PCSK9 as a CVD Biomarker? Levels May Predict Event Risk Independent of LDL-C

Deborah Brauser

March 11, 2016

STOCKHOLM, SWEDEN — Measures of circulatory proprotein convertase subtilisin/kexin type 9 (PCSK9) in older individuals may help determine those who are at increased risk for CV events, new research suggests[1].

The prospective cohort study of more than 4000 participants, all of whom were 60 years of age and free of CVD at enrollment, showed that those with higher baseline serum PCSK9 concentrations were significantly more likely to experience incident CVD within 15 years of follow-up vs those with the lowest levels of PCSK9 (P<0.0001).

Even after adjustment for LDL cholesterol, as well as other known CV risk factors such as hypertension, diabetes, obesity, and statin use, the association between increased circulatory PCSK9 and increased risk of CVD remained significant (P=0.006).

Lead investigator Dr Karin Leander (Institute of Environmental Medicine, Stockholm, Sweden) admitted to heartwire from Medscape that her team was a bit surprised by the findings.

"PCSK9 is an interesting biological marker. And if our results are confirmed by others, it seems it has a role in cardiovascular disease etiology beyond that of LDL-cholesterol regulation," said Leander

The investigators add that it might also help clinicians to better identify those who will respond better to PCSK9-inhibiting therapy. The findings were published online February 19, 2016 in Circulation.

New Role for PCSK9

As reported by heartwire , the FDA approved the PCSK9-inhibitors alirocumab (Praluent, Sanofi/Regeneron) last July and evolocumab (Repatha, Amgen) last August for lowering LDL cholesterol. Both drugs have also been approved by the European Medicines Agency.

Instead of studying PCSK9 as a target for lipid-lowering treatment, however, the investigators sought to measure it to determine its possible relationship with CVD risk.

Between August 1997 and December 1998, they enrolled 4232 residents of Stockholm County, Sweden (52% women) and followed them through December 2012 through record linkage with national registries. Lipids, glucose, blood pressure, and body-mass index (BMI) were measured at baseline, and questionnaires on physical activity and other characteristics were collected.

The main outcome was a composite of fatal or nonfatal MI, chronic ischemic heart disease, angina pectoris, sudden cardiac death, and fatal or nonfatal stroke. During the follow-up period, the participants experienced 491 total incident CVD events.

The hazard ratio (HR), adjusted for sex, was 1.69 (95% CI 1.3–2.2) for incident CVD during follow-up for those with PCSK9 levels in the highest quartile (>122.3 ng/mL) vs those in the lowest quartile (<73.1 ng/mL). The fully adjusted HR was 1.48 (95% CI 1.1–2.0).

Treatment Target?

The full group of women had a higher median concentration of PCSK9 (108.9 ng/mL) compared with the men (80.5 ng/mL)—and there were more women than men in the two highest quartiles (94.4–122.3 ng/mL, 63% women; >122.3 ng/mL, 73% women). However, the association between this marker and incident CVD was similar "across the genders," report the researchers (PCSK9 interaction with sex, P=0.89).

For the full group of participants, multiple models with multiple adjustments showed HRs for CVD increasing as PCSK9 levels increased.

Interestingly, further analyses showed that increased PCSK9 levels with low LDL cholesterol were significantly associated with CVD risk, as was elevated LDL cholesterol with low PCSK9, but high levels of both were not.

"Our data help advance the body of evidence needed to determine whether serum PCSK9 holds promise as an independent CVD risk factor and treatment target," conclude the investigators.

The study was funded by the Swedish Research Council, the Swedish Heart and Lung Foundation, and Fondation Leducq. Lilly supplied "laboratory analyses of serum PCSK9 concentration." Personnel costs for registry linkage was funded by Pfizer. The study authors report no relevant financial relationships.

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