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Therapies Targeting PCSK9 Would Reduce Cardiovascular, Increase Diabetes Risk

NEW YORK (GenomeWeb) – Genetic variants in the PCSK9 gene have the same effect on cardiovascular disease and diabetes risk as variants within the HMGCR gene, which encodes the target of lipid-lowering statins.

According to an international team of researchers, this suggests that therapies targeting PCSK9 should have similar effects as statins on cardiovascular events, but with the same potential risk of developing diabetes.

Brigham and Women's Hospital's Marc Sabatine and his colleagues developed genetic scores for nearly 113,000 people based on what variants they harbored in their PCSK9 and HMGCR genes. As they reported in the New England Journal of Medicine this week, the researchers examined the effect of these genetic scores on LDL cholesterol levels and on the risk of cardiovascular events and diabetes, and found that variants in PCSK9 and HMGCR had nearly identical effects.

"Our findings suggest that treatment with a PCSK9 inhibitor, used either alone or in combination with a statin, should reduce the risk of cardiovascular events to the same degree as do statins per unit reduction in LDL cholesterol," Sabatine said in a statement, noting that such inhibitors are currently being tested in cardiovascular outcomes trials.

The genetic scores for each of the 112,772 participants from 14 prospective cohorts added together the number of LDL-lowering alleles the participants had at loci near those genes that had been linked in previous studies to LDL cholesterol levels. The researchers weighted the scores based on the extent to which the variants affected LDL levels.

As they expected, participants with higher PCSK9 scores had lower mean LDL levels than those with low scores. They also had an 8.4 percent lower risk of myocardial infarction or death from coronary heart disease, the researchers reported. A dose-response analysis indicated that increasing PCSK9 scores were linked to stepwise decreases in LDL levels and a corresponding stepwise decrease in risk of myocardial infarction or death from coronary heart disease.

Similarly, participants with higher HMGCR scores had lower mean LDL levels and a 6.6 percent lower risk of myocardial infarction or death from coronary heart disease.

When Sabatine and his colleagues adjusted for a standard decrement in LDL cholesterol levels of 10 milligram per deciliter, PCSK9 variants were associated with an 18.9 percent decrease in risk of coronary events, while HMGCR variants were associated with a similar 19.1 percent decrease in risk. The team also validated its findings in a separate group of 62,240 cases and 127,299 controls.

The overall findings suggested to the researchers that therapies targeting PCSK9 could have a similar effect as statins, which target HMGCR, on reducing the risk of cardiovascular events.

At the same time, Sabatine and his colleagues reported that participants with higher PCSK9 scores also had an 11.2 percent higher risk of diabetes, after adjustment, than those with lower scores. Participants with higher HMGCR scores likewise had a 12.7 percent increased risk of diabetes.

This indicated, they said, that PCSK9 might also increase the risk of diabetes, but further noted that the increased risk of diabetes was lower than the protective effect for cardiovascular events. "Therefore, as with statins, the reduction in cardiovascular risk with PCSK9 inhibitors should far exceed any potential increased risk of diabetes," they wrote in their paper.