Bempedoic Acid: When Clinical Trials Come Full Circle

Written by Joseph Kummer, MD

Throughout the years, Bryan Heart has actively been involved in hundreds of clinical research trials.

Research trials vary vastly from:

• Surgical procedures
• Cutting edge technology
• Devices
• Innovative medications
• Data registries

Medication Study of Bempedoic Acid: CLEAR Serenity

One particular study – CLEAR Serenity – that Bryan Heart began in 2017, involved a study medication: bempedoic acid. The information obtained during that study has helped this medication come full circle to be available to patients today. 

Statin medications

The first-line choice in treating patients with or at high risk for atherosclerotic cardiovascular disease (ASCVD) is statin medications.

Benefits of Statin Medications
Benefits of statin therapy in this population have been proven in countless trials over many decades, and there is widespread consensus that maximal statin therapy should be prioritized for LDL-C lowering.

Concerns of Statin Medications
However, many patients either do not tolerate statins or do not achieve their target LDL-C despite maximal statin therapy. In sharp contrast to the robust data supporting initial statin therapy, there is relatively limited data to guide the choice of second-line agents.

PCSK9 Inhibitors v. Ezetimibe: Lowering LDL-C

Several medications have demonstrated both safety and efficacy in LDL-C reduction. However, studies evaluating clinical outcomes for these agents have been generally weak or inconsistent. Ezetimibe and PCSK9 Inhibitors have only limited outcome data to support their use, despite proven efficacy with LDL-C lowering with excellent safety and tolerability profiles. Although PCSK9 Inhibitors provide significantly greater LDL-C lowering than ezetimibe, ezetimibe’s low cost and oral dosing have generally made it a favored second-line agent over the much more expensive and injectable-only PSCK9 Inhibitors.

Bempedoic Acid with Ezetimibe

Bempedoic acid by itself (Nexletol®) and in combination with Ezetimibe (Nexlizet™) were approved by the FDA in February 2020 for patients with ASCVD and those with heterozygous familial hypercholesteremia who are statin-intolerant or need additional LDL-C lowering despite maximally tolerated statin therapy. Bempedoic acid is the first non-statin oral medication approved in almost 20 years for LDL-C lowering.

How does Bempedoic acid work?

It works in a novel mechanism by inhibiting ATP-citrate lyase. This enzyme is a component of the cholesterol synthesis pathway in the liver. Statins inhibit HMG-CoA Reductase, which is a component of the same pathway but about two steps downstream from the ATP-citrate lyase action. Bempedoic acid is administered as a prodrug that is converted to its active form in the liver. Metabolites of statins are produced not only in the liver but also in skeletal muscle, which can lead to myalgias. The conversion of bempedoic acid, however, occurs entirely in the liver with no action in skeletal muscle. Therefore, myalgias with this medication occur with no greater frequency than placebo.

Cautions & Considerations

There is only one available dose of bempedoic acid: 180 mg po daily. As you would expect, the combination pill with ezetimibe is 180mg/10mg. Although there are actually no contraindications to bempedoic acid, caution is encouraged with its use in patients with gout as it has been shown to raise uric acid levels.

More common but less severe adverse effects include:

• Upper and lower respiratory infections
• Back pain
• Abnormal LFTs
• Anemia

While there are no formal requirements for following laboratory data for patients taking this medication, it would be wise to follow uric acid levels for patients with a history of elevated uric acid levels or a history of gout.

Another important side effect that needs to be considered is tendon rupture. This was seen in one out of every 200 patients (0.5% prevalence) on this medication in clinical trials.⁴ Cases have been seen involving the biceps tendon, rotator cuff, and Achilles tendon. Caution should be used in prescribing this to patients with a history of tendon rupture, those above 60 years of age, those with renal insufficiency, and those on steroids or fluoroquinolones, as they may be at higher risk of this potentially significant side effect.

Proven Benefits

There is little doubt about the efficacy of bempedoic acid for lowering LDL-C. Randomized trials have shown a 30% LDL-C reduction with bempedoic acid as monotherapy. This is superior to an observed 15% to 25% reduction from ezetimibe either as monotherapy or in addition to statin therapy. The combination pill (Nexlizet™) demonstrated a 48% LDL-C reduction.⁷ Nonetheless, even the combination therapy is mildly inferior to the addition of a PCSK9 Inhibitor to statin therapy, where an LDL-C reduction of 45% to 64% is expected.

I would describe my personal thoughts on this medication as generally favorable and cautiously optimistic. From my review of the literature, I think it’s quite clear that bempedoic acid is effective at LDL-C lowering, is very well tolerated, and has an acceptable safety profile. The obvious question that remains is whether or not this medication improves important clinical outcomes. The CLEAR OUTCOMES trial is an ongoing phase three trial that seeks to answer this question. This is a bold and arguably risky trial for a new medication, but I believe it is exactly what we need to know. The trial will enroll a total of 14,032 statin-intolerant patients with or at high risk of ASCVD. Patients will be randomized to bempedoic acid vs placebo.⁸ The primary composite endpoint is time to first occurrence of cardiac death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The trial is expected to be completed in March 2022.

My Take on The CLEAR Study

I am very pleased with the design of this trial for two reasons. First, it looks at the medication’s effectiveness as a stand-alone agent. Similar trials with other agents were often evaluated in addition to statin therapy, which makes the relative contribution of each agent less clear and of course doesn’t provide guidance on monotherapy. Second, each of the elements of the composite endpoint are very relevant with no “soft” outcomes (e.g., evaluation for chest pain). It will be very exciting if this trial demonstrates a benefit of this new medication.

So what is the best medication to add for LDL-C lowering after maximal statin therapy? Ezetimibe is currently the recommend choice largely due to its low cost and favorable tolerability and safety profiles. I think that bempedoic acid is a reasonable medication to consider in this situation as well. Of course, the outcomes data in March of 2022 will greatly help to clarify this question. For now, I offer the following thoughts: Bempedoic acid is generally safe and very well tolerated, but I would avoid it in most patients with gout. Also, the 0.5% risk of tendon rupture is a concern. I would not generally use this instead of ezetimibe, but using the combination of bempedoic acid with ezetimibe seems very reasonable. Note that the price of bempedoic acid alone is the same as its combination pill with ezetimibe, but of course either will be significantly more expensive than ezetimibe by itself. For patients in whom the higher cost and potential side effects are not prohibitive, I see little reason not to use it in combination with ezetimibe for any patient who needs additional LDL-C lowering.

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 Sources

1. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA 2019;322:1780-8.
2. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-32.
3. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019;8:e011662.
4. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 2018;277:195-203.
5. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2020;27:593-603.
6. Tibuakuu M, Blumenthal RS, Martin SS, et al. Bempedoic acid for LDL-C lowering: What do we know?. JACC on-line. August 10^th, 2020.
7. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol 2016;10:556-67.
8. Esperion Therapeutics. Evaluation of major cardiovascular events in patients with, or at high risk for, cardiovascular disease who are statin intolerant treated with bempedoic acid (ETC-1002) or placebo (CLEAR Outcomes). 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT02993406. Accessed 07/15/2020.