This study investigated the impact of prior statin treatment on a range of five different COVID-19 outcomes in three different Swedish population-based cohorts - general population, individuals with COVID-19 onset and a COVID-19 hospitalization cohort. Our main findings show that prior statin treatment was significantly associated with a reduced risk of COVID-19 test-positivity, diagnosis, hospitalization and mortality in the 3 studied population cohorts. These findings strengthen and support evidence on the hypothesis of pleiotropic protective effects of statins in COVID-19 from prior cohort studies (23-30) and align with evidence summarized by recent meta-analyses and systematic reviews on the association of statin use and the potential protective effects against progression and severity of COVID-19 (15, 16, 18, 31, 32). A recent Swedish cohort study using register data with a smaller sample size limited to the Stockholm Region similarly showed statin use to be a protective factor for COVID-19 death (29). That study had shorter follow-up than ours, but similar to our main exposure definition, defined statin exposure broadly as any statin treatment initiated before the pandemic. not regular statin user).
As noted previously, plausible biological and clinical mechanisms, both direct and indirect, by which statins might protect against COVID-19 disease or severity have been proposed (7, 15, 16, 33-35). Statins have potential effects to reduce the cytokine release syndrome in COVID-19 by inhibiting Toll-like receptor 4 (TLR4) and down-modulating macrophage activity (36-38). Statins have further been demonstrated to suppress the expression of both TLR2 and TLR4, leading to an immune response shift towards an anti-inflammatory response (39).
Beyond their cholesterol-lowering effect, statins could also affect the plasma membrane composition, where cholesterol is a dominating component. This effect is particularly important for enveloped viruses like SARS-CoV-2 that must pass the plasma membrane twice upon cell infection and again upon egress of newly synthesized virus particles. Recent studies have demonstrated that cholesterol is important in forming syncytia, multinucleated cells, that characterizes SARS-CoV-2 cell entry (40). Statins may well cause a reduction of syncytia by reducing plasma membrane cholesterol levels, thus reducing viral infection. Preliminary results indicate that statins indeed can reduce SARS-CoV-2 infection of lung epitheial cells (I. Parmryd, personal communication).
Statins also exert pleiotropic effects affecting inflammation and oxidative stress (36) of potential relevance for infection and lung protection. Statins may diminish the complications of COVID-19 by improving endothelial function, reducing serum PAI-1 levels and attenuating TGF-and VEGF in lung tissue (34). Furthermore, statins can constrain SARS-CoV-2 reproduction by restraining the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp)(34). Moreover, the effectiveness of statin treatment in significantly decreasing hospitalizations and deaths has been shown for influenza and Ebola virus diseases (41, 42).
Alongside their potential benefits in COVID-19, the side effects of statin treatment need to be considered, such as elevated creatinine kinase (CK) and elevated serum glucose levels, which have been reported in severe COVID-19 patients (43). Although statin treatment is commonly considered safe and well-tolerated, statins may induce liver injury (44). Current European guidance for the diagnoses and management of cardiovascular disease during the COVID-19 pandemic recommends temporarily restraining statin treatment in patients with high liver enzymes (45). Future studies should preferably assess both positive and negative statin effects in COVID-19 patients.
Conflicting findings of the beneficial effects of prior statin treatment on COVID-19 have been reported in retrospective studies. Recent cohort studies have reported increased, decreased and unaffected risk for COVID-19 severity and mortality (46-50). Residual confounding may be an issue, and more carefully adjusted studies show more consistent protective results (15, 16). We have investigated individuals at three stages in the COVID-19 disease progression using 3 different cohorts: healthy before disease onset, from COVID-19 onset, and from COVID-19 hospitalization – with careful adjustment for confounding using propensity score analysis with ATT weighting. Protective effects of statins were seen for COVID-19 death for all three cohorts and in our overall population cohort and COVID-19 onset population also for the less severe outcomes (hospitalization), supporting a protective effect of statin on COVID-19 infection and severity. Despite some indications of an overall stronger protection in women than in men, we did not really observe consistent sex differences, which would have been consistent with the overall higher risk for severe COVID-19 outcomes seen in men during the pandemic (51).
Our study has several strengths and limitations that merit discussion. Using a population-based database in Sweden, we investigated the impact of statin use both in the population and in well-defined cohorts of COVID-19 patients for several different clinical COVID-19 outcomes. The completeness of data from nationwide administrative registries (including high-quality socio-economic data) and efficient linkages of different register data for COVID-19 patients to identify test-positive disease, clinical diagnoses and severe COVID-19 outcomes (hospitalization, ICU admission and death) are fundamental strengths of this study and support generalization of the results. In this study, we outlined statin exposure in the prior year into two different ways. Our main exposure definition was any statin exposure in the prior year, consistent with definitions commonly used in many studies. As a sensitivity analysis, we also used a more specific exposure definition, regular statin use, defined as ≥3 (generally 3-month) prescriptions in the prior year, to better capture individuals with likely ongoing regular statin use at index date, recognizing the variable adherence to actual daily statin intake in real-life data. Our sensitivity analysis with this definition gave very similar results, suggesting that the main exposure definition has adequate specificity for the hypothesized true exposure. We assume that short-term mechanisms of current use at the index would most likely be relevant for the observed effects we report. Our sensitivity analysis with this definition gave very similar results, suggesting that the main exposure definition has adequate specificity for the hypothesized true exposure. However, the study also has some limitations. Some exposure misclassification is possible, both of statin exposed and unexposed individuals, but this is unlikely to be related to the outcomes (which were totally unanticipated prior to index dates), and potential bias would thus tend to be towards the null. Unless the exposure misclassification is substantial, and the effect in the misclassified individuals is highly different, such bias would also have limited impact. Misclassification errors in identifying COVID-19 outcomes are also possible, especially under ascertainment of test-positive milder disease, but it is unlikely this differs between statin-treated and untreated. For the more severe outcomes, this issue is likely of less concern. Although propensity score weighting was used to minimize potential confounding, we cannot exclude some remaining bias from patient selection, treatment indication and residual confounding due to unmeasured confounders such as health risk behaviour (physical activity, smoking) and laboratory parameters (dyslipidemia). Nevertheless, the exposure cohorts were quite well balanced after propensity score weighting, and the results were consistent across the studied cohorts and follow-up periods from different index time points.