades, inc eased imbalances in he human– animal–ecosys em in e ac ion, 1 d i en by clima e change, loss o biodi e si y, he demog aphic explosion, globaliza ion, and/o inc eased con ac wi h wildli e, ha e gi en ise o a signi ican inc ease in eme ging in ec ious diseases, including he 2019 co ona i us disease (COVID‐19). 2 The consequences o he lack o esou ces o ackle COVID‐19 ha e highligh ed he impo ance o ha ing adequa e means o p epa e o new public heal h h ea s. In his espec , he Wo ld Heal h O ganiza ion (WHO) conside s h ee ac ion s a egies o comba p esen and u u e pandemics e ec i ely, ha is, apid diagnos ic me hods, accina ion, and he apeu ic ea men . 3 In he case o COVID‐19, challenges in he dis ibu ion and accep ance o accines, 4,5 as well as he ulne abili y o elde ly popula ions and/o popula ions wi h he p esence o como bidi ies, 6 make i necessa y o ha e e ec i e ea men s ha complemen he accina ion plan, o al e na- i ely, o p o ide ea men co e age in popula ions wi hou access o accina ion. O e he cou se o he pandemic, a numbe o medica ions indica ed o ch onic condi ions ha e a ac ed a en ion as ega ds hei possible e ec on he suscep ibili y and se e i y o COVID‐19. 7,8 In his same di ec ion, a numbe o s udies ha e epo ed ha s a ins, which ank among he main enance d ugs mos used by he elde ly popula ion and/o popula ions wi h como bidi ies, 8 migh imp o e p ognosis o COVID‐19. 9,10 The explana ion o his possible p o ec i e ac i i y o s a ins could lie in hei many pleio opic (o noncholes e ol‐dependen ) e ec s, which include an i‐in lamma o y, 11 immunomodula o , 12 an i h- ombo ic, 13 and an i i al p ope ies. 14 Indeed, hese medica ions ha e shown an i i al capaci y in p e ious ou b eaks, such as he H1N1/09 in luenza 15 and Ebola i us pandemics. 16,17 I has also been sugges ed, on heo e ical g ounds, ha hey could be o use in se e e acu e espi a o y synd ome co ona i us (SARS‐CoV) and Middle Eas espi a o y synd ome co ona i us (MERS‐CoV) in ec ions. 18 To da e, published s udies (bo h obse a ional and expe i- men al) on he u ili y o s a ins in pa ien s wi h COVID‐19 epo inconsis en esul s. 10,19–22 One o he possible causes o hese disc epancies may be due o he s uc u al di e si y o s a ins, which endows hem wi h signi ican ly di e en p ope - ies. 23,24 Mos o he s udies, howe e , examine he e ec s o he pha macological g oup o s a ins in gene al, wi hou analyzing he e ec o he ac i e ing edien s sepa a ely. 19 In he ew s udies o his ype a ailable, he esul s ob ained also display inconsis encies. 25–27 Acco dingly, he aim o ou s udy was o e alua e he associa ion be ween ch onic use o s a ins—bo h o e all and by ac i e ing edien —and (1) se e e COVID‐19 ou comes ( isk o hospi aliza ion and mo ali y); (2) p og ession o se e e COVID‐19 ou comes; and (3) suscep i- bili y o he i us. 2|METHODS 2.1 |S udy se ing and popula ion The s udy popula ion comp ised all ci izens o Galicia o e 18 yea s o age who we e bene icia ies o he Galician Heal h Se ice (GHS). This egion, si ua ed in he no hwes o Spain, has a popula ion o almos 3 million inhabi an s, p ac ically all o whom (98%) a e co e ed by he GHS. 2.2 |Design We used a popula ion‐based, case–con ol design. Cases (subjec s wi h COVID‐19, hospi alized and nonhospi alized) we e selec ed by exhaus i e sampling, and con ols we e d awn om he same popula ion as cases, which enabled us o ob ain a alid es ima e o he p e alence o exposu e and co a ia es in he sou ce popula ion. The s udy pe iod was om Ma ch o Decembe 2020. 2.3 |Cases and con ols We conduc ed a o al o ou subs udies, which di e ed in hei de ini ions o cases and con ols (Figu e 1and Suppo ing In o ma- ion: Table S1) o espond o each s udy's designa ed objec i es, ha is, he associa ion be ween ch onic use o s a ins and (1) isk o hospi aliza ion; (2) isk o mo ali y; (3) p og ession o se e e ou comes o COVID‐19; and (4) suscep ibili y o he i us. 2.3.1 |Case–con ol 1: Se e e COVID‐19 ou comes—hospi aliza ion To analyze he isk o hospi aliza ion due o COVID‐19, cases we e de ined as all subjec s wi h a con i med diagnosis o COVID‐19 (polyme ase chain eac ion [PCR+]) wi h a maximum gap o 10 days be ween PCR da e and hospi al admission and (1) wi h he eason o admission COVID‐19 o (2) symp oma ology compa ible wi h COVID‐19 ( espi a o y ac in ec ion, i al pneumonia, sho ness o b ea h, cough, e e , e c.), because in he i s mon hs o he pandemic, no speci ic coding was a ailable. Con ols we e andomly selec ed om among he gene al popula- ion ha had no diagnosis o COVID‐19 (no PCR+ es ) in 2020 and we e ma ched (up o 20 con ols pe case) by age, sex, p ima y‐ca e se ice o e e ence, pandemic wa e, and s a us o he heal h p o essional o ensu e hesame isko exposu e oSARS‐CoV‐2. 2.3.2 |Case–con ol 2: Se e e COVID‐19 ou comes—mo ali y To assess he isk o mo ali y due o COVID‐19, cases we e de ined as all subjec s hospi alized o COVID‐19 2o 10 | VISOS‐VARELA ET AL. 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License (Case–con ol 1) who died du ing admission o any o he GHS hospi als in 2020. The con ols we e he subg oup o con ols om he case–con ol 1 subs udy who we e hen ma ched wi h cases om his subs udy. 2.3.3 |Case–con ol 3: P og ession o se e e COVID‐19 ou comes To s udy he isk o p og ession o se e e COVID‐19 ou comes, de ined as in ec ed pa ien s' need o hospi aliza ion due o COVID‐19, cases we e de ined as all pa ien s wi h COVID‐19 (PCR+) hospi alized due o COVID in 2020 (Case–con ol 1). Con ols we e all pa ien s wi h COVID‐19 (PCR+) who did no equi e hospi al admission due o COVID‐19 in 2020. In his model, he con ols a e no ma ched, so while a dec ease in he s udy's e ec i eness is o be expec ed, i s alidi y is no a ec ed. 28,29 2.3.4 |Case–con ol 4: Suscep ibili y o he i us To es ima e he isk o in ec ion, cases we e all subjec s ha had a diagnosis o COVID‐19 (PCR+) in 2020, bo h hospi alized and nonhospi alized. As con ols, we used he sample o subjec s who had no diagnosis o COVID‐19 (no PCR+) in 2020 (Case‐con ol 1). As in he p og ession model, con ols we e also no ma ched. 28,29 2.4 |Da a sou ces and da a collec ion Real‐wo ld da a we e ex ac ed om he Galician in eg a ed heal hca e da abase, which combines GHS sys em heal h eco ds wi h o he heal h da abases (p esc ip ion and dispensing o medica ions, labo a o y da a, and Na ional Heal h Sys em hospi al‐discha ge egis e [Minimum Basic Da a Se (MBDS)/Conjun o Mínimo Básico de Da os]). We collec ed in o ma ion on he clinical cou se o he disease, exposu e o he d ug unde s udy, and o he co a ia es. All da a we e ex ac ed by an independen in o ma ion echnology company. 2.5 |Exposu e The a iableo exposu ewasch onicuseo s a ins(ATCC10AAcode). We eco ded da a on s a ins p esc ibed and dispensed du ing each subjec 's ollow‐up pe iod, which co e ed he 3 mon hs immedia ely p eceding he index da e. The index da e was de ined as 10 days be o e diagnosis o COVID‐19 (PCR+ es da e), o p e en he p esence o symp oms o he disease om al e ing exposu e o he medica ion. Fo FIGURE 1 Popula ion‐based mul iple case–con ol design. VISOS‐VARELA ET AL. | 3o 10 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License con ols, he index da e was assumed o be he same as ha o he cases wi h which hey we e ma ched. Sepa a e analyses we e pe o med by pha macological subg oup (C10AA) and by ac i e ing edien , ha is, sim as a in (C10AA01), lo as a in (C10AA02), p a as a in (C10AA03), lu as a in (C10AA04), a o as a in (C10AA05), osu as a in (C10AA07), and pi a as a in (C10AA08). S udy co a ia es included demog aphic and socioeconomic a i- ables, hospi aliza ion da a and clinical a iables o COVID‐19 (whe e applicable), como bidi ies (hype ension, diabe es melli us, ch onic obs uc i e pulmona y disease, obesi y, ischaemic hea disease, ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal ailu e, cance , as hma, and cu en smoke ), and exposu e o medica- ions o he han hose speci ically add essed by his s udy. To es ima e pa ien s' deg ee o ch onici y, he numbe o di e en d ugs p esc ibed anddispensedwasusedasap oxy. 30 All co a ia es we e eco ded ac oss he 3 mon hs p eceding he index da e. 2.6 |S a is ical analysis Owing o he s uc u e o he da a collec ed, we analyzed he ou come a iables (se e e COVID‐19 ou comes, p og ession o se e e ou comes, and suscep ibili y o he i us) using mul ile el logis ic eg ession. 31 These models ha e a numbe o ad an ages o e condi ional eg es- sion, 31–33 since hey allow o (1) analysis o ma ched and unma ched models; (2) he in oduc ion o andom e ms o con ol o he e oge- nei y o ini ial clus e s and ime pe iods; and (3) s a a in which cases coincide in exposu es wi h con ols con inue o coun as e en s o he pu pose o calcula ion and es ima es. To cons uc he models, he ollowing ou le els we e conside ed: pa ien ; case and con ol s a a ( o he se e e COVID‐19 ou comes models); heal h cen e ; and pandemic wa e. We used andom e ec s o e alua e he e ec o he pandemic wa e and nes ed andom e ec s o pa ien s, case and con ol s a a, and heal h a ea. Resul s we e exp essed as adjus ed odds a ios (aORs) wi h hei 95% con idence in e als (95% CIs), wi h adjus men s being made o he abo e‐men ioned co a ia es. We ob ained adjus ed es ima es o he e ec o ea men wi h s a ins (i.e., ac ually dispensed) in compa ison wi h no lipid‐lowe ing d ug ea men . S a is ical signi icance was se a 0.05, and all s a is ical analyses we e pe o med using he ee R s a is ical so wa e p og amme ( e sion 4.1.2). 3|RESULTS The b eakdown o he 82 135 s udy pa ien s was as ollows: 2821 we e hospi alized cases (PCR+), 397 o whom died du ing admission; 26 996 we e nonhospi alized cases (PCR+); and 52 318 we e subjec s who did no es PCR+ du ing 2020. The coho 's cha ac e is ics a e de ined in Tables 1and 2. TABLE 1 Demog aphic and clinical cha ac e is ics o COVID‐19 cases and ma ched con ols (se e e ou comes: hospi aliza ion and mo ali y). Se e e COVID‐19 ou comes Hospi aliza ion Mo ali y Cha ac e is ic Cases (N= 2821) Con ols (N= 52 318) Cases (N= 397) Con ols (N= 7129) Sex; n(%) Male 1457 (51.6) 26 998 (51.6) 236 (59.4) 4274 (60.0) Female 1364 (48.4) 25 320 (48.4) 161 (40.6) 2855 (40.0) Age, median (IQR) 74 (60–85) 73 (60–84) 84 (77–89) 84 (75–88) Heal h p o essional; n(%) 78 (2.8) 1203 (2.3) 0 (0.0) 0 (0.0) Como bidi ies; n(%) Hype ension 1639 (58.2) 26 292 (50.3) 295 (74.3) 4687 (65.7) Diabe es 782 (27.8) 10 233 (19.6) 157 (39.5) 1760 (24.7) COPD 369 (13.1) 4305 (8.2) 87 (21.9) 875 (12.3) Obesi y 830 (29.5) 10 104 (19.3) 114 (28.7) 1536 (21.5) Ischemic hea disease 326 (11.6) 4479 (8.6) 86 (21.7) 914 (12.8) Ce eb o ascula acciden 277 (9.8) 3631 (6.9) 72 (18.1) 725 (10.2) Hea ailu e 430 (15.3) 3780 (7.2) 106 (26.7) 796 (11.2) A ial ib illa ion 425 (15.1) 5405 (10.3) 84 (21.2) 1137 (15.9) Ch onic enal ailu e 403 (14.3) 4059 (7.8) 99 (24.9) 882 (12.4) Cance 475 (16.9) 7277 (13.9) 98 (24.7) 1340 (18.8) As hma 267 (9.5) 3070 (5.9) 25 (6.3) 368 (5.2) Cu en smoke 737 (26.1) 7842 (15.0) 83 (20.9) 866 (12.1) Abb e ia ions: COPD, ch onic obs uc i e pulmona y disease; IQR, in e qua ile ange. 4o 10 | VISOS‐VARELA ET AL. 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License Among s a in use s, a o as a in was he mos popula , ollowed by sim as a in (Tables 3and 4). In bo h cases, he doses mos equen ly dispensed we e hose o mode a e in ensi y (68.0% and 62.1%, espec i ely). 3.1 |Se e e COVID‐19 ou comes—hospi aliza ion E alua ion o he isk o hospi aliza ion was based on 2821 cases and 52 318 con ols (Table 3). S a ins as a whole displayed s a is ically signi ican di e ences (aOR = 0.87; 95% CI: 0.79−0.96, p= 0.004). In he analysis by ac i e ing edien , a o as a in (aOR = 0.83; 95% CI: 0.74–0.92, p< 0.001) showed a s a is ically signi ican educ ion in he isk o hospi aliza ion. 3.2 |Se e e COVID‐19 ou comes—mo ali y Assessmen o he isk o mo ali y was based on 397 cases and 7129 con ols (Table 3). S a is ically signi ican di e ences we e obse ed o s a ins as a whole (aOR = 0.71; 95% CI: 0.56−0.90, p= 0.005). In he analysis by ac i e ing edien , bo h a o as a in (aOR = 0.70; 95% CI: 0.53 0.93, p= 0.014) and sim as a in (aOR = 0.59; 95% CI: 0.40−0.87, p= 0.008) showed a s a is ically signi ican educ ion in isk o mo ali y. 3.3 |P og ession o se e e COVID‐19 ou comes A o al o 2821 cases and 26 996 con ols (nonhospi alized cases) we e used o asce ain he isk o p og essing o se e e ou comes o COVID‐19 (Table 1). No s a is ically signi ican di e ences we e ound o SSRIs o e all o o any o he ac i e ing edien s indi idually. 3.4 |Suscep ibili y o he i us In he analysis o he isk o SARS‐CoV‐2 in ec ion, 82 315 pa ien s we e included: o hese, 29 817 we e COVID‐19 cases (hospi alized and nonhospi alized) and 52 318 we e con ols (Table 4). A small signi ican educ ion in isk was obse ed o s a ins as a whole (aOR = 0.94; 95% CI: 0.90−0.99, p= 0.013), and a educ ion in isk o a sligh ly highe magni ude was obse ed o a o as a in (aOR = 0.91; 95% CI: 0.86−0.96, p< 0.001). TABLE 2 Demog aphic and clinical cha ac e is ics o COVID‐19 cases and ma ched con ols (p og ession o se e e COVID‐19 ou comes and suscep ibili y o he i us). P og ession o se e e COVID‐19 ou comes Suscep ibili y o he i us Cha ac e is ic Cases (N= 2821) Con ols (N= 26 996) Cases (N= 29 817) Con ols (N= 52 318) Sex; n(%) Male 1457 (51.6) 11 217 (41.6) 12 674 (42.5) 26 998 (51.6) Female 1364 (48.4) 15 779 (58.4) 17 143 (57.5) 25320 (48.4) Age, median (IQR) 74 (60–85) 47 (33–63) 49 (34–67) 73 (60–84) Heal h p o essional; n(%) 78 (2.8) 1238 (4.6) 1316 (4.4) 1203 (2.3) Como bidi ies; n(%) Hype ension 1639 (58.2) 6208 (23.0) 7847 (26.3) 26 292 (50.3) Diabe es 782 (27.8) 2519 (9.3) 3301 (11.1) 10 233 (19.6) COPD 369 (13.1) 759 (2.8) 1128 (3.8) 4305 (8.2) Obesi y 830 (29.5) 3960 (14.7) 4790 (16.1) 10 104 (19.3) Ischemic hea disease 326 (11.6) 865 (3.2) 1191 (4.0) 4479 (8.6) Ce eb o ascula acciden 277 (9.8) 867 (3.2) 1144 (3.8) 3631 (6.9) Hea ailu e 430 (15.3) 678 (2.5) 1108 (3.7) 3780 (7.2) A ial ib illa ion 425 (15.1) 1076 (4.0) 1501 (5.9) 5405 (10.3) Ch onic enal ailu e 403 (14.3) 712 (2.6) 1115 (3.7) 4059 (7.8) Cance 475 (16.9) 1755 (6.5) 2230 (7.5) 7277 (13.9) As hma 267 (9.5) 2170 (8.0) 2437 (8.2) 3070 (5.9) Cu en smoke 737 (26.1) 4108 (15.2) 4845 (16.2) 7842 (15.0) Abb e ia ions: COPD, ch onic obs uc i e pulmona y disease; IQR, in e qua ile ange. VISOS‐VARELA ET AL. | 5o 10 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License TABLE 3 Se e e COVID‐19 ou comes: isk o hospi aliza ion and mo ali y. Se e e COVID‐19 ou comes Risk o hospi aliza ion Risk o mo ali y CASES: PCR+ hospi alized (N= 2821) CONTROLS: no PCR+(N= 52 318) Adjus ed OR a (95%CI) pValue CASES: PCR+ deceased (N = 397) CONTROLS: no PCR+ (N = 7129) Adjus ed OR a (95%CI) pValue S a ins (C10AA) 1009 (35.8) b 18 207 (34.8) b 0.87 (0.79–0.96) 0.004 164 (41.3) b 2896 (40.6) b 0.71 (0.56–0.90) 0.005 Sim as a in (C10AA01) 276 (9.8) 5272 (10.1) 0.91 (0.79–1.04) 0.168 33 (8.3) 824 (11.6) 0.59 (0.40–0.87) 0.008 Lo as a in (C10AA02) 4 (0.1) 54 (0.1) 1.21 (0.43–3.39) 0.721 2 (0.5) 8 (0.1) 3.65 (0.75–17.80) 0.109 P a as a in (C10AA03) 73 (2.6) 1220 (2.3) 0.95 (0.74–1.22) 0.692 13 (3.3) 199 (2.8) 0.82 (0.44–1.51) 0.524 Flu as a in (C10AA04) 17 (0.6) 205 (0.4) 1.40 (0.85–2.33) 0.190 5 (1.3) 34 (0.5) 2.14 (0.78–5.88) 0.141 A o as a in (C10AA05) 538 (19.1) 9732 (18.6) 0.83 (0.74–0.92) <0.001 95 (23.9) 1603 (22.5) 0.70 (0.53–0.93) 0.014 Rosu as a in (C10AA07) 83 (2.9) 1469 (2.8) 0.84 (0.66–1.06) 0.149 16 (4.0) 193 (2.7) 0.95 (0.54–1.69) 0.868 Pi a as a in (C10AA08) 29 (1.0) 420 (0.8) 1.10 (0.75–1.63) 0.615 4 (1.0) 67 (0.9) 0.84 (0.30–2.39) 0.750 Abb e ia ion: OR, odds a io. a Adjus ed o : sex, age, s a us o heal h p o essional, como bidi ies (hype ension, diabe es, COPD, obesi y, ischemic hea disease, ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal ailu e, cance , as hma, cu en smoke ), cu en use o o he pha macological ea men , and numbe o ea men s o ch onic diseases. Addi ionally, he p ima y‐ca e se ice o e e ence and he pandemic wa e we e included as andom e ec s. b The o e all numbe o subjec s exposed o s a ins (C10AA) is lowe han he sum o hose exposed o he ac i e ing edien s o indi idual s a ins (C10AA01, C10AA02, C10AA03, C10AA04, C10AA05, C10AA07, C10AA08), due o he ac ha some subjec s we e exposed o mo e han one s a in ac oss he s udy pe iod. 6o 10 | VISOS‐VARELA ET AL. 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License TABLE 4 P og ession o se e e COVID‐19 ou comes and suscep ibili y o he i us. P og ession o se e e COVID‐19 ou comes Suscep ibili y o he i us CASES: PCR+ cases hospi alized (N= 2821) CONTROLS: PCR+ nonhospi alized (N= 26 996) Adjus ed OR a (95% CI) pValue CASES: PCR+ hospi alized & nonhospi alized (N= 29 817) CONTROLS: no PCR+ (N = 52 318) Adjus ed OR a (95%CI) pValue S a ins (C10AA) 1009 (35.8) b 4181 (15.5) b 0.95 (0.84–1.05) 0.332 5190 (17.4) b 18 207 (34.8) b 0.94 (0.90−0.99) 0.013 Sim as a in (C10AA01) 276 (9.8) 1202 (4.5) 0.94 (0.80–1.10) 0.422 1478 (5.0) 5272 (10.1) 0.98 (0.92−1.05) 0.623 Lo as a in (C10AA02) 4 (0.1) 6 (0.0) 1.22 (0.29–5.18) 0.784 10 (0.0) 54 (0.1) 0.94 (0.46−1.92) 0.862 P a as a in (C10AA03) 73 (2.6) 240 (0.9) 1.15 (0.84–1.56) 0.386 313 (1.0) 1220 (2.3) 0.88 (0.77−1.01) 0.073 Flu as a in (C10AA04) 17 (0.6) 27 (0.1) 1.93 (0.95–3.88) 0.067 44 (0.1) 205 (0.4) 0.95 (0.67−1.35) 0.774 A o as a in (C10AA05) 538 (19.1) 2204 (8.2) 0.95 (0.83–1.08) 0.411 2742 (9.2) 9732 (18.6) 0.91 (0.86−0.96) <0.001 Rosu as a in (C10AA07) 83 (2.9) 420 (1.6) 0.85 (0.65–1.12) 0.241 503 (1.7) 1469 (2.8) 0.97 (0.87−1.09) 0.635 Pi a as a in (C10AA08) 29 (1.0) 105 (0.4) 1.17 (0.74–1.86) 0.508 134 (0.4) 420 (0.8) 1.08 (0.88−1.34) 0.456 Abb e ia ion: OR, odds a io. a Adjus ed o : sex, age, s a us o heal h p o essional, como bidi ies (hype ension, diabe es, COPD, obesi y, ischemic hea disease, ce eb o ascula acciden , hea ailu e, a ial ib illa ion, ch onic enal ailu e, cance , as hma, cu en smoke ), cu en use o o he pha macological ea men , and numbe o ea men s o ch onic diseases. Addi ionally, he p ima y‐ca e se ice o e e ence and he pandemic wa e we e included as andom e ec s. b The o e all numbe o subjec s exposed o s a ins (C10AA) is lowe han he sum o hose exposed o he ac i e ing edien s o indi idual s a ins (C10AA01, C10AA02, C10AA03, C10AA04, C10AA05, C10AA07, C10AA08), due o he ac ha some subjec s we e exposed o mo e han one s a in ac oss he s udy pe iod. VISOS‐VARELA ET AL. | 7o 10 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License 4|DISCUSSION In his la ge popula ion‐based case–con ol s udy, ch onic use o a o as a in was associa ed wi h a lowe isk o hospi aliza ion (aOR = 0.83; 95% CI: 0.74−0.92, p< 0.001) and mo ali y (aOR = 0.70; 95% CI: 0.53−0.93, p= 0.014), a ibu able in pa o a lowe isk o suscep ibili y o SARS‐CoV‐2 (aOR = 0.91; 95% CI: 0.86−0.96, p< 0.001). Ou esul s also indica e ha sim as a in appea s o be associa ed wi h an impo an dec ease in isk o mo ali y (aOR = 0.59; 95% CI: 0.40−0.87, p= 0.008). The wide deg ee o he e ogene- i y obse ed in he es ima ed ORs o he di e en s a ins sugges s ha he e is no class e ec and ha he e ec o each s a in mus he e o e be conside ed indi idually. This s udy's la ge sample size enabled us o analyze he e ec o s a ins by ac i e ing edien , on he ollowing ou come a iables: (1) se e e COVID‐19 ou comes (de ined as isk o hospi aliza ion and mo ali y); (2) p og ession o se e e ou comes; and (3) suscep ibili y o he i us. We we e hus able o asce ain he ole played by each in he clinical cou se o he disease. Speci ically, we ound ele an esul s o a o as a in and sim as a in, he s a ins wi h he g ea es p e alence o use in he s udy popula ion and o e all. 34,35 Ano he impo an inding o ou s udy is ha he clinical bene i s o s a ins in COVID‐19 would no seem o be due o a class e ec , in iew o he a iabili y obse ed in he es ima ed ORs o he espec i e ac i e ing edien s. Indeed, he e is s ong e idence o show ha s a ins display independen pleio opic e ec s o he common lipid‐lowe ing mechanism o ac ion and ha hese di e among he ac i e ing edien s. 36 Fu he mo e, pha macokine ic cha ac e is ics migh also ha e an in luence on he p o ec i e capaci y agains COVID‐19, since lipophilic s a ins, such as a o as- a in and sim as a in, show a wide issue dis ibu ion and a e hus able o exe p o ec i e e ec s on a g ea e numbe o issues. 37 Hence, we eel ha he esul s ob ained by ou s udy o s a ins as a whole could be due o he educ ion in isk obse ed in he wo mos used ac i e ing edien s (a o as a in and sim as a in). The impo an educ ion in isk o mo ali y associa ed wi h ch onic use o a o as a in (30%; 95% CI: 7%−47%) is in line wi h p e ious obse a ional s udies. 37–41 Compa ison wi h expe imen al s udies is mo e complica ed because, in hese ypes o s udies, ea men commences when he disease has al eady been con- ac ed, he eby ende ing i impossible (i) o assess he possible e ec on suscep ibili y o he i us (some hing which, in he case o ou s udy, is aken in o accoun by design) and (ii) o e alua e ch onic use, which is p ecisely wha is hough o ha e a p o ec i e e ec agains COVID‐19. 19,42,43 We ound only one s udy ha examined he associa ion be ween a o as a in and isk o hospi aliza ion due o COVID‐19, 38 and epo ed a e y simila e ec magni ude (0.89; 95% CI: 0.84–0.95) e sus (0.83; 95% CI: 0.74−0.92). Al hough hospi aliza ion is mo e dependen on clinical c i e ia and he a ailabili y o hospi al beds, i may be o g ea in e es in public heal h. 44,45 Thus, ou indings ega ding he ma ked educ ion in isk o hospi aliza ion and mo ali y associa ed wi h a o as a in, aken oge he wi h i s bene i ‐ isk‐cos a io, 40 could imply ha conside a ion should be gi en o a o as a in being ecommended as a i s ‐line d ug o pa ien s wi h indica ion o lipid‐lowe ing ea men , in si ua ions o high COVID‐19 incidence. Inso a as sim as a in is conce ned, ou mo ali y esul s a e also consis en wi h he scan li e a u e a ailable. 34,37,38 Due o his d ug's po en ial as adju an ea men o COVID‐19 desc ibed in p eclinical models, 46,47 we eel ha he mo ali y‐ ela ed esul s ob ained by us should be he subjec o u he epidemiological esea ch. The main s eng hs o his s udy a e i s la ge sample size (encompassing mo e han 82 000 subjec s) and adjus men o many con ounding a iables, which enabled us o accu a ely es ima e he possible associa ion be ween ch onic use o di e en s a ins and p ognosis o COVID‐19 (suscep ibili y, p og ession o se e e COVID‐19 ou comes, hospi aliza ion, and mo ali y). Fu he mo e, exposu e o d ugs was based on dispensing da a (i.e., medica ions eally acqui ed by pa ien s), unlike o he s udies which use p esc ip ion‐based da a sou ces (p esc ip ions issued). The s udy also has se e al limi a ions. Fi s , he ac o i being an obse a ional s udy wi h seconda y da abases means ha one canno ule ou he exis ence o esidual con ounding o unmeasu ed o misclassi ied co a ia es, such as he absence o da a on he deg ee o se e i y o he main como bidi ies associa ed wi h g ea e COVID‐19 se e i y. Second, he lack o ma ching in he subs udies on suscep ibili y and p og ession o se e e COVID‐19 ou comes could be conside ed a u he limi a ion. E en so, his ci cums ance has no impac on he alidi y o he s udy, since he absence o ma ching would only esul in lowe e ec i eness a he han a highe isk o biases. 28,29 Finally, he da a a ailable o s udy pu poses pe ain o 2020, when he p edominan SARS‐CoV‐2 a ian s in his coun y we e hose o he 19B clade. 48 Tha said, howe e , we ha e no eason o belie e ha he e ec o a o as a in (and sim as a in) agains COVID‐19 migh be in luenced by he p esence o dominan a ian s. 5|CONCLUSIONS Despi e no able scien i ic and medical ad ances, COVID‐19 con- inues o be a public heal h h ea . In p esen and u u e pandemics alike, apid iden i ica ion o known e ec i e he apies is undamen- al, 49 and o his end, i is necessa y o dis inguish be ween d ug‐class a ge s and molecule‐speci ic mechanisms. Ou esul s show ha ch onic use o a o as a in (and possibly, o sim as a in) is associa ed wi h a educ ion in se e e COVID‐19 ou comes. Gi en ha he p e alence o s a in use is e y high in de eloped coun ies, 50 a g ea numbe o people could be doubly bene i ed (i.e., COVID‐19 and ca dio ascula p e en ion) by ea men wi h a o as a in. AUTHOR CONTRIBUTIONS I ene Visos‐Va ela: W i ing o iginal d a p epa a ion. Ma uxa Zapa a‐Cacha ei o: Concep ualiza ion; me hodology; w i ing— e iew and edi ing. Samuel Pin os‐Rod íguez: W i ing— e iew and 8o 10 | VISOS‐VARELA ET AL. 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License edi ing. Rosendo Buga ín‐González: Me hodology; w i ing— e iew and edi ing. F ancisco Ja ie González‐Ba cala: Me hodology; w i ing— e iew and edi ing. Ma ia T. He dei o: Me hodology; w i ing— e iew and edi ing. Ma ía Piñei o‐Lamas: Fo mal analysis. Adol o Figuei as: Concep ualiza ion; me hodology; unding acquisi- ion; w i ing— e iew and edi ing. Ángel Salgado‐Ba ei a: Concep- ualiza ion; me hodology; w i ing— e iew and edi ing. ACKNOWLEDGMENTS The au ho s should like o hank he SERGAS Gene al Heal hca e Di ec o a e o u nishing he da a needed o conduc his s udy, DXC Technology o i s wo k in ex ac ing he s udy da a, and Michael Benedic o e iewing and e ising he English. This s udy was sponso ed by he Ca los III Ins i u e o Heal h ia he “COV20/ 00470”p ojec (co unded by he Eu opean Regional De elopmen Fund, “A way o make Eu ope”). CONFLICT OF INTEREST STATEMENT The au ho s decla e no con lic o in e es . DATA AVAILABILITY STATEMENT The da a se s gene a ed and analyzed du ing he cu en s udy a e no publicly a ailable due o Galician Public Heal h Sys em es ic ions. ETHICS STATEMENT The s udy was app o ed by he Galician Clinical Resea ch E hics Commi ee ( e e ence 2020‐349), ce i ied by he Spanish Agency o Medicines and Medical De ices, and conduc ed in acco dance wi h he Helsinki Decla a ion and Spanish legisla ion go e ning biomedical s udies and espec o human igh s. The s udy p o ocol was egis e ed a he Eu opean Union Elec onic Regis e o Pos ‐ Au ho isa ion S udies (EU PAS, eg. no. EUPAS44587) and is a ailable online a h ps://www.encepp.eu/encepp/ iewResou ce.h m?id= 44588. Da a ex ac ion was au oma ed and anonymous o ensu e subjec s' con iden iali y and p i acy. ORCID I ene Visos‐Va ela h p://o cid.o g/0000-0001-6466-6213 Ma uxa Zapa a‐Cacha ei o h p://o cid.o g/0000-0002- 0648-7716 Samuel Pin os‐Rod íguez h p://o cid.o g/0009-0007-8315-6463 F ancisco Ja ie González‐Ba cala h p://o cid.o g/0000-0001- 5847-4784 Ma ia T. 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S a in and ou comes o co ona i us disease 2019 (COVID‐19): a sys ema ic e iew, me a‐analysis, and me a‐ eg ession. Nu Me ab Ca dio asc Dis. 2021;31(6):1662‐1670. doi:10.1016/j.numecd.2021.02.020 VISOS‐VARELA ET AL. | 9o 10 10969071, 2023, 7, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/jm .28971 by Uni e sidade de San iago de Compos ela, Wiley Online Lib a y on [31/10/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License