Cardiovascular genetic risk score guides PCSK9 therapy

2019 04 24 18 42 4242 Dna Blue 400

Results from a genetic risk test were significantly associated with risk for cardiovascular events in a new analysis of the large outcomes study of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab, researchers reported on November 17 at the American Heart Association (AHA) annual meeting in Philadelphia.

The analysis provided new insights into the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) study, which supported a U.S. Food and Drug Administration (FDA) label change for evolocumab (Repatha, Amgen) to include a risk reduction claim. Results were presented at the meeting and also published in the journal Circulation (November 11, 2019) by Brigham and Women's Hospital cardiologist Dr. Christian Ruff and colleagues.

The researchers studied risk scores in participants of the study, which enrolled 14,928 individuals with atherosclerotic cardiovascular disease. Using a 27-single-nucleotide polymorphism (SNP) genetic risk score, Ruff et al categorized participants as having low, intermediate, or high risk for major cardiovascular and ischemic stroke events. The results were adjusted for clinical factors that put participants at high risk, such as diabetes and hypertension. At baseline, the low-density lipoprotein cholesterol (LDL-C) levels were similar (94 mg/dL for high risk, 92 mg/dL for intermediate risk, and 91 mg/dL for low risk).

Those in the top 20% for risk based on the genetic score had a twofold greater risk reduction associated with evolocumab treatment than the overall trial population, the researchers found. This is the first study to show the connection between a genetic risk score and benefit from PCSK9 treatment, they noted.

"This 27-single-nucleotide polymorphism genetic risk score can be used to personalize therapy, identifying patients with higher risk in whom PCSK9 inhibition should be strongly considered," Ruff et al wrote. "Treatment with evolocumab in patients with high genetic risk completely mitigates the increased genetic risk, lowering their event rate to that of the patients with low genetic risk."

PCSK9 inhibitors offer robust LDL lowering and risk reduction beyond what is possible with maximally tolerated statins. In separate news, the American College of Cardiology (ACC) on November 11 said that cholesterol therapies have been helping those in the U.S. get to lower cholesterol levels, in line with joint guidelines from the ACC and AHA.

In a study of data for 32,278 patients, age-adjusted total cholesterol declined from 206 mg/dL in 2005-2006 to 191 mg/dL in 2013-2014; it dropped again to 187 mg/dL in 2015-2016. In addition, average LDL-C in adults on lipid-lowering medication dropped from 122 mg/dL in 2005-2006 to 107 mg/dL in 2013-2014 and 101 mg/dL in 2015-2016. Results were published in the November issue of the Journal of the American College of Cardiology (Patel et al, Vol. 74:20, pp. 2525-2528).

However, there is still a lot of room for improvement when it comes to managing LDL-C. In a separate study also presented at the AHA meeting, researchers with the Transform LDL-C Risk initiative reported that a large majority of patients with atherosclerotic cardiovascular disease do not achieve target LDL-C levels, based on data from the ACC's outpatient Pinnacle Registry.

Out of 1.9 million patients with atherosclerotic cardiovascular disease, 21% had no record of taking lipid-lowering therapy and 84.5% did not meet the LDL-C target of less than 70 mg/dL for high-risk groups, according to the researchers. Furthermore, of 1.3 million prescribed only a statin, 67% did not meet the 70-mg/dL target.

The Transform LDL-C Risk initiative is funded by Sanofi and Regeneron, which jointly market the PCSK9 inhibitor alirocumab (Praluent).
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