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Genetic analysis links PCSK9 inhibition and CV mortality
Key clinical point: Long-term low levels of LDL cholesterol by means of PCSK9 gene variation are associated with a reduced risk of cardiovascular death.
Major finding: A growing number of PCSK9 alleles were tied to lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV death (P = .001).
Study details: A genetic analysis of 109,566 people from the Copenhagen City Heart Study and Copenhagen General Population Study.
Disclosures: The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors report no conflicts of interest.
Benn M et al. J Am Coll Cardiol. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517.
One question that remains from the current study is whether prolonged inhibition of PCSK9 in patients with increased LDL cholesterol levels will reduce cardiovascular mortality in the context of primary and secondary prevention.
The recent development of PCSK9 inhibitors was heavily influenced by genetic analyses showing that person-specific variants in the PCSK9 gene could lower LDL levels and reduce rates of coronary heart disease. Because of the rarity of these gene variants, their impact on mortality on a large-scale basis remains unclear.
Although numerous clinical trials have shown that PCSK9 inhibition can reduce CVD-related events in both chronic and high-risk patients, no study has clearly shown an effect on cardiovascular death. However, the relationship between lipid levels and clinical outcomes is difficult to assess owing to the presence of confounding factors. Certain types of genetic analysis may help eliminate these challenges by analyzing large populations over extended periods of time.
The genetic analysis by Dr. Benn and colleagues showed an association between long-term exposure to lower levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, and reduced cardiovascular mortality. These findings, alongside other studies, provide further support for the relationship between PCSK9 inhibition and prevention of cardiovascular mortality.
Gregory G. Schwartz, MD, PhD , and Matthew R.G. Taylor, MD, PhD , are with the University of Colorado in Aurora. Dr. Schwartz reported having financial affiliations with Resverlogix, Roche, Sanofi, and The Medicines Company. These comments are adapted from their editorial (J Am Coll Cardiol. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.518 ).