Could Statins Curb Fatal or Severe COVID-19? Some Clues

Preliminary research looking into the benefits of statins suggests they may reduce the risk of fatal or severe illness in patients with COVID-19. Whether they exert direct benefit or merely help to mitigate cardiovascular disease as a risk factor remains to be established, experts say.

In four studies of nearly 9,000 patients with COVID-19, including three large-scale studies that adjusted for multiple confounding variables, those taking statins had a 30% lower risk of fatal or severe disease when compared with those not taking statins (pooled HR 0.70; 95% CI 0.53-0.94).

“Much is left to be determined on the regimen of statins for the treatment of COVID-19, though available evidence suggests that statin therapy of moderate-to-high intensity could be effective,” according to study authors Chia Siang Kow, MPharm (International Medical University, Kuala Lumpur, Malaysia), and Syed Shahzad Hasan, PhD  (University of Huddersfield, England). “Nevertheless, we await more data from prospective studies to substantiate our findings. Future well-designed randomized controlled trials are also needed to confirm the benefits of statins in COVID-19 patients.”

Writing in the American Journal of Cardiology, where the study was published online August 11, 2020, the researchers state that the pandemic has spurred interest in repurposing existing drugs for the treatment of COVID-19. In addition to lowering LDL cholesterol levels, statins are known to have pleiotropic effects, including anti-inflammatory, antioxidative, immunomodulatory, and antithrombotic properties. COVID-19 is characterized by intense, system-wide inflammation, as well as endothelial dysfunction, and patients are at risk for cardiovascular sequelae such as myocarditis, heart failure, cardiogenic shock, ACS, venous thromboembolism, and stress cardiomyopathy. The hope is statins could dampen inflammation, as well as protect against damage to the endothelial tissue by increasing production of nitric oxide and inhibiting platelet aggregation.

Whether there is a clinical benefit is to be determined, but certainly we should be implementing everything we know about preventive cardiology. Seth Martin

“Besides, statins are known to experimentally upregulate ACE2 expression, and therefore might be protective towards lung injury induced by [the] coronavirus,” write Kow and Hasan.

Data showing statins can reduce the severity of COVID-19, or protect against death, are limited. Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA and Center for Outcomes Research & Evaluation at Yale University School of Medicine, New Haven, CT), who wasn’t involved in the study, told TCTMD that many investigators have been raising the possibility that statins “may mitigate the outcomes in patients with COVID-19” on the basis of signals in prior studies. For example, he said, a secondary analysis from HARP-2, a randomized clinical trial testing simvastatin in patients with acute respiratory distress syndrome (ARDS), showed there was a survival advantage at 28 and 90 days with simvastatin in patients with the hyperinflammatory ARDS phenotype.

Along with Aakriti Gupta, MD, and Mahesh Madhavan, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York), Bikdeli also conducted a retrospective analysis of patients admitted to two New York City hospitals with COVID-19 in the first few months of the pandemic, available as a preprint. Of 2,626 patients hospitalized, more than one-third were prior statin users, and a propensity-matched analysis suggested that statin use was significantly associated with a lower risk of inpatient mortality when compared with those not taking statins.

Also commenting on the analysis for TCTMD, Seth Martin, MD (Johns Hopkins Hospital, Baltimore, MD), said the present study is encouraging observational evidence. For him, these new data should remind physicians of the importance of guideline-directed medical therapy in at-risk patients or those with existing atherosclerotic CVD.

If I had to say what the clinical message would be, it would be to redouble efforts about all that we know about preventive cardiology. Seth Martin

“If patients get some additional bonus benefit, that’s great, but this is preliminary and speculative,” said Martin. “As the authors acknowledge, if you really want to know if statins have a benefit in COVID, you need to do a randomized controlled trial. The reality is that many of the patients at risk for the complications of COVID are also going to be at risk for cardiovascular disease. To me, if I had to say what the clinical message would be, it would be to redouble efforts about all that we know about preventive cardiology and the [American Heart Association/American College of Cardiology] guidelines. If we do that better, we’re protecting patients, and whether there’s a specific COVID benefit, who really knows?”

Prospective studies are ongoing, including some randomized trials, said Bikdeli, noting that he is the coprimary investigator of the INSPIRATION trial, a 2x2 factorial study that is testing whether atorvastatin compared with placebo improves clinical outcomes of critically ill COVID-19 patients. It is also testing whether an “intermediate” dose of prophylactic anticoagulation is superior to the standard dose for reducing the risk of venous thromboembolism, need for extracorporeal membrane oxygenation, or all-cause mortality. 

In terms of the biology underpinning the hope that statins might be a cheap, readily available treatment to mitigate the risk in patients with COVID-19, Martin was skeptical. “You can find biologic plausibility in almost anything, to be honest,” he said. “Whether there is a clinical benefit is to be determined, but certainly we should be implementing everything we know about preventive cardiology.”