High Lp(a) Linked to ASCVD Risk Even When LDL Cholesterol Is Low

Among people with low levels of LDL cholesterol—even those who achieve very large absolute reductions with statin therapy—higher levels of lipoprotein(a) are associated with an increased risk of cardiovascular disease events, a new meta-analysis shows.

The study, say investigators, suggests that reducing LDL cholesterol with lipid-lowering therapies will not be enough to offset the risk associated with atherogenic Lp(a).

“You can control LDL cholesterol-mediated risk and you'll have a benefit, but at each level of LDL, you'll have a higher risk if your Lp(a) is elevated,” senior investigator Sotirios Tsimikas, MD (University of California San Diego), told TCTMD. “In other words, you won't get all the benefit you might get from a statin if your Lp(a) is elevated.”

Lead author Harpreet S. Bhatia, MD (University of California San Diego), said their findings were consistent no matter how they looked at the data. Even among patients with LDL-cholesterol levels close to 70 mg/dL, those with Lp(a) exceeding 50 mg/dL had a higher risk of atherosclerotic cardiovascular disease (ASCVD) events.  

“Even though we get the LDL down as low as we could with the statins that were used in these trials, the risk still persists with the high Lp(a),” Bhatia told TCTMD. “It fits with our thought that Lp(a) is going to be an important independent target down the road.”

Lp(a) is a large lipoprotein similar to LDL, but the structure contains apolipoprotein(a) linked to apolipoprotein B-100. Largely genetically determined, Lp(a) has been shown to be an independent predictor of ASCVD risk and calcific aortic stenosis. Several genetic studies have shown a causal relationship between high levels of Lp(a) and cardiovascular disease and there are multiple therapies in development to treat and lower it.

In the US guidelines, Lp(a) is considered a “risk enhancer,” a surrogate that can help with treatment decisions for selected patients. In the absence of available therapies, some guidelines, such as those from the National Lipid Association and European Atherosclerosis Society, recommend being more aggressive with LDL lowering to offset the risk associated with high Lp(a). 

“Historically, the thought was that if you control LDL, you don't need to worry about Lp(a),” said Tsimikas. “A lot of clinicians grew up believing that for the last two decades.”

The reason for such thinking, he added, stemmed from a small angiographic study suggesting that if LDL levels were tightly controlled, there was no progression of disease evident in the lumen. However, Tsimikas said that plaque can still be present in the artery, growing outward and expanding without luminal stenosis. Several studies in recent years have largely debunked the idea that LDL cholesterol only matters in those with elevated Lp(a), while other studies show that cardiovascular risk is still elevated in statin-treated patients if their high Lp(a) is high, say investigators.  

Both LDL and Lp(a) Matter

For their study, published in Circulation, the researchers wanted to better understand the interaction between LDL-cholesterol levels and Lp(a) for ASCVD risk. They performed a meta-analysis of six randomized, placebo-controlled trials of statin therapy—4D, 4S, CARDS, JUPITER, LIPID, and MIRACL—with 27,658 patients who had complete Lp(a) and LDL cholesterol data. The mean Lp(a) levels across the studies ranged 9.00 mg/dL in CARDS to 13.9 in LIPID, while the achieved LDL-cholesterol level with statin therapy ranged from 61.2 mg/dL in JUPITER to 125.4 mg/dL in 4S.

Baseline Lp(a) and LDL-cholesterol levels each were independently associated with ASCVD risk overall. The risk of ASCVD associated with Lp(a) was modeled in multivariate-adjusted models with a reference Lp(a) level of 5 mg/dL. Above this threshold, the risk associated with Lp(a) increased in a log-linear fashion in both the placebo- and statin-treated patients.

You won't get all the benefit you might get from a statin if your Lp(a) is elevated. Sotirios Tsimikas

Across all quartiles of achieved LDL cholesterol with statin therapy, those with elevated Lp(a) levels (> 50 mg/dL) had a higher risk of ASCVD events when compared with those with normal Lp(a) levels (≤ 50 mg/dL). The increased relative risk associated with elevated Lp(a) ranged from 38% higher in those with the lowest achieved LDL-cholesterol levels (Q1: 3.1 to 77.0 mg/dL) to 90% higher in those with the highest LDL levels (Q4: > 140.7 mg/dL).  

In a similar analysis that focused on the absolute change in LDL cholesterol with statin therapy, an increased risk of ASCVD was also observed with elevated Lp(a). In those with the largest absolute reduction in LDL, which ranged from a 52- to 193-mg/dL decrease, the relative risk of ASCVD was 28% higher in those with elevated Lp(a) compared with patients who achieved similar absolute reductions and had low Lp(a) levels. Even in the group of patients with the smallest absolute change in LDL, those with elevated Lp(a) were at heightened risk for ASCVD. 

“Whether you look at achieved or the absolute change in LDL, at each one of those levels, if Lp(a) is elevated, cardiovascular risk continues to accrue,” said Tsimikas. “The implication is you have to treat both. You can't now say: treat the LDL and don't worry about your Lp(a). You have to treat LDL for the LDL-mediated risk, but you have to address the Lp(a)-mediated risk as an independent variable.”  

Slope of the Risk Curve

One interesting aspect of the analysis, said Tsimikas, is that while the risk associated with Lp(a) increased in a log-linear fashion in both the placebo- and statin-treated patients, the relationship of risk seemed to be more pronounced in the statin-treated patients.

“The slope [of ASCVD risk] seems to be a little higher for statin-treated patients than placebo-treated patients,” he said. “I think the explanation for that is that when you treat with a statin, you get rid of the LDL-mediated risk and what’s remaining is the Lp(a)-mediated risk. That seems to be the driver of the relationship.”

Tsimikas also noted that statins tend to increase Lp(a), but it’s unknown if this increase is clinically relevant. He emphasized that if patients have an indication for statin therapy, regardless of Lp(a) levels, they should take it because doing so will lower their risk of ASCVD. “We should definitely make sure that people follow the guidelines until we understand this more and then we can give more nuanced recommendations,” he said.

It fits with our thought that Lp(a) is going to be an important independent target down the road. Harpreet S. Bhatia

With the Lp(a)HORIZON trial, which started in 2019 and completed enrollment in 2022, investigators are testing whether the antisense oligonucleotide pelacarsen (Ionis/Novartis Pharmaceuticals) can reduce the risk of major adverse cardiovascular events in more than 8,000 patients with elevated Lp(a) and CVD. The trial will be completed in 2025. While pelacarsen is leading the pack, other Lp(a)-lowering therapies are also being developed, including the small-interfering RNA technologies lepodisiran (Eli Lilly), olpasiran (Amgen), and zerlasiran (Silence Therapeutics). Muvalaplin, a selective, small molecule inhibitor of Lp(a), is an oral agent in development.

Bhatia said that he broadly measures Lp(a) in his patients even though there are no approved Lp(a)-lowering therapies yet. Knowing the number can help individualize patient risk, he said, noting that in those with high Lp(a) the goal is to get other risk factors under control and to emphasize lifestyle changes, such as exercise and a healthy diet.

In terms of pharmacotherapy, PCSK9 inhibitors can reduce Lp(a) levels, said Bhatia, and there are secondary analyses from various trials showing that the incremental benefit of those drugs may be attributable to the effect on Lp(a). Aspirin is also an option for some high-risk patients with elevated Lp(a).

“Lp(a) appears to be prothrombotic and to have some possible proplatelet effects, so aspirin may have a particular benefit in that situation.,” said Bhatia. “If someone is at low risk of bleeding, I go over the data, and there's limitations to it for sure—it’s not something that's been studied yet in a big, randomized trial—but I will offer it to patients.”

He noted that many of the existing efforts are simply a bridge as clinicians await the results from the ongoing clinical trials. Beyond treatment, however, measuring Lp(a) routinely can also help with cascade screening and with directing select patients into the ongoing randomized trials.