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High Lp(a) Levels Harmful In Patients With And Without ASCVD

Elevated lipoprotein(a) increases the risk of major adverse cardiovascular events in patients with and without preexisting atherosclerotic cardiovascular disease (ASCVD), a new study shows.

The analysis, however, suggests there may be different thresholds for risk with heightened Lp(a) in these diverse patient populations, investigators say.

"When we use Lp(a) as a risk marker, it behaves quite differently between patients with ASCVD and patients without ASCVD," senior investigator Ron Blankstein, MD (Brigham and Women's Hospital, Boston, MA), told TCTMD. For those without ASCVD, for example, "the threshold of risk is only for those who have a very high Lp(a), above the 90th percentile, which in our study corresponded to roughly 216 nmol/L."

Blankstein said patients referred to specialty clinics because of elevated Lp(a) are often concerned about their risk of cardiovascular events, but that these new data can be reassuring.

"Not everybody who has a high Lp(a) is going to have an event," he said, noting that the event rates in patients without ASCVD are still quite low. In the primary-prevention patient, "unless they have a really high Lp(a), I think we can reassure some of those patients that their Lp(a) level is not that high," said Blankstein.

For patients with ASCVD, the risk of major adverse cardiovascular events plateaued at Lp(a) levels around 112 nmol/L, or more than 53 mg/dL, in the present study, "suggesting Lp(a) may be a marker of increased risk at an even lower level in secondary prevention," said Blankstein.

Right now, there's a lot of excitement in cardiovascular medicine about Lp(a), not just as a marker but also as a potential target for therapies that can lower it, said Blankstein. Lp(a) levels are highly determined by genetics, and it's been estimated that approximately 20% of the population have Lp(a) levels 50 mg/dL or higher (125 nmol/L), which is considered elevated. A number of studies, including genetic analyses, have shown that higher Lp(a) levels are linked with ASCVD and calcific aortic valve disease.

Not everybody who has a high Lp(a) is going to have an event. Ron Blankstein

There are two ongoing phase III clinical trials testing whether lowering Lp(a) reduces the risk of cardiovascular events. The Lp(a)HORIZON study is testing pelacarsen (Novartis/Ionis Pharmaceuticals), an antisense oligonucleotide, in patients with ASCVD and is furthest along, with results expected next year. The OCEAN(a)-Outcomes trial is testing olpasiran (Amgen), a small-interfering RNA that targets LPA, the gene that encodes for apolipoprotein(a), in patients with ASCVD but results aren't expected until late 2026 or beyond. 

"Just knowing that there are therapies on the horizon, we wanted to take a look at a large US cohort, to see what the association is between Lp(a) and outcomes," said Blankstein. "I think that's important because a lot of the [observational] outcome studies have been done outside the US and there may be some variability, perhaps, based on genetics and ancestry."

Mass General Brigham Lp(a) Registry

The new retrospective study, which was published yesterday in the Journal of the American College of Cardiology, included 16,419 individuals (median age 60 years; 41% women) with Lp(a) levels measured at the Brigham and Women's Hospital and Massachusetts General Hospital between 2000 and 2019. Of these, 62% of patients had a history of ASCVD, which was defined as a prior MI, coronary revascularization, or ischemic stroke. Those with a history of ASCVD had a higher median Lp(a) level than those without ASCVD (37.8 vs 31.1 nmol/L; P < 0.001), and the median follow-up time was 12 years.

For those with ASCVD, 53.3% had Lp(a) levels in the 1st to 50th percentile (0-41 nmol/L), 20.5% had levels in the 51st to 70th percentile (42-111 nmol/L), 18.0% in the 71st to 90th percentile (112-215 nmol/L), and 8.3% had levels in the 91st percentile and beyond (≥ 216 nmol/L). For those without ASCVD, the corresponding values were 58.0%, 17.9%, 17.1%, and 7.0%, respectively.  

The annual event rates for the primary composite endpoint of MI, coronary revascularization, ischemic stroke, or cardiovascular death across the four Lp(a) percentile groups (lowest to highest) were 4.1%, 4.9%, 5.3%, and 5.3% in patients with ASCVD at baseline. In those without ASCVD, the rates were 1.1%, 1.2%, 1.3%, and 2.2%, respectively.

In a fully adjusted model, the risk of the primary composite outcome in patients with ASCVD increased with higher Lp(a) levels but plateaued at approximately 70 nmol/L. In contrast, the risk of major adverse cardiovascular events increased linearly with rising Lp(a) levels in those without preexisting ASCVD, but the difference in risk was not statistically significant until the highest levels.

MACE Risk by Percentile of Lp(a): Adjusted HR (95% CI)

Percentile

ASCVD

(n = 10,181)

No ASCVD

(n = 6,238)

1st-50th

Reference

Reference

51st-70th

1.14 (1.05-1.24)

1.09 (0.90-1.32)

71st-90th

1.21 (1.11-1.32)

1.17 (0.97-1.41)

91st-100th

1.26 (1.12-1.41)

1.93 (1.54-2.42)

While there is no treatment available yet, European guidelines recommend measuring Lp(a) at least once in the patient's lifetime and US guidelines consider elevated Lp(a) to be a "risk-enhancing" feature.

"Right now, it's not widely adopted by everyone in the US," said Blankstein. "It's now used at least for risk assessment and our paper very much supports that, whether someone's already had a prior ASCVD event, in which case they fall into that secondary-prevention population, or if they've never had an event, in which case they fall under the primary-prevention umbrella."

In an editorial, Nathan Wong, (University of California, Irvine), PhD, like others before him, asks whether Lp(a) is ready for "prime time." Guidelines in the US still relegate screening to patients at high risk for ASCVD, such as those with a family history of premature disease. Wong, however, endorses universal Lp(a) screening, even before the outcomes trials are complete.

"But assuming positive results from ongoing cardiovascular outcomes trials for Lp(a), in order for treatment of elevated Lp(a) to have adequate population impact, we must do better to identify those at risk," he writes, noting that less than 1% are screened for elevated Lp(a) in the US. He adds that there can be as much a 10-year lag between guideline recommendations and widespread adoption.

"The failure to screen and identify those with Lp(a)-associated risks represents a missed opportunity to address this risk, not only with our existing repertoire of treatments but hopefully in the future with the development of promising therapies targeting Lp(a)," writes Wong.

Benefit Beyond Phase III Trials?

To TCTMD, Blankstein noted that both Lp(a)HORIZON and OCEANS(a)-Outcomes are secondary-prevention studies. In the former, patients were randomized to treatment if they had ASCVD and Lp(a) levels 70 mg/dL or higher (approximately 175 nmol/L), while OCEANS(a)-Outcomes randomized ASCVD patients with Lp(a) levels 200 nmol/L or higher during initial screening.

The results of this new analysis, however, suggest that benefit of Lp(a) reduction might extend to ASCVD patients with lower baseline Lp(a) levels than included in those two phase III trials, said Blankstein.

"Somebody asked me last week about this," said Blankstein. "They asked, 'Does this mean that those studies were conducted wrong?' Absolutely not. I think these are the first ever studies to try to prove the Lp(a) hypothesis—that lowering Lp(a) lowers risk—and I think it was appropriate to select the really high-risk patients. If those studies show that there is efficacy of these agents, then we'll need to think about whether those agents could be extended to people who have lower Lp(a)."

Universal Risk Tool Works Well In Both Primary And Secondary Prevention

A risk calculator that incorporates established cardiovascular risk factors and additional cardiac biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), accurately predicts the risk of future events in patients with and without established atherosclerotic cardiovascular disease (ASCVD), a new study shows.

Importantly, the universal risk assessment approach identified a significant proportion of individuals without preexisting ASCVD who had risks similar to or greater than what was seen in those with prior disease, say investigators.

"Using our equation, we observed that the top 20% of people without atherosclerotic cardiovascular disease actually have a higher risk than the bottom 40% of people with cardiovascular disease," senior investigator Kunihiro Matsushita, MD, PhD (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD), told TCTMD.

Matsushita said that for patients the universal approach could be helpful in quantifying risk across a lifetime.

"We believe it can provide an advantage in terms of more continuous care from before they have an event to after they have one," he said. "They are able to recognize a difference, for example, that before they developed cardiovascular disease their risk might be 5% but now it's 15% after developing it. In that case, they may be more motivated to change their lifestyle or adhere to treatment."

The universal approach is based on the awareness that there is substantial heterogeneity in risk among patients with and without ASCVD. For example, there are patients who have established ASCVD with excellent control of various risk factors, such as LDL cholesterol or blood pressure, while there are those without prior ASCVD who have an unhealthy lifestyle and/or hypercholesterolemia or hypertension.

At present, the American College of Cardiology and the American Heart Association (ACC/AHA) recommend the use of the pooled cohort equation (PCE) to identify primary-prevention patients who would benefit from lipid-lowering therapy or antihypertensive medication based on their 10-year risk of ASCVD. In secondary prevention, risk classification has largely focused on short-term prognosis in patients with preexisting ASCVD.

"The concept of primary and secondary prevention has been the cornerstone of guiding treatment," said Matsushita. "In the past, this made sense because people with cardiovascular disease had a really high risk while those without it had a much lower risk."

Matsushita pointed out that secondary-prevention therapies have improved dramatically in the last number of years and that it's more important now to risk stratify patients with preexisting disease to help select those who benefit from more aggressive treatment. Even the new cholesterol guidelines make a distinction between high and very high risk to guide treatment decisions with some of the more potent and expensive lipid-lowering medications. 

"Depending on the risk, the direction of treatment could be different," said Matsushita.

ASCVD Risk on a Spectrum

The new study, published online ahead of the February 6, 2024, issue of the Journal of the American College of Cardiology with Yejin Mok, PhD (Johns Hopkins Bloomberg School of Public Health), as lead author, explored the possibility of developing a long-term risk calculator for those with and without ASCVD. To do so, they evaluated whether established risk factors, as well as additional cardiac biomarkers, might be able to predict the risk of MI, stroke, and heart failure (HF) in the ARIC study cohort. To develop the model, they tested established risk factors from the PCE and considered various risk enhancers from the ACC/AHA cholesterol guidelines, as well as high-sensitivity cardiac troponin T (hs-cTnT), among others.

Over a median follow-up of 18.9 years, 3,209 participants (35%) developed MACE. In the base model, each risk factor was associated with a similar risk of MACE in those with and without ASCVD. In the LASSO regression analysis, the investigators identified 10 variables that universally predicted MACE in patients with and without ASCVD, including age, diabetes, systolic blood pressure, antihypertensive medication, smoking status, hs-CRP, NT-proBNP, and hs-cTnT. The model also included interactions between age and total cholesterol with history of ASCVD.  

Overall, the C-statistic for predicting MACE with the model was 0.747 for patients without ASCVD and 0.691 for those with preexisting disease. The model also had good calibration in both cohorts (calibration slope 1.05 and 0.92 in the no-ASCVD and ASCVD groups, respectively). The risk model was also validated in 5,322 patients enrolled in the MESA study.

"These C-statistics are similar to the existing risk prediction models that we are using," said Matsushita.

For clinicians, one advantage is that the calculator will allow them to identify patients without ASCVD who have a future predicted risk akin to someone with a history of disease. This concept is not completely new, said Matsushita, noting that a diagnosis of diabetes is considered a risk equivalent that shifts patients into a higher-risk bucket even without an ASCVD diagnosis. In secondary prevention, the calculator gives doctors a better sense of longer-term risk prediction that isn't present with existing calculators.

In an editorial, Pier Sergio Saba, MD, PhD (Sassari University Hospital, Italy), along with Sadeer Al-Kindi, MD, and Khurram Nasir, MD, MPH (both Houston Methodist DeBakey Heart & Vascular Center, Texas), write that a universal assessment of risk across the spectrum would be a beneficial contribution to cardiovascular care. Given the wide variation of risk within the primary- and secondary-prevention buckets, a binary, categorical classification system is too simplistic, they write, adding that this continuous-risk concept could allow doctors to intensify treatment in the absence of ASCVD.

Like Matsushita, the editorialists say the model needs to be validated in prospective cohort studies and real-world patients, and that it should be compared with existing models. Additionally, given the use of cardiac biomarkers, a careful cost-benefit analysis is necessary. Still, they believe that universal risk assessment could also have an impact in the design of future research trials, noting that investigators can also move away from binary ASCVD/no-ASCVD inclusion criteria.

10 FAQs About Treatment For High Cholesterol, Answered

If you've been diagnosed with high cholesterol, your first step is to make lifestyle changes, such as eating a heart-healthy diet and getting regular exercise.

But, if lifestyle changes alone aren't enough to lower your level of low-density lipoprotein (LDL, or "bad") cholesterol and boost your level of high-density lipoprotein (HDL, or "good") cholesterol, you may need to talk to your doctor about prescription medications designed to help you control your cholesterol.

If it's your first time taking cholesterol medication, you'll likely have questions about your new treatment. Here are some common questions to consider asking your doctor — and a brief summary of how they may respond.

1. What Are the Target Levels for LDL and HDL Cholesterol?

Before learning what target cholesterol levels are, it helps to understand the different types of cholesterol, a waxy, fatlike substance made by your liver and also found in certain foods. LDL is known as the bad cholesterol, because it can build up in your arteries, increasing your risk of heart attack and stroke. HDL removes LDL from arteries and carries it back to the liver, where it's broken down and flushed from your body.

According to the Centers for Disease Control and Prevention (CDC), the target LDL level for most adults is less than 100 milligrams per deciliter (mg/dL), and the HDL target is 40 mg/dL or higher for men and 50 mg/dL or higher for women. They also recommend a total cholesterol level of 125 to 200 mg/dL. Total cholesterol is calculated by adding up your LDL and HDL, plus 20 percent of your level of triglycerides — another type of fat that can raise heart disease risk.

But, most cardiologists focus less on these numbers and more on your risk of heart disease when managing cholesterol, according to Peter Schulman, MD, an attending cardiologist and professor of medicine at University of Connecticut Health in Farmington. "We don't really require specific numbers anymore, because the research on LDL levels to date has been inconclusive," he explains. Still, depending on your age and overall health, if your LDL and total cholesterol are above the recommended targets, you should talk to your doctor about how you can improve them.

2. How Will I Know if I Need Medication to Treat My Cholesterol?

These days, most cardiologists will determine your need for cholesterol-lowering drugs based on your risk of heart disease and stroke, using a tool called the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator Plus. The tool is available online and as a mobile app, but it's best to use the calculator with your doctor, Dr. Schulman says. The calculator measures your 10-year risk of coronary artery disease, heart attack, and stroke by taking into account your age, blood pressure, cholesterol, and other factors, such as whether you have diabetes or are being treated for high blood pressure. Generally, if your ASCVD risk is 7.5 percent or higher, your doctor will recommend cholesterol-lowering drugs, Schulman says. Also, if you've had a heart attack or stroke, or you have coronary artery disease, "You should be on a cholesterol-lowering medication to reduce your risk of having another heart problem in the future," he adds.

3. What Medications Are Available to Treat High Cholesterol? How Do They Work?

If diet and exercise aren't enough to help you maintain healthy cholesterol levels, the American Heart Association (AHA) recommends treatment with drugs called statins. They work in the liver to prevent cholesterol from forming and reduce the amount of cholesterol circulating in your blood, according to the AHA. They're most effective at lowering LDL levels but can also help reduce triglycerides and raise HDL. The AHA recommends statins for adults with a history of heart disease or stroke caused by atherosclerosis, as well as adults ages 40 to 75 with high cholesterol. If your LDL levels are over 190 mg/dL while taking statins, your doctor may recommend "high-intensity" (high-dose) statin treatment, with the goal of dropping your bad cholesterol by 50 percent or more.

If statins are insufficient or not well tolerated, other cholesterol-lowering drugs may be prescribed. These include PCSK9 inhibitors, which remove cholesterol from the blood; selective cholesterol absorption inhibitors, which prevent cholesterol from being absorbed in the intestines; and resins or bile acid–binding drugs, which help the intestines increase cholesterol disposal. In addition, fibrates, niacin, and omega-3 fatty acid–based medications can be used to boost HDL and reduce triglycerides. All of these non-statin drugs can be used alone or in combination with statins to manage cholesterol. Your doctor will help you determine which medication, or combination of medications, is right for you.

4. How Often Should I Have My Cholesterol Levels Tested?

Once you've started a new treatment plan to manage your cholesterol, your doctor should check your levels in 4 to 12 weeks, using a fasting or non-fasting lipid test, according to the AHA. After that, they'll likely monitor your levels every 3 to 12 months, depending on how well you're doing. These evaluations will focus on the amount you've reduced your LDL levels, rather than the levels themselves, the AHA notes. The percentage reduction in LDL cholesterol will give your doctor a snapshot of how your new treatment is working.

5. Do Cholesterol Medications Have Side Effects?

Muscle pain may be the most common side effect of statins, Schulman says. This pain may range from mild soreness, tiredness, or weakness in your muscles to severe pain that makes your daily activities difficult, according to Mayo Clinic.

That said, research hasn't yet clearly tied muscle symptoms to statins, and doctors emphasize the cardiovascular benefits of these medications. One review found that there isn't any strong evidence to show that statins can cause muscle pain. And in another review, the study authors noted that while statins were found to cause some mostly mild pain in participants, the risk of muscle symptoms was small, compared with the cardiovascular benefits that would be gained.

In very few cases, statins may cause a muscle-damaging condition called rhabdomyolysis or increase inflammation in the liver. In addition, most statins include a U.S. Food and Drug Administration (FDA) warning on their labels indicating that the drugs may cause memory loss or confusion. In some older adults — 85 and up — the risk of memory loss may outweigh any health effects associated with high cholesterol, Schulman says. For them, Schulman recommends a lower statin dose or an alternative drug.

Finally, statins may also increase blood sugar levels in people with diabetes, according to the CDC. The risk of these side effects is generally low and varies from person to person, so you should talk to your doctor about whether the benefits of taking these drugs — lowering cholesterol and helping prevent heart attack and stroke — make the risks worthwhile.

Non-statin drugs generally have gastrointestinal-related side effects, such as nausea, vomiting, upset stomach, gas, and constipation, as well as muscle pain and headaches. In general, the risk of these side effects is very low, Mayo Clinic says. In addition, if you're pregnant or planning to become pregnant, talk to your doctor about whether it's safe to continue taking your cholesterol-lowering medication.

6. Can I Stop Taking Cholesterol Medication Once My LDL Level Comes Down?

Once your doctor prescribes a statin, you'll likely be on the drug for the rest of your life, according to Cleveland Clinic, because your LDL would likely rise within a few weeks of stopping the medication. If you're experiencing side effects, your doctor may adjust your dose or switch you to another statin or medication. "Studies suggest that you can still get about 70 percent of the cholesterol-lowering benefits of statins even if you take them only two or three times per week, instead of daily," Schulman explains.

One study found that taking statins intermittently, from alternating days to once a week, was still effective in lowering LDL. If you have or develop other health conditions, such as liver disease, that make statin use risky, your doctor may prescribe an alternative, such as injectable PCSK9 inhibitors, which are administered with a small needle every two weeks. These drugs are expensive but work well in people who can't tolerate statins, Schulman says. Still, you and your doctor will need to work out a plan for discontinuing statin treatment safely. You should never stop taking medication without talking to your doctor.

7. Can Other Medications, Supplements, or Foods Interfere With Cholesterol Medication?

Some medications may cause statins to not work as well or rise to harmful levels in your blood, the AHA says. But, just because you're on one of these medications doesn't mean you can't take a statin. Instead, your doctor may want to monitor you more frequently or lower your statin dose, Schulman explains. Examples of drugs that may interfere with statins, according to the AHA, include antibiotics and antifungals used to treat infections; prescription and over-the-counter antacids; high blood pressure medications; and oral contraceptives. If you're taking any of these, be sure to tell your doctor before starting a statin.

Grapefruit and grapefruit juice can also have negative effects on some statins, Schulman notes. Generally, this can be avoided by not consuming the fruit or its juice at the same time you take your statin dose.

8. Do I Still Need to Exercise and Watch My Diet if I'm Taking Cholesterol Medication?

The short answer is yes. You'll still need to exercise regularly and eat a heart-healthy diet rich in fruits, vegetables, whole grains, and lean protein and low in saturated and trans fats, even while taking medication to lower LDL, the AHA says. Other lifestyle changes that can help lower cholesterol include quitting smoking and losing excess weight.

9. Can Complementary Therapies Help Manage High Cholesterol?

According to Mayo Clinic, there are few natural products that have been shown to lower cholesterol, but some supplements may also be helpful. Just as omega-3 fatty acid–based drugs can help treat high cholesterol, so, too, can over-the-counter supplements containing this nutrient.

Foods such as salmon are also an excellent source of omega-3s. In addition, red yeast rice supplements may also lower LDL and total cholesterol, Schulman says. In fact, it contains a compound similar to what's found in prescription statins. "A lot of people use red yeast rice because they don't want to take a statin, but they're basically taking a statin anyway," he notes. "People who can tolerate red yeast rice, in terms of any side effects, can often tolerate statins."

The only disadvantage of using supplements containing omega-3s or red yeast rice is that these products aren't regulated by the FDA. "So, you have no idea how much of them you're actually taking," Schulman adds. You should always talk to your doctor before trying a supplement or other complementary therapy, to ensure it's safe for you.

10. Might My Treatment Plan Change if I Experience a Complication, Such As a Heart Attack?

In general, cholesterol-lowering drugs lower your risk of heart attack or stroke, but they don't eliminate it, according to the AHA. If you have a heart attack or stroke while taking statins, it's possible the drugs alone aren't working well enough to control your cholesterol. Or, you may have developed another health condition that increases your risk of heart disease, such as high blood pressure or type 2 diabetes. Either way, it's likely that if your overall health changes, your doctor will want to reevaluate your treatment plan and either adjust your statin dose or change the medication you're taking, Schulman says.

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