Where do we go from CLEAR?
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In the past decade, there have been major advances in lipid-lowering therapeutics, and another was made apparent in March at the American College of Cardiology Scientific Session.
In addition to statins, available lipid-lowering therapies currently include ezetimibe, PCSK9 inhibitors, a small interfering RNA approach against PCSK9, angiopoietin-like protein 3 (ANGPTL3) inhibitors, and now bempedoic acid (Nexletol, Esperion Therapeutics).
As a result of the CLEAR Outcomes trial presented at ACC and simultaneously published in The New England Journal of Medicine, it has now been shown that bempedoic acid improves nonfatal CV outcomes. (Read Healio’s in-depth coverage of the trial here.)
Bempedoic acid is the first oral nonstatin agent to show an improvement in CV outcomes in both primary and secondary prevention populations.
Bempedoic acid is a prodrug adenosine triphosphate-citrate lyase (ACL) inhibitor that blocks cholesterol synthesis in the liver via the same metabolic pathway as statins, one enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Similar to statins, this inhibition depletes intracellular cholesterol and results in upregulation of hepatocyte membrane LDL receptors. This, in turn, reduces circulating low LDL cholesterol levels. Because the activity of bempedoic acid is specific to liver tissue, it is associated with lower rates of muscle-related adverse events. Previous placebo-controlled trials have shown LDL reductions of up to 27% with bempedoic acid monotherapy, and 20% on background statin therapy, and now we have confirmation of the expected benefit on CV outcomes.
Study design
The phase 3, randomized, multicenter, double-blind, placebo-controlled CLEAR Outcomes trial included 13,970 patients aged 18 to 85 years from 1,250 sites in 32 countries with a history of atherosclerotic CVD events (secondary prevention) or primary prevention patients at high risk for future ASCVD events, with a documented history of statin intolerance and LDL level of at least 100 mg/dL. Notably, 48% of participants were women (which deservedly received audience applause during the ACC presentation) and more than 90% of patients were white. Seventy percent of patients comprised a secondary prevention population (51% with coronary disease, 11% with peripheral artery disease and 15% with cerebrovascular disease).
Mean baseline LDL was 139 mg/dL in both treatment and control groups. Both had identical baseline rates of statin use (23%) and ezetimibe (12%).
Patients were randomly assigned to 180 mg bempedoic acid or placebo once daily and followed for a median of 3.4 years.
Main findings
After 6 months of treatment, the intervention group had an LDL of 107 mg/dL compared with 136 mg/dL in the control group. This represents a 29 mg/dL absolute difference in reduction and 21.1% difference in percent reduction of LDL (95% CI, 20.3-21.9). There was a 21.6% reduction in high-sensitivity C-reactive protein (95% CI, –23.7 to –19.6).
The primary outcome and key secondary outcomes are summarized in the Table. For the primary outcome, a four-part composite endpoint of time to first occurrence of CV death, nonfatal MI, nonfatal stroke or coronary revascularization, the number needed to treat (NNT) to prevent one event was 63 and the absolute risk reduction was 1.6%.
Absolute risk reductions for key secondary endpoints included 1.3% for CV death/nonfatal MI/nonfatal stroke, 1.1% for fatal or nonfatal MI (NNT = 91) and 1.4% for coronary revascularization (NNT = 71).
There were no significant differences between the two groups in the incidence of serious adverse events or adverse events leading to drug discontinuation. Abnormal liver enzymes (> 3 times the upper limit of normal) occurred in 4.5% in the bempedoic acid group and 3% in the placebo group. Rates of renal impairment, defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours or at least 50% within 7 days, were also higher in the bempedoic acid group compared with placebo (11.5% vs. 8.6%). Hyperuricemia and gout occurred more frequently in the bempedoic acid group compared with placebo (10.9% vs. 5.6% and 3.1% vs. 2.1%, respectively). The patients receiving bempedoic acid developed cholelithiasis more frequently than the placebo group (2.2% vs. 1.2%). Rates of myalgia were similar in both groups but numerically higher in the placebo group (5.6% vs. 6.8%). There were no significant differences between the two trial groups in frequency of new-onset or worsening diabetes, neurocognitive disorders, atrial fibrillation or tendinopathies including tendon rupture. The lack of signal for tendon pathology is notable, as prior phase 3 studies have shown a slight excess rate of tendinopathies with bempedoic acid, and this advisory is noted in the FDA prescribing label.
Clinical implications
These findings represent an exciting development in dyslipidemia therapeutics, demonstrating not only LDL reduction but also decreased rates of major adverse CV events among patients with established ASCVD or at high risk for ASCVD. Notably, there was substantial use of other nonstatin LDL-lowering therapies including PCSK9 inhibitors in the control group, leading to lower LDL in the control group and decreasing the difference in LDL reduction between the intervention and placebo groups. Thus, the magnitude of risk reduction seen with bempedoic acid, though clinically and statistically significant, was likely an underestimate.
Bempedoic acid will extend our current options for evidence-based nonstatin lipid-lowering therapies to target LDL and reduce ASCVD risk per American Heart Association/ACC guidelines.
Questions raised
While CLEAR Outcomes answers important questions, it raises several others that merit discussion, including costs, appropriate candidacy and how to best fit bempedoic acid into existing treatment paradigms.
It will be important to consider not only the magnitude of the benefits, but also the cost of this therapy. At current wholesale cash prices, bempedoic acid costs hundreds of dollars per month. Even among patients with adequate health insurance and drug coverage, costs can be burdensome, and some of these costs will be distributed across the population and health systems. Cost-effectiveness analyses can help us understand if the reduction in outcomes justifies costs before extending the indication for bempedoic acid more broadly beyond the statin-intolerant and very high-risk patients.
There are several other existing evidence-based lipid-lowering therapies to consider before initiating bempedoic acid, namely statins and ezetimibe. There are extensive trial data supporting the safety and efficacy of statins as first-line therapy for LDL and CV risk reduction. Ezetimibe also reduces risk for major adverse CV events, and statins and ezetimibe are available as inexpensive generic formulations at a fraction of the cost of newer therapies.
The investigators in the CLEAR Outcomes trial did an admirable job ensuring that participants understood the benefits and risk reduction achieved with statins and the ability of most patients to tolerate alternative statins or lower doses before participating in the trial. It is critical that similar discussions like this are integrated into shared decision-making between clinicians and patients when contemplating initiation of nonstatin lipid-lowering therapy.
Guideline recommendations
The 2018 AHA/ACC/Multisociety Cholesterol Guideline recommends statins as the first-line therapy, with addition of ezetimibe or a bile acid sequestrant among very high-risk primary and secondary prevention patients after maximizing or if unable to tolerate statins, using an LDL threshold of 70 mg/dL or greater to intensify therapy. If still above goal, the next recommended therapy is a PCSK9 inhibitor, though these guidelines were published before bempedoic acid was FDA-approved.
The 2019 European Society of Cardiology Guidelines on Dyslipidemia have an LDL goal of less than 55 mg/dL for high-risk patients, and like the American guideline, recommends the medication sequence of statin followed by ezetimibe or a PCSK9 inhibitor to meet this goal. Bempedoic acid is reserved for patients with statin intolerance, and usually in combination with ezetimibe.
The 2022 ACC consensus statement on nonstatin therapies for LDL reduction has a similar recommended algorithm, favoring the sequence of statin followed by ezetimibe and PCSK9 inhibitor, prior to adding bempedoic acid if further LDL reduction is still needed. In practice, shared decision-making with patients will play a big role, considering patient preference for oral vs. injectable therapy, and considering the magnitude of LDL reduction desired by the patient and clinician. Larger amounts of LDL lowering can be better achieved with PCSK9-directed therapy, which can lower LDL by about 50% to 60%.
Contexts to consider
Statin intolerance is a common and frustrating clinical scenario that leads to inadequate uptake of guideline therapy and persistent residual risk. The CLEAR Outcomes trial offers strong evidence that bempedoic acid is a good option for patients that require LDL reduction and are unable or unwilling to take a statin. The combination of ezetimibe and bempedoic acid can produce LDL reductions of about 40%, comparable to a moderate-intensity statin (eg, atorvastatin 20 mg), and this combination will likely be used frequently for statin-intolerant patients.
As most patients in CLEAR Outcomes were not taking a statin, the baseline LDL of 139 mg/dL seen in CLEAR Outcomes is relatively high for modern lipid trials (compared with about 90 mg/dL baseline seen in the landmark PCSK9 inhibitor trials). As such, a more modest percentage LDL reduction translated to larger absolute decrease in LDL, and more meaningful risk reduction. Nevertheless, LDL remained suboptimal in many participants, and this reinforces the importance of seeking opportunities to use bempedoic acid in combination with ezetimibe and other lipid-lowering therapies. After CLEAR Outcomes, it will also be important to gather longer-term follow-up data on the participants to determine the safety and efficacy of bempedoic acid beyond the intermediate duration seen in this trial.
Importantly, the CV risk reduction seen in CLEAR Outcomes was commensurate with the absolute LDL reduction patients experienced, and consistent with previous Cholesterol Treatment Trialists meta-analysis pooled estimates of expected relative risk reduction (RRR) per unit decrease in LDL (about 20% RRR for every 39 mg/dL reduction in LDL). In keeping with the scientific principle of reproducibility, it is remarkable that multiple classes of LDL-lowering drugs have now shown this consistent relationship of LDL to ASCVD risk reduction. This trial adds to the strong evidence among multiple nonstatin therapies for the primacy of LDL in the pathogenesis of atherosclerosis, and the critical connection between LDL lowering and ASCVD risk reduction.
The CLEAR Outcomes trial included both primary (30%) and secondary (70%) prevention populations. Notably, the HR in the primary prevention subgroup was lower than that in the secondary prevention population. This is intriguing and may represent a chance finding. However, it is reminiscent of the strong primary prevention effect seen with rosuvastatin in the JUPITER trial. We can speculate this finding could in part reflect the importance of early reduction of LDL in the course of atherosclerosis pathogenesis, when plaque is more modifiable. Once complex plaque has formed, significant residual risk remains, even with aggressive lipid-lowering therapy, and thus early LDL reduction, even among a primary prevention population, may be even more effective to mitigate this risk. Regardless of whether this is a real or chance finding, it is a welcome reminder of the major opportunity in primary prevention of ASCVD.
There has been significant discussion about the lack of CV and all-cause mortality signal seen in modern lipid-lowering trials. This once again was seen in CLEAR Outcomes, which did not surprise us. In modern times, the vast majority of ASCVD events are nonfatal events. For example, 30-day mortality in Medicare Advantage and traditional Medicare patients with acute MI in 2018 was about 18% for STEMI and about 11% for non-STEMI. Since modern CV care works well to keep people alive who have ASCVD events, longer-term follow-up can be necessary to detect a mortality signal. This was recently demonstrated for evolocumab (Repatha, Amgen), where a CV mortality benefit was not seen in the original FOURIER trial, and then in the FOURIER-OLE study, a CV mortality benefit was observed after longer-term follow-up out to a median of 5 years.
Implementation and other challenges
Despite the attendant excitement of a new oral therapy with trial-proven efficacy for reduction of major adverse CV events, there remain significant gaps in implementation and uptake of existing therapies and guideline recommendations for ASCVD prevention and CV risk reduction.
There has been some improvement in population-wide cholesterol control over the past 2 decades, with a modest increase in statin use and low uptake of nonstatin therapy, but far below what is required to significantly improve the rates of ASCVD and its associated complications and costs across the population.
Recent population surveillance data have shown a concerning slowing in the rate of decline of ASCVD mortality, with an increase in the absolute number of deaths attributable to ASCVD, heart disease and stroke. New and creative approaches are desperately needed to address the gaps in implementation of evidence and guidelines, and there is ongoing research in digital health and technology to help bridge these gaps.
Before initiating expensive novel therapies, even with proven efficacy, it will be critically important to ensure accurate cholesterol measurement and risk assessment, implement healthy lifestyle changes and maximize existing cost-effective therapies. This will require dedicated effort among both clinicians and patients with frequent follow-up, diligent risk assessment and surveillance, motivational interviewing and frequent titration of therapies as indicated to achieve recommended targets and to reduce the burden of ASCVD among patients and populations. Furthermore, and perhaps more important, we need a fundamental rethinking of systems of care and our approach to delivering therapeutics for CVD prevention, such that care can be more reliable and scalable.
A valuable evidence-based tool
The CLEAR Outcomes trial adds a valuable evidence-based tool to the lipid-lowering armamentarium and represents an important contribution to the field of cardiology and lipid therapy. The authors should be commended on a well-designed and executed randomized trial. Bempedoic acid was shown to be a safe and effective therapy for CV risk reduction, among both primary and secondary prevention patients who were statin intolerant. It provides another proven tool for LDL reduction to reduce ASCVD risk and will be of particular value for patients who are unable or unwilling to take statin therapy.
References:
- Ballantyne CM, et al. Eur J Prev Cardiol. 2020;doi:10.1177/2047487319864671.
- Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;doi:10.1016/S0140-6736(10)61350-5.
- Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2012;doi:10.1016/S0140-6736(12)60367-5.
- Ferraro RA, et al. Drugs. 2022;doi:10.1007/s40265-022-01691-6.
- Gao Y, et al. J Am Heart Assoc. 2023;doi:10.1161/JAHA.122.028205.
- Grundy SM, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000625.
- Javaid A, et al. Am J Prev Cardiol. 2022;doi:10.1016/j.japc.2022.100379.
- Johnson T, et al. Cardiovasc Digit Health J. 2022;doi:j.cvdhj.2022.06.002.
- Landon BE, et al. JAMA. 2022;doi:10.1001/jama.2022.20982.
- Lloyd-Jones DM, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.07.006.
- Marvel FA, et al. Circ Cardiovasc Qual Outcomes. 2021;doi:10.1161/CIRCOUTCOMES.121.007741.
- Nicholls SJ, et al. Am Heart J. 2021;doi:10.1016/j.ahj.2020.10.060.
- Nissen SE, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215024.
- O’Donoghue M, et al. Circulation. 2022;doi:10.1161/CIRCULATIONAHA.122.061620.
- Reith C, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)01545-8.
- Roger VL, et al. Circulation. 2020;doi:10.1161/CIR.0000000000000756.
- Sajja A, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2021.11.042.
- Visseren FLJ, et al. Eur Heart J. 2021;doi:10.1093/eurheartj/ehab484.
For more information:
Michael R. Goetsch, MD, is a cardiology fellow at Johns Hopkins Medicine. Twitter: @mrgoetschmd.
Francoise A. Marvel, MD, is assistant professor of medicine in the division of cardiology at Johns Hopkins Medicine. Twitter: @doctormarvelmd.
Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board. Twitter: @rblument1.
Seth S. Martin, MD, MHS, is director of the Johns Hopkins Ciccarone Center’s Advanced Lipid Disorders Program and professor of medicine at Johns Hopkins University School of Medicine. He is also a member of the Cardiology Today Editorial Board. Twitter: @sethshaymartin.
The authors can be reached at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Halsted 560, Baltimore, MD 21827.
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