Big Reductions in ASCVD Events With Bempedoic Acid in Primary Prevention

While there can be a debate over the effect size, or the reduction in mortality, experts say the drug fills an unmet need.

Big Reductions in ASCVD Events With Bempedoic Acid in Primary Prevention

Treating high-risk, statin-intolerant patients without a prior cardiovascular event with bempedoic acid (Nexletol; Esperion) leads to a significant reduction in their risk of atherosclerotic cardiovascular disease (ASCVD), according to a primary prevention analysis from the CLEAR Outcomes study.

In this subgroup, treatment with bempedoic acid cut the risk of the primary composite endpoint of cardiovascular mortality, nonfatal MI, nonfatal stroke, or coronary revascularization by approximately one-third when compared with placebo.

The new results, which were published recently in JAMA, underscore the importance of treating primary prevention patients at high risk for future ASCVD events, according to researchers.

“I see this study as a wake-up call,” lead investigator Steven Nissen, MD (Cleveland Clinic, OH), told TCTMD. “It tells us that we really need to do a better job of identifying and treating high-risk, primary prevention patients.”

The full CLEAR Outcomes results, released earlier this year, included 13,970 primary and secondary prevention patients intolerant to statin therapy at high risk for ASCVD. In the overall cohort, bempedoic acid reduced the absolute risk of the primary endpoint by 1.6%, which translated into a 13% relative reduction in risk.

This week’s new analysis focuses solely on 4,206 trial participants who had not had a prior cardiovascular event, of whom two-thirds had diabetes. Mean LDL-cholesterol level at baseline was 142.4 mg/dL. In these patients, LDL levels were reduced by 30.2 mg/dL more with bempedoic acid than with placebo. Similarly, treatment also reduced high-sensitivity C-reactive protein (CRP) levels by 0.56 mg/L more compared with placebo.

I will reiterate—this is not a substitute for statins. Steven Nissen

Michael Blaha, MD (Johns Hopkins University, Baltimore, MD), who wasn’t involved in the study, believes the new findings are important given the challenges of treating these high-risk patients who are unable to tolerate a statin. “The results are very clinically welcome to show that we can reduce LDL cholesterol and reduce [ASCVD] events in this group,” he told TCTMD. 

When it comes to the magnitude of event reduction with bempedoic acid seen here—as well as the reductions in some of the individual endpoints, such as mortality—Blaha said the results should be interpreted cautiously.

“I’m quite skeptical of the size of the effect in light of what we saw in the overall trial,” he said. “But I don’t think you really need to hang your hat on these other outcomes, like mortality, to be really excited about the findings because of the patient population. They’re tough to treat and don’t have a lot of options. Any sort of event reduction is welcome here.” 

Salim Virani, MD (Baylor College of Medicine, Houston, TX, and Aga Khan University, Karachi, Pakistan), who also was not involved with CLEAR Outcomes, said the new analysis provides encouraging data on the benefits of bempedoic acid in the primary prevention setting, noting that it “provides more evidence-based choice beyond statin therapy.”

Like Blaha, he urged caution interpreting the results, particularly when comparing the magnitude of benefit in the primary and secondary prevention patients. Here, unlike in other studies, the benefit of treatment was larger in primary prevention than what was observed in secondary prevention patients who made up the bulk of the randomized trial. “The results are encouraging, and we’re always hopeful to have more options as clinicians,” Virani said. “But you do have to careful in not overinterpreting the results, because it is a subgroup of a large trial.”

CLEAR Outcomes


Bempedoic Acid

(n = 2,100)


(n = 2,106)


(95% CI)

Primary Endpoint: CV Death, Nonfatal MI, Nonfatal Stroke, or Coronary Revascularization (5-Component MACE)





CV Death, Nonfatal MI, or Nonfatal Stroke (3-Component MACE)





CV Death, Nonfatal MI, Nonfatal Stroke, Coronary Revascularization, or Hospitalization for Unstable Angina (5-Component MACE)





After a median follow-up of 39.9 months, treatment with bempedoic acid reduced the risk of the 4-component MACE endpoint 30%—an absolute reduction of 2.3%—compared with placebo. This translated into a number needed to treat (NNT) of 43 to prevent one event. For the 3-component MACE endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, the absolute reduction in risk was 2.4% and the NNT was 42.

Additionally, there was a significant 39% relative reduction, or 0.8% absolute reduction, in the risk of fatal and nonfatal MI. Treatment with bempedoic acid had no significant effect on the risk of nonfatal stroke, coronary revascularization, or hospitalization for stable angina.

“These are very striking results,” said Nissen. “We haven’t seen data on lipid-lowering drugs in primary prevention for a very long time.”

The last study was JUPITER, a 2008 randomized trial that showed the value of lowering LDL-cholesterol levels with rosuvastatin in primary prevention patients with elevated high-sensitivity CRP levels. In that study, which was stopped early, rosuvastatin reduced the risk of MACE by 44% when compared with placebo-treated patients.

Despite those striking benefits, statins remain underused in high-risk patients without a prior event in the United States, Nissen noted. In one registry of nearly 50,000 patients with LDL levels exceeding 190 mg/dL, more than 40% weren’t even taking a statin, he said. European data also show that high-risk, primary prevention patients aren’t being adequately treated to LDL-cholesterol targets outlined in the guidelines.

“We’re doing a good job getting people treated in secondary prevention, but we’re not doing a good job in primary prevention,” said Nissen. “We need to get the message to people that high-risk, primary prevention patients need treatment, particularly if they have diabetes.”

In this primary prevention subgroup, investigators saw no significant difference in the risk of serious treatment-emergent adverse events (AEs) or AEs warranting drug stoppage. Hyperuricemia was more common with bempedoic acid (12.1% vs 6.3% with placebo), as was the incidence of gout (2.6% vs 2.0%). Treatment also led to a higher incidence of cholelithiasis (2.5% vs 1.1%), as well as increases in creatinine and hepatic enzyme levels.

Nissen pointed out that the number of patients who discontinued treatment because of myalgias, a reported side effect of statins, was lower with bempedoic acid than with placebo. 

Mortality Benefit Observed Here

Of note, investigators observed a significant reduction in mortality with treatment in the primary prevention subgroup—something not seen in the overall trial: an absolute 1.6% difference in all-cause mortality (HR 0.73; 95% 0.54-0.98) and a 1.3% difference in cardiovascular mortality (HR 0.61; 95% CI 0.41-0.92).

In an editorial accompanying the study, Dhruv Kazi, MD (Beth Israel Deaconess Medical Center, Boston, MA), suggests that while it’s “tempting” to interpret the reductions in mortality to a survival benefit with bempedoic acid, it’s also possible the findings are a play of chance. Subgroup analyses should be interpreted with caution, he argues, noting that performing a large number of such analyses increases the risk of false-positive results. Kazi noted that the survival curves separate very quickly, but the true effect of lipid lowering with bempedoic acid would have a delayed onset. Moreover, there was no mortality benefit in the main trial.

Any sort of event reduction is welcome here. Michael Blaha

“The most likely explanation then is that the large mortality benefit with bempedoic acid in the primary prevention cohort is a chance finding, or, if there is a true underlying survival benefit, the effect size is likely much smaller than that estimated by this analysis,” he writes.

Calling the editorial fair overall, Nissen countered that while there is always the possibility of “chance,” they observed a large relative reduction in CV deaths, along with an upper bound of the confidence interval that suggests this is a legitimate and real effect of treatment. “It’s very similar to what was seen in JUPITER,” said Nissen, highlighting the 20% reduction in all-cause mortality seen in that study.   

To TCTMD, Virani stressed that it’s the overall findings that matter most. He pointed out that there was a significant interaction by baseline CVD risk category in the main CLEAR Outcomes trial. In that original analysis, there was a reduction in risk in the primary prevention cohort, but the confidence intervals in the secondary prevention group suggested that result wasn’t statistically significant.    

“Does that mean it doesn’t work in secondary prevention, which is 70% of the trial? Does that make sense?” Virani asked. “No. The overall result is significant. It is a positive trial. That’s why I would say that one should be cautious when overinterpreting results and looking too much into subgroups and significant outcomes, like mortality.”   

Speculating on the some of the differences seen between subgroups, Blaha pointed out that CLEAR Outcomes enrolled a high-risk population without ASCVD, noting there isn’t much physicians can do aside from prescribing a statin or getting blood pressure under control. “So, if you go out and enroll a high-risk, primary prevention population who can’t take a statin, these patients aren’t getting much background risk reduction from other strategies,” he said. “It’s really opens it up for a big finding in this group.”

Keeping Statins First-line Option

The US clinical cholesterol guidelines recommend high-intensity statin therapy for patients with ASCVD and those at high risk for ASCVD. The recent years have seen a number of other lipid-lowering agents come to market, including PCSK9 inhibitors and inclisiran (Leqvio; Novartis), but statins remain the cornerstone of primary and secondary prevention.

In CLEAR Outcomes, which included a comprehensive informed consent process, all patients were deemed statin intolerant because of muscle-related side effects.

You do have to careful in not overinterpreting the results, because it is a subgroup of a large trial. Salim Virani

“Statins remain first-line treatment, but in patients who can’t tolerate statins, bempedoic acid is an alternative,” said Nissen. “This is what we’ve said all along with CLEAR Outcomes and I will reiterate—this is not a substitute for statins.”  

Virani agreed.

“This trial opens up another line of treatment, but it shouldn’t replace statin therapy in cases where statins can be used,” he said. “I think that’s something clinicians should be very mindful of. We have long-term safety and efficacy data for statins, and we don’t have that data for very many therapies in cardiology. [Statins] should remain the therapy of first choice.”

Virani said there are real-world data showing that many patients can tolerate some type of statin—either a different brand, lowered dosages, or dosing every other day—if they initially developed side effects. For this reason, efforts should continue to rechallenge patients who report muscle-related symptoms, said Virani, a sentiment also shared by Nissen and Blaha.

To TCTMD, Blaha expressed some concern that physicians may give up too easily on statins.

“I do fear a little bit of jumping to this drug at the first sign of statin intolerance,” he said. “Hopefully there isn’t too much of an educational campaign pounding people over the head with statin intolerance, statin intolerance, statin intolerance. While’s it’s important, we don’t want to send the incorrect message that statin intolerance is everywhere and you need to be using this drug.”

Statins, he added, lower LDL cholesterol and CRP to a greater extent than bempedoic acid and have a proven safety track record. 

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Nissen reports receiving grants to perform clinical trials from AbbVie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion Therapeutics Inc, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics.
  • Kazi reports grant support from the Institute for Clinical and Economic Review Research for research to examine the economic value of novel lipid-lowering agents.
  • Virani reports research support from the department of Veterans Affairs, National Institutes of Health, and Tahir and Jooma Family. He also reports honorarium from the American College of Cardiology.
  • Blaha reports serving on advisory board for Novo Nordisk, Boehringer Ingelheim, and Agepha Pharma.