High Lp(a) warrants intervention, even without other cardiovascular risk factors

A new study shows that the oft-ignored metric is strongly associated with heart attacks, regardless of the presence or absence of standard modifiable risk factors for cardiovascular disease

Peter Attia

Read Time 4 minutes

When considering how to assess and reduce one’s risk of chronic disease, it’s often tempting to focus solely on modifiable risk factors. For instance, we can quit smoking, lose excess fat mass, or take medications to reduce elevated blood pressure or cholesterol levels. But when it comes to risk assessments and management strategies for cardiovascular disease (CVD), one non-modifiable factor should never be ignored: lipoprotein(a), known more commonly as Lp(a).

As explained on the podcast by Dr. Benoit Arsenault, elevated Lp(a) is the single most important – and most prevalent – hereditary risk factor for CVD, yet we currently lack any simple means of addressing it therapeutically. Indeed, in the absence of options for reducing high Lp(a), many physicians do not even bother to test this variable. But results from a new study highlight just how critical Lp(a) is for CVD risk assessment – and how, despite the lack of options for modifying one’s Lp(a) levels, this metric can nevertheless have substantial implications for risk management decisions.

Study design and cohort

The retrospective study by Shiyovich et al. investigated the association between Lp(a) and incident acute myocardial infarction (MI, otherwise known as a heart attack), as well as how this association was related to standard modifiable risk factors (SMuRFs) for heart disease.¹ (I will admit, it is a bit difficult for me to keep writing the word “SMuRFs” without thinking of, well, you know.) The researchers utilized data from 6,238 adults (mean age: 54; 45% female) who had undergone routine Lp(a) testing in the Boston area between January 2000 and July 2019 (derived from the Mass General Brigham Lp(a) Registry). Data from individuals with severe kidney dysfunction, cancer, or prior known atherosclerotic cardiovascular disease were excluded from the study. Participants were followed for a median of 8.8 years to assess incidence of fatal or non-fatal MI.

Participants were classified as having “high Lp(a)” if their Lp(a) levels exceeded the 90th percentile (based on established whole-population reference ranges) or “low Lp(a)” if their Lp(a) levels were below the 50th percentile, corresponding to >168 nmol/L and <19 nmol/L for high and low cutoffs, respectively. Overall, Lp(a) levels among participants were slightly lower than those of the general population, with 58% of participants meeting the definition of low Lp(a) and 7% of participants meeting the definition of high Lp(a).

SMURFs were defined as hypertension, smoking, diabetes, or non-Lp(a) dyslipidemia, with non-Lp(a) dyslipidemia being defined as: 1) total cholesterol ≥240 mg/dL; (2) LDL cholesterol ≥160 mg/dL; (3) HDL cholesterol <40 mg/dL in men or <50 mg/dL in women; or (5) total triglycerides ≥175 mg/dL. Notably, a fairly large proportion of participants (23.7%) had no SMuRFs, while 17.8% had at least three. As numbers of SMuRFs increased, rates of high Lp(a) also increased modestly, and rates of low Lp(a) decreased.

Heart attack risk increases with SMuRFs and high Lp(a) 

The authors reported that a total of 234 participants (3.75%) experienced an acute MI over the follow-up period. As expected, a higher number of SMuRFs was associated with increased risk of incident MI across the entire cohort, with two SMuRFs corresponding to a threefold increase in risk relative to no SMuRFs (HR=3.05; 95% CI: 1.93-4.83; P<0.001) and ≥3 SMuRFs corresponding to a 6.5-fold increase in risk (HR=6.51; 95% CI: 4.18-10.16; P<0.001). This trend persisted when low-Lp(a) and high-Lp(a) subgroups were analyzed independently. Not really surprising. 

But the most critical finding from the study was that high Lp(a) was associated with a greater risk of MI than low Lp(a) across all numbers of SMuRFs (see Figure below), indicating that elevated Lp(a) is a major risk factor for heart attack regardless of the presence or absence of other risk factors. Indeed, Shiyovich et al. reported that risk among those with high Lp(a) was over 3x that of those with low Lp(a) (HR=3.19; 95% CI: 2.20-4.65; P<0.001), making the increased risk imparted by high Lp(a) equivalent to the increase in risk associated with having two SMuRFs.

Figure: Incidence rates of acute myocardial infarction for subgroups defined by the number of standard modifiable risk factors (SMuRFs) and low versus high Lp(a). Error bars represent 95% confidence intervals. Green arrow shows how high Lp(a) imparts an excess risk comparable to that associated with two SMuRFs. Modified from Shiyovich et al. 2024.

How does this impact CVD risk management decisions?

These results indicate that high Lp(a) is a major risk factor for CVD no matter what other risk factors a patient may or may not have, and therefore, patients with high Lp(a) should always be treated aggressively. But as we mentioned earlier, we lack pharmacological or behavioral options for reducing Lp(a) levels. (Some physicians use PCSK9 inhibitors off-label to lower Lp(a) by ~25%, but results are highly variable, and this level of Lp(a) reduction may not be sufficient to significantly reduce CVD risk.) So although this study confirms the strong association between elevated Lp(a) and risk of cardiovascular events, is there any practical utility to this knowledge? Is it worth it to find out you have high Lp(a) if you can’t do anything to lower it?

Absolutely. While we may not be able to reduce Lp(a) itself, we can reduce overall CVD risk by treating other CVD risk factors. The discovery that a particular patient has high Lp(a) can thus serve as a sign that hypertension, diabetes, and especially elevated apoB levels (or less accurately, LDL-C) should be managed more aggressively than they otherwise might be in order to offset the risk imparted by Lp(a).

The bottom line

The study by Shiyovich et al. underscores that high Lp(a) is a major, hereditary risk factor for atherosclerotic cardiovascular disease, even among those with no other red flags, yet many who have high Lp(a) are unaware of it due to the fact that this metric is often ignored and undertested. Fortunately, awareness of the importance of Lp(a) for CVD risk is growing; an increasing number of healthcare facilities test for this variable, and several companies have even begun to market direct-to-consumer, at-home Lp(a) test kits. But ultimately, simply knowing one has high Lp(a) is just the first step. To reduce risk of CVD events, this information must be used to motivate more aggressive approaches toward other, modifiable risk factors.


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1. Shiyovich A, Berman AN, Besser SA, et al. Association of Lipoprotein (a) and Standard Modifiable Cardiovascular Risk Factors With Incident Myocardial Infarction: The Mass General Brigham Lp(a) Registry. J Am Heart Assoc. 2024;13(10):e034493. doi:10.1161/JAHA.123.034493

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