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  • PCSK9 Inhibition May Reduce Inflammation, Mortality in Patients with Severe COVID-19

    Patients with intense COVID-19 inflammation while infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have better survival rates with PCSK9 inhibition than with placebo treatment, a new study shows.

    PCSK9 inhibitor treatment also reduces rates of death and the need for intubation, as well as levels of interleukin (IL)-6, in patients with severe COVID-19, the study suggests.

    This information was reported by Eliano P. Navarese, MD, PhD, of Nicolaus Copernicus University and Sirio Medicine, both in Bydgoszcz, Poland, and the University of Alberta and colleagues in a manuscript published Monday online and in the Jan. 24 issue of the Journal of the American College of Cardiology.

    Inflammation in patients with SARS-CoV-2 has potential to cause severe outcomes. On top of respiratory distress syndrome, systemic inflammatory problems can quickly cascade into immune dysregulation. Increased levels of IL-6 contribute to a greater inflammatory response in patients with COVID-19 and, thus, increased severity of COVID-19 symptoms.

    Vascular inflammation and COVID-19 inflammatory responses are influenced by low-density lipoprotein (LDL) homeostasis, which is maintained in part by proprotein convertase subtilisin/kexin type 9 (PCSK9). This study investigated the impacts of PCSK9 inhibition in patients with severe COVID-19. PCSK9 inhibition and a placebo were used as treatment, and both clinical and laboratory outcomes were observed in this double-blind, multicenter trial.

    A total of 60 patients were hospitalized for severe COVID-19 and randomized 1:1 to receive a subcutaneous injection of evolocumab or placebo in a 140-mg dose. Patients had ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio of ≤300 mm Hg. Death or the need for intubation at 30 days was the primary endpoint. Change in circulating IL-6 at 7 and 30 days from baseline was the main secondary endpoint.

    The study randomly assigned 30 patients to each group, and baseline characteristics were well-balanced. In the PCSK9 group, 37% of the patients were female, their mean age was 66.07 ± 12.09 years and their mean body mass index (BMI)  was 29.94 ± 5.40 kg/m2. In the placebo group, 40% of patients were female, their mean age was 66.23 ± 11.85 years and mean BMI  was 29.80 ± 5.21 kg/m2. Some comorbidities included diabetes, cardiovascular disease and chronic obstructive pulmonary disease.

    Patients who received the PCKS9 inhibitor had lower rates of death and the need for intubation within 30 days than patients who received the placebo (23.3% vs 53.3%, risk difference: –30%; 95% confidence interval [CI]: –53.40% to –6.59%). Serum IL-6 over time was lower in patients treated with PCSK9 inhibitor than patients in the placebo group (30-day decline: –56% vs –21%). Patients who had above-the-median levels of IL-6 at baseline had lower mortality rates when treated with the PCSK9 inhibitor vs the placebo (risk difference: –37.50%; 95% CI: –68.20% to –6.70%).

    The investigators concluded that COVID-19 patients treated with PCSK9 inhibition compared with placebo had significantly reduced mortality and need for intubation. Because patients with high baseline inflammation had reduced mortality after receiving the PCSK9 inhibitor, the investigators noted that intensity of inflammation may drive future treatment therapies. The levels of IL-6 were also reduced in the PCSK9 inhibition group.

    In an accompanying editorial, Sascha N. Goonewardena, MD, of the University of Michigan, and Robert S. Rosenson, MD, of the Mount Sinai Icahn School of Medicine, New York, discussed current treatments for COVID-19. They noted that cardiovascular disease and lipid-related risk factors are associated with more severe COVID-19, and PCSK9 inhibition has — until now — been limited to ex vivo studies.

    The editorialists wrote that the current study contributes to both knowledge of COVID-19 treatments and PCSK9 dynamics.

    “Even though the presented study is small and hypothesis generating, the striking improvement in COVID-19–associated events with the use of [PCSK9 inhibitors] suggests that either acute lower LDL or LDL-independent effects can modulate inflammation in COVID-19,” Goonewardena and Rosenson said.

    The editorialists concluded by saying further investigation is needed.

    “Ongoing studies of lipid-modulating therapies in COVID-19 will further illuminate the connection between lipoprotein metabolism and inflammation,” they said.

    References:

    Navarse EP, Podhajski P, Gurbel PA, et al. PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection. J Am Coll Cardiol 2023;81:224-234.

    Goonewardena SN, Rosenson RS. PCSK9: The Nexus of Lipoprotein Metabolism and Inflammation in COVID-19. J Am Coll Cardiol 2023;81:235-236.

    Image Credit: creativeneko – stock.adobe.com

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