Three Common Biomarkers Closely Tied to Women’s 30-Year Risk of CV Events

For women, levels of LDL cholesterol, high-sensitivity C-reactive protein (hs-CRP), and lipoprotein(a) at middle age are strongly associated with cardiovascular events over the next three decades, according to an analysis of the Women’s Health Study.

Each of the biomarkers appeared to matter, researchers found, though combining their impact into a single measure captured the widest variations in risk.

Friday at the European Society of Cardiology (ESC) Congress 2024, Paul M. Ridker, MD (Brigham and Women’s Hospital, Boston, MA), kicked off his presentation by posing a question: “Has the time come for universal screening for three simple and, most importantly, modifiable risk markers?”

Based on their results, which were simultaneously published in the New England Journal of Medicine, the answer would be yes, Ridker urged.

“High-sensitivity CRP, LDL cholesterol, and Lp(a) can be instrumental for understanding biology, predicting risk, and targeting cardiovascular interventions,” he said.

Unlike hs-CRP and LDL, Lp(a) levels typically hold steady over a person’s lifetime, though data from OCEAN(a)-DOSE suggest that novel RNA interference therapies could reduce the lipoprotein. Several of these drugs are in development, including lepodisiran (Eli Lilly), zerlasiran (Silence Therapeutics), and pelacarsen (Novartis/Ionis Pharmaceuticals). Phase III data—needed to confirm that reducing Lp(a) indeed reduces CVD outcomes—are expected first for pelacarsen, with the Lp(a)HORIZON trial scheduled to complete next year.

Just last year, the US Food and Drug Administration approved colchicine as the first anti-inflammatory for decreasing CV events, which Ridker believes bolsters the case for hs-CRP testing.

“Reflecting both completed and ongoing clinical trials, our guidelines for primary and secondary prevention are slowly shifting to include greater focus on modifiable risk markers, including these three, each of which has been shown to predict short-term risk among individuals taking and not taking statin therapy,” Ridker explained.

Yet, “data are quite scarce on the long-term, 25- to 30-year risk associated with these biomarkers, both when used alone and in combination,” Ridker continued. This is particularly true among women, “for whom cardiovascular disease remains underdiagnosed and undertreated.”

In an email to TCTMD, Ridker stressed that “the goal is to move prevention forward into our 30s and 40s, and not wait until our 60s to start preventive care,” he told TCTMD.

For his part, Ridker sees immediate applications for their data.

“These three tests are widely available and inexpensive,” he said, though patients may need to request testing for hs-CRP and Lp(a) along with the more common LDL measurement. Importantly, “each of these is modifiable either with behavior changes and/or drug therapy,” Ridker stressed. “But if we don’t know why an individual patient is at risk, we can’t provide the correct treatment—these three biomarkers were selected because each represents a different but crucial pathway. Without them, we are flying blind.”

If we don’t know why an individual patient is at risk, we can’t provide the correct treatment. Paul Ridker

For their study, Ridker and colleagues analyzed data for 27,939 US women who were initially healthy when they enrolled in the Women’s Health Study between 1992 and 1995. Mean age at baseline, when they each had their biomarker levels tested, was 54.7 years, and 94.0% were white. One-quarter had hypertension, 12.0% smoked tobacco, and 14.4% had at least one parent who’d experienced an MI before age 65. Mean body mass index was 25.9 kg/m².

The biomarkers in question—hs-CRP, LDL cholesterol, and Lp(a)—exist independently of and don’t appear to influence each other, Ridker noted. “They represent different biologic processes that men and women may have in terms of why they develop plaques and why those plaques rupture. Each of them is modifiable with therapies that we already have: we have proven data for LDL-lowering, proven data for inflammation-lowering, and we may have proven data for Lp(a)-lowering when those trials are completed.”

The primary endpoint was a first MACE: either MI, coronary revascularization, stroke, or CV death. Over 30 years of follow-up, 3,662 of these events occurred. Comparing the highest versus lowest quintiles of baseline levels for the three biomarkers, the researchers found that increasing levels were associated with higher likelihood of the primary endpoint by 30 years. The strongest predictor of long-term risk was hs-CRP, and similar associations were seen for the individual endpoints of coronary heart disease and stroke.

Risk of First MACE Over 30 Years: Highest vs Lowest Baseline Level

Further calculations that simultaneously adjusted for each of the other biomarkers attenuated the associations, though each remained significant. The strength of the associations for hs-CRP and LDL also shrunk slightly over time.

Notably, Ridker et al say, “each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.”

Risk was higher for participants who had one biomarker (HR 1.27; 95% CI 1.19-1.37), two biomarkers (HR 1.66; 95% CI 1.51-1.83), or three biomarkers in quintile 5 (HR 2.63; 95% CI 2.16-3.19) compared with those who had none.

The researchers also calculated cumulative incidence curves that adjusted for age and competing risk of death. With the individual curves for hs-CRP and LDL, “you would see very little spread in 5 years to 10 years, but by 30 years you can see major differences,” Ridker pointed out to the ESC audience. With Lp(a), on the other hand, “things are now a little bit different. This is a genetically determined risk marker. It does not generally change over time, and consistent with all prior cohorts, the risk is really not graded as it is for LDL or CRP. The risk is accumulated entirely among those at the very highest levels.”

Ridker called out several messages that could be applied going forward.

“We can't treat what we don't measure. While imaging tests can tell us who to treat, measurement of these biomarkers can tell us what to treat with. I think we have to marry these two ways of doing prevention together,” he said, drawing attention to the need for lifelong interventions that address lifetime risk.

Ridker concluded: “Given the remarkable consistency of the data I've just shown you in primary prevention, [along] with prior cohorts we and others have shown in 45,000 contemporary secondary prevention patients, we believe the time has probably come for universal screening of these three simple modifiable cardiovascular risk factors.”

A Compelling Concept

Annika Rosengren, MD, PhD (University of Gothenburg, Sweden), a co-chair of the session, praised the concept for its “simplicity” and inclusion of “only three biomarkers that everyone knows and has heard about.”

Roger S. Blumenthal, MD, and Seth S. Martin, MD (both from Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD), in an NEJM editorial, agree that taking a long-term view is “an attractive strategy since atherosclerosis begins early in life and progresses over decades.”

Though they offer some caveats—the Women’s Health Study participants tended to be healthier than many female patients, for instance, and statin therapy rose in use over the years—the editorialists say the fact that the links between biomarker levels and CV events spanned three decades “is powerful evidence of the importance of these measures for the prediction of risk.”

Moreover, the long-term view espoused here “is aligned with the growing focus on cardiovascular-kidney-metabolic health and the emergence of the PREVENT tool for estimating 30-year risk,” Blumenthal and Martin write.