The role of statin therapy in COVID-19

KEYWORDS:

• anti-viral
• COVID-19
• SARS-CoV-2
• statins
• therapy

Though the tide has turned, we remain in the midst of a global COVID-19 pandemic. Highly effective vaccines have tipped the balance in our battle with COVID-19 and are our biggest tools in fighting this disease. Additionally, pre- and post-exposure targeted therapeutics can fill in some of the gaps where COVID-19 infections arise either due to breakthrough cases or unvaccinated hosts. Still, we continue to witness waves of infection that wax and wane with each newly emerged variant of the virus. Vaccine hesitancy remains a national and global problem, and access to novel therapeutic agents is limited. For these reasons, the question of whether statins can play a therapeutic role in COVID-19 remains relevant.

Statin therapy has long been utilized to improve cardiovascular outcomes through lipid lowering along with anti-inflammatory processes and plaque stabilization effects. Some of these effects can be helpful in COVID-19, where organ dysfunction can arise due to severe inflammation, which can trigger cytokine storm and endothelial dysfunction [1] When cardiovascular death ensues, it is often due to plaque rupture and/or thrombosis amidst this inflammatory cascade and destabilized state [2]. In the setting of COVID-19, statins may confer protection via numerous proposed mechanisms including a direct inhibitory effect on the virus as well as inhibition of viral fusion to lung epithelial cells, but also through anti-inflammatory effects, immune system modulation, reduction of oxidative stress, and improvement in endothelial cell function with plaque stabilization within the coronary vasculature [3,4].

Statins are taken primarily by patients with underlying cardiovascular disease, or by those at increased risk for cardiovascular disease. They are rarely taken by healthy individuals. Because of this, it has been difficult to establish whether the beneficial effects of statins in the setting of COVID-19 extend above and beyond protecting against plaque rupture in patients with underlying cardiovascular disease to a more global anti-SARS-CoV-2 effect that might prove useful even to patients without a baseline indication for statin use. Although a number of randomized, controlled trials of statin therapy for treating COVID-19 have been registered in clinicaltrials.gov and could someday give insight into this question, so far only a few have reported results [4].

While data from randomized, controlled studies are still lacking, some observational studies have provided evidence that anti-SARS-CoV-2 effects are not a major contributor to the observed beneficial effects in COVID-19 patients. In a study of over 230,000 veterans who tested positive for SARS-CoV-2, statin use was associated with a nearly 20% lower odds of death at 30 days (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.77–0.85) [5]. However, when the same outcome was evaluated among the over 4.5 million veterans without a positive test for SARS-CoV-2 during the same time frame, the association with statins was even stronger (OR for 30-day mortality on statins 0.60, 95% CI 0.58–0.62), suggesting that statins may not exert SARS-CoV-2 specific effects.

Another relevant observational study included data from the American Heart Association COVID-19 Cardiovascular Disease Registry and evaluated the outcomes of 10,541 patients hospitalized with COVID-19 from the start of the pandemic through September 2020 [6]. Use of statin therapy was associated with a 41% lower odds of in-hospital mortality after adjusting for demographics, comorbid conditions, hospital site, insurance status, and time trends in disease severity (OR 0.59; 95% CI 0.50–0.69). Statin therapy was also associated with a significantly 25% lower adjusted odds of developing severe COVID-19, defined as need for intensive care unit (ICU) admission, mechanical ventilation, in-hospital death, or discharge to hospice. In propensity-matched analysis, the association between statin therapy and improved COVID-19 outcomes was primarily seen among those with underlying cardiovascular disease, in whom statins were associated with a 32% lower odds of in-hospital death and a 20% lower odds of severe outcome. In contrast, there was no significant association between statin use and outcomes among those without underlying cardiovascular disease: the 16% lower odds for in-hospital mortality and 8% lower odds for a severe outcome were not statistically significant.

These results could be concordant with findings from one of the few multicenter, randomized controlled trial of statins in COVID-19 that has been published to date. In the Intermediate vs Standard-Dose Prophylactic Anticoagulation in Critically ill Patients With COVID-19: An Open Label Randomised Controlled Trial-statin (INSPIRATION-S) study, 587 adults with COVID-19 admitted the ICU in one of 11 hospitals in Iran were randomized to 30 days of atorvastatin 20 mg daily or placebo [7]. To be included, subjects had to have no definite indication for baseline statin (or therapeutic anticoagulation) use. The primary outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality within 30 days from randomization. There was no significant difference in outcome between those randomized to atorvastatin versus placebo (OR 0.84, 95% CI 0.58–1.21). Of note, event rates were lower than expected in this study, perhaps due in part to the exclusion of those ‘sicker’ patients with indications for statins or anticoagulation – indeed, none of the participants had a history of coronary artery disease or stroke, and only 17% had diabetes. In this population void of underlying cardiovascular disease, either there was no benefit to statins, or the event rate was too low and/or the benefit from statins too small to register. Timing, dosing, and duration of statin therapy may also be relevant factors.

Taken together, the findings from these studies suggest that the greatest benefit of statins in reducing COVID-19 morbidity and mortality may be via stabilization of underlying cardiovascular disease rather than via direct antiviral effects. This could be through mitigation of the inflammatory cascade triggered by COVID-19 as well as other mechanisms, leading to plaque stabilization, along with reduction in thrombosis, arrhythmia, and/or myocardial disease.

While statins appear to be less beneficial against COVID-19 in patients without CVD, another key question to address is whether we can nonetheless identify subpopulations within whom statins can, in fact, improve outcomes absent a baseline indication for statin therapy. Higher rates of circulating inflammatory markers due to COVID-19 have been associated with increased risk of poor outcomes [8,9]. Future randomized, controlled studies of statins in COVID-19 should aim to evaluate whether inflammatory markers could serve as an indicator for patients in whom statins might be more beneficial. A beneficial effect may also be more likely if statins are initiated sooner after COVID-19 diagnosis; or if they are continued and evaluated beyond 30 days, given evidence of prolonged myocardial inflammation in some COVID-19 patients [10].

As we await results from the currently registered clinical trials, the current data are at the very least reassuring as to statin safety. Statins are already indicated in patients with underlying cardiovascular disease, and there is some evidence that they should not be withdrawn upon hospitalization for COVID-19. Future studies should account for and evaluate the outcomes associated with statin withdrawal among those on statins at baseline [11]. Beyond those with established indications for statins, at present, we still lack large, well-designed, randomized, double-blind studies assessing the early initiation of high-dose statins in a range of COVID-19 patients. Ideally, this would include studies among patients with limited access to vaccines, such as those in developing countries, who may not have received the full vaccine plus booster series.

Statins will never be a panacea that can fend off all the ills of COVID-19, and not only because they are unlikely to fully counter the effects of the disease. In parallel with vaccine hesitancy, which has led to suboptimal prevention of COVID-19 worldwide, ‘statin hesitancy’ has long been responsible for suboptimal cardiovascular prevention. It is possible that the ‘vaccine hesitant’ and ‘statin hesitant’ populations have substantial overlap. Nonetheless, as COVID-19 transitions from pandemic to endemic, it is more important than ever to have generic, inexpensive treatments that are readily available to all who may benefit, and who chose to utilize them.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.