Non-Statin Therapies for Patients at High Risk for Cardiovascular Disease

Erin Michos, MD, MHS, opens a discussion surrounding the utilization of bempedoic acid for patients with intolerance to statin-based therapies.

Erin Michos, MD, MHS: Hi, I’m Dr Erin Michos. I’m the associate director of preventive cardiology at Johns Hopkins University School of Medicine [in Baltimore, Maryland]. Welcome to this AJMC® Post Conference Perspectives about the ACC [American College of Cardiology] Annual Scientific Session in conjunction with the World Congress of Cardiology. This was an exciting meeting that I was happy to be part of, with a lot of great science about the lipid field, as well as some great implementation science. We’ll cover some of those studies.

The first trial I want to discuss is something we’ve been awaiting for a while: the cardiovascular outcome trial for bempedoic acid, called CLEAR Outcomes. The background for this is that many high-risk patients with ASCVD [atherosclerotic cardiovascular disease] or at high risk for ASCVD are not at LDL [low-density lipoprotein] goal. Unfortunately, statin intolerance or perceived intolerance is a very common problem in clinical practice. It limits the ability of many high-risk patients not to be effectively treated.

This trial enrolled nearly 14,000 individuals who had cardiovascular disease, two-thirds with secondary prevention, or high risk for cardiovascular disease, one-third with primary prevention. All had statin intolerance or could take only a low-dose statin. They had to sign a form that they know that statins are beneficial for cardiovascular disease, but they’re unable to take them. Everybody had to have an LDL above 100 mg/dL to get in, indicating they had significant residual risk related to their LDL cholesterol.

They’re randomized to bempedoic acid vs placebo. Bempedoic acid is an oral medication that inhibits cholesterol synthesis in the same pathway as statins. But it’s a pro-drug, so it’s activated only in the liver and does not confer the same muscle adverse effects that we see with statins. Over 40 months, those randomized to bempedoic acid compared with placebo experienced a 13% reduction in 4-point major adverse cardiovascular events [MACEs]. There also was a 15% reduction in 3-point MACE, which is cardiovascular death, nonfatal MI [myocardial infarction], and nonfatal stroke. There was also a reduction in myocardial infarction. This was translated by the fact that bempedoic acid conferred a 21% reduction in LDL cholesterol, about 29 mg/dL. This LDL reduction did translate to meaningful reductions in cardiovascular events.

One thing I was excited about in this trial was that 48% [of the participants] were women. Historically, cardiovascular clinical trials underenroll female patients, so there was a near parity in this trial. That’s because women are more likely than men to experience statin adverse effects and have statin intolerance. This is an important clinical question.

The other thing that was notable is that the benefit was as large or even larger in the primary prevention group, where the hazard ratio for MACE for bempedoic acid compared with placebo was 0.68. That was pretty substantial. This is important because, for secondary prevention patients, we have a lot more other tools—like PCSK9 inhibitors or inclisiran—but we have fewer nonstatin options for primary prevention patients. I was very excited to have a new tool in the toolkit.

Just a couple of notes about adverse effects. First, it was reassuring that there was no increased risk of tendon rupture. Some of the earlier studies with this agent suggested an increased risk of tendon rupture, and that was in the FDA label as a possible adverse effect. There wasn’t any mechanism for it, and I was relieved in this 14,000-person trial that we saw no signal for tendon rupture, so we can put that question to rest. There was also no increased risk of new-onset diabetes. We do see an increased risk of new-onset diabetes with statins and in high-risk patients, particularly at higher doses. Patients are often very concerned about that, but we saw no excess diabetes risk with bempedoic acid.

As we’ve seen in earlier studies of bempedoic acid, there was a slightly increased risk of gout. It was 3.1% with bempedoic acid vs 2.1% with placebo, and there was a slight 1% increased risk in cholelithiasis. That’s because this trial enrolled so many women who had diabetes and obesity that we might see this signal. But it was very modest. Overall, it’s very exciting to find another nonstatin agent and an oral agent that can reduce major cardiovascular events that isn’t a statin.

I liked the 2022 ACC Expert Consensus Decision Pathway, which outlined how to implement nonstatin therapies among certain patient risk groups. It starts with risk assessment. We have different thresholds for adding nonstatin therapy based on a patient’s risk. For patients in that very high-risk group—ASCVD at very high risk, such as those who’ve had a recent acute coronary syndrome, stroke myocardial infarction, or a symptomatic peripheral arterial disease with other risk-enhancing factors—we want to get the LDL to less than 55 mg/dL. If patients are reporting statin intolerance, we don’t have to try all the statins and all the doses and all the varying combinations. You can move on pretty quickly to add nonstatin agents to try to get patients at very high risk down to goal, although statins should always be tried because many patients can have partial intolerance and still have some statins on board.

In the expert contention decision pathway, for these very high-risk patients, once you’re on the maximum tolerated statin, if you’re still above these LDL thresholds, they recommended PCSK9 monoclonal antibodies or ezetimibe. They also have a consideration that you could consider using inclisiran instead of the monoclonal antibody PCSK9, or bempedoic acid could be an additional consideration. But every time you add a nonstatin, it’s important that you continue to follow the LDL to monitor adherence and make sure you’re achieving the goals that you hope to. If you’re unable to achieve these goals as recommended, you can refer patients to a lipid specialist as well as a registered dietitian.

Transcript edited for clarity.

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