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PCSK9 Inhibition During Inflammatory Stage of COVID-19 Infection
Quick Takes
- PCSK9 inhibition compared to placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19.
- Given the pilot nature of the study and that the study was not designed to statistically test any hypothesis of superior efficacy/safety of PCSK9 inhibition in patients with COVID-19, these findings should be considered preliminary.
- Large-scale prospective trials are indicated to confirm the clinical benefit of PCSK9 inhibition in patients with COVID-19 and clarify the pathophysiological mechanisms contributing to improved outcomes prior to their widespread use.
Study Questions:
What is the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition versus placebo on clinical and laboratory outcomes in patients with severe coronavirus disease 2019 (COVID-19)?
Methods:
The IMPACT-SIRIO 5 (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19) investigators conducted a pilot, double-blind, placebo-controlled, multicenter trial among 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and PO2/FiO2 ratio ≤300 mm Hg, and randomized them 1:1 to receive a single 140 mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was changes in circulating interleukin-6 (IL-6) at 7 and 30 days from baseline. Outcome differences in the two arms were analyzed by risk difference (RD) expressed in percentage points with 95% confidence intervals (CIs).
Results:
Patients randomized to PCSK9 inhibitor had lower rates of death or need for intubation within 30 days versus placebo (23.3% vs. 53.3%, RD, -30%; 95% CI, -53.40 to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline, -56% vs. -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition versus placebo (RD, -37.50%; 95% CI, -68.20 to -6.70%).
Conclusions:
The investigators report that PCSK9 inhibition compared to placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in patients with severe COVID-19.
Perspective:
This pilot study reports that PCSK9 inhibition compared to placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Furthermore, patients with more intense inflammation had better survival with PCSK9 inhibition versus placebo, suggesting that inflammatory intensity may drive its therapeutic benefits. Given the pilot nature of study and the fact that the study was not designed to statistically test any hypothesis of superior efficacy/safety of PCSK9 inhibition in patients with COVID-19, the study findings should be considered preliminary. Large-scale prospective trials are indicated to confirm the clinical benefit of PCSK9 inhibition in patients with COVID-19 and clarify the pathophysiological mechanisms contributing to improved outcomes prior to their widespread use.
Clinical Topics: COVID-19 Hub, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Novel Agents
Keywords: COVID-19, Critical Care, Dyslipidemias, Inflammation, Interleukin-6, Intubation, PCSK9, PCSK9 protein, human, Primary Prevention, Proprotein Convertase 9, SARS-CoV-2, Subtilisins, Vascular Diseases
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