The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, driven by the emergence of new and more transmissible variants. The mortality and long-term morbidity are known to be probably fueled by the cytokine storm that is typically observed in patients with severe and critical COVID-19.

Much attention has been focused on ways to reduce the deadly exaggeration of normal inflammatory reactions to this pathogen. A new research paper posted to the medRxiv* preprint server describes the alleviation of hyper-inflammatory phenomena following the administration of statins, drugs more widely known for their use in reducing blood cholesterol levels, to patients with COVID-19.

With severe COVID-19 pneumonia, pro-inflammatory cytokines such as tumor necrosis factor (TNF), IL-6 and IL-1β are produced in abundance in response to the viral infection. As the disease progresses, the systemic effects of these cytokines leads to increased vascular permeability, multi-organ failure and death.

Lipid metabolism is strongly suspected of playing a pivotal role in this inflammation since cytokines are lipid derivatives, and lipids are essential elements of the cell membranes that help internalize the virus and facilitate further replication and transcription.

High cholesterol levels in the tissues have been shown to promote SARS-CoV-2 endocytosis into the host cell, allowing infection establishment. Statins act by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inside the cells. This action not only prevents upregulation of the myeloid differentiation primary response 88 to the presence of the virus but leads to increased expression of the protective angiotensin-converting enzyme 2 (ACE2) molecule on the cell membranes.

Earlier studies

Prior research suggested reduced mortality as the result of statin use, but some studies reported contradictory findings. A comprehensive overview of the current literature is lacking. The available meta-analyses of statin use in COVID-19 patients do not report whether the patients were put on statins following hospitalization or if these drugs were in prior use.

The current preprint is a meta-analysis of the studies carried out so far on this aspect of COVID-19 management.

Mortality reduced with statins

There were 12 comparative studies on mortality due to COVID-19 in statin users vs. non-users. These showed that the use of statins prior to hospitalization for this condition did not confer a benefit in terms of reduced mortality. However, when administered to COVID-19 patients following hospitalization, the risk of mortality fell by 47%, with the odds of death dropping by 43%, compared to non-users.

This difference was not found among COVID-19 patients who were more seriously ill, requiring intensive care unit (ICU) admission. If this group was excluded, the benefit for statin users among hospitalized patients in terms of reduced mortality remained identical at 43%, with the odds of death dropping by 36%.

ICU admissions and the need for mechanical ventilation were not affected by statin use, whether prior to or following hospital admission.

What are the implications?

This stringent meta-analysis reports on a total of over 110,000 patients, making it the most high-powered study now available. The use of separate assessments for COVID-19 mortality and ICU admissions following statin administration also led to distinct risk evaluations for these outcomes.

The observational design of all included studies precludes the expectation of highly comparable study and control groups (statin users and non-users, respectively). To compensate for this, the researchers compared adjusted relative risk ratios rather than unadjusted event rates.

This study's findings seem to indicate that the risk of death, ICU admission, and mechanical ventilation do not differ between statin non-users and those who used statins prior to being hospitalized with COVID-19. However, there are a number of possible interpretations.

For one, patients are currently not always put on statins after hospitalization for COVID-19 as these drugs are not part of routine management. As such, patients who do receive these drugs in this setting are more likely to be receiving them as part of their treatment for acute cardiovascular events such as myocardial injury due to COVID-19, acute coronary syndrome, or stroke.

This indicates the strong potential for including a higher number of sicker patients in the post-admission statin users group, which would likely have poorer outcomes anyway. The comparison of this group with prior statin users may yield an overestimation of the possible protective association of statin use before hospitalization with better outcomes.

On the other hand, many studies that report pre-hospitalization statin use do not record post-admission continuation of these drugs. An earlier study shows that up to 42% of patients stop these drugs following admission. This would perturb the analysis of the protective effect of statin use before admission for COVID-19.

In turn, this could lead to wrong associations between statin use after admission and adverse outcomes by failing to account for the withdrawal of these drugs during the hospitalization period.

The absence of reduced mortality risk among ICU patients may suggest that the use of statins is most beneficial at the early stages of COVID-19-induced inflammation. This requires confirmation by more extensive studies, however.

Overall, the lower risk of mortality with statin use post-admission is likely to be underestimated since many of these patients were put on statins for other cardiovascular indications, which put them at higher risk of death. The findings, therefore, support continuing statin use in patients who are already taking these drugs.

Further randomized controlled trials will be needed to understand the role of statins as a specific treatment to reduce the mortality associated with COVID-19.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.