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Genetic analysis links PCSK9 inhibition and CV mortality

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Analysis first to show cardiovascular mortality benefit

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 ).



Long-term genetically low levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, were associated with a reduced risk of CV mortality, but not all-cause mortality, in a large cohort of individuals.


“We tested the hypothesis that genetically low LDL cholesterol due to PCSK9 [proprotein convertase subtilisin/kexin type 9] variation is causally associated with low cardiovascular and all-cause mortality in a general population of Northern European ancestry,” wrote Marianne Benn, MD, DMSc, and colleagues. The findings were published in the Journal of the American College of Cardiology.

The researchers conducted a large-scale genetic analysis of 109,566 persons from the Copenhagen City Heart Study and Copenhagen General Population Study. In addition, the team included a validation cohort of 431,043 individuals from the UK Biobank.

The median duration of follow-up was 10 years (0-42 years), and the median age at study entry was 57 years.

Study participants were genotyped for several PCSK9 variants and a weighted allele score based the effects of LDL cholesterol, individual allele frequency, and number of variant alleles was calculated for each subject.

Weighted scores were categorized into five stepwise noncontinuous score ranges, with lower levels of LDL cholesterol linked to higher allele scores.

After analysis, the researchers found that a growing number of PCSK9 alleles were associated with lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV mortality (P = .001), but not with reduced all-cause mortality (P = .11).

“Our genetic data did not show a reduction in risk of all-cause mortality, and only showed a reduction in risk of all-cause mortality in statin trials and not in the PCSK9-inhibitor trials meta-analyzed,” the researchers wrote. “This may be explained by the low frequency of cardiovascular disease in the 2 populations studied,” they explained.

One key limitation was the homogeneous makeup of the study population. Dr. Benn and colleagues acknowledged this could limit the generalizability of the results.

“Long-term LDL cholesterol treatment (e.g., with PCSK9 inhibitors), may translate into reductions in cardiovascular mortality,” they concluded.

The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors reported no conflicts of interest.

SOURCE: Benn M et al. JACC. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517

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