Guest Editorial: Bempedoic Acid Therapy for Patients with Statin Intolerance

Hyperlipidemia is a significant causal factor in the development of atherosclerotic cardiovascular disease, the leading cause of death in developed countries.(1) The burden of atherosclerotic cardiovascular disease (ASCVD) has decreased over the past several decades,  with approximately half the decline attributable to medical therapy (2) directly correlating with absolute LDL-C reduction.(3) This improvement has been primarily attributed to the increased utilization of statins, which have exhaustive evidence over numerous randomized controlled trials for their safety and efficacy in primary and secondary prevention.

Despite decades of progress in lipidlowering therapy, adequate LDL-C reduction remains a laudable but difficult to achieve goal, especially in patients with known ASCVD, familial hypercholesterolemia (FH), and those with multiple risk factors for cardiovascular disease(4,5) In these cases, statin therapy is the first-line treatment, but when used alone is often not sufficient to achieve sufficient ASCVD risk reduction.(6) Further, it often is reduced or stopped due to statin-intolerance.

Bile acid sequestrants, fibrates, ezetimibe, niacin, mipomersen, and PCSK9 inhibitors are non-statin alternatives, but their use is limited due to efficacy, cost, and side effects. Ezetimibe (EZE) and PCSK9 inhibitors have been shown to lower the risk of cardiovascular events, leading to the recommendations of the 2018 AHA/ACC/Multisociety Cholesterol Guidelines for the use of EZE and/or PCSK9 inhibitors as add-on therapy to statins in patients with high-risk and very-high risk ASCVD.(5) The small amount of LDL-C reduction offered
by ezetimibe and the high cost of PCSK9 inhibitors limits widespread use.

Further complicating the picture, the last ten years have been marked by increasing awareness of the potential side effects of statin use. In 2011 and 2013, the US Food and Drug Administration mandated safety labeling changes for high-dose simvastatin due to concerns regarding muscle injury (7) and an increased risk for diabetes, especially at high doses.(8) Though data from randomized controlled trials suggest that the incidence of musclerelated adverse events is low (9-11), statin-associated muscle symptoms (SAMS) account for >90% of side effects attributed to statins (12), and patient-reported data suggest an incidence as high as 29% in clinical practice.(13-15) Such side effects have resulted in variable adherence with stain therapy (16,17), which is associated with a sub-optimal reduction of LDL-C and a higher risk for cardiovascular events.(18,19)

Despite the myriad of options for lipid lowering therapy, options with adequate efficacy in statin-intolerant patients are limited. For example, EZE has limited efficacy as monotherapy and can be associated with muscle-related adverse events when taken as monotherapy or
combination therapy with statins.(20,21) Mipomersen was found to lower LDL-C by 47% in patients with SAMS in a phase 2 RCT but had a high incidence of hepatic steatosis and transaminase elevation.(22) Other non-statin lipid-lowering therapies such as bile acid sequestrants, niacin, and fibrates are not well studied in patients with SAMS and have modest effects on LDL-C. The limitations in these therapies highlight the unmet need for additional pharmacologic therapies.

Bempedoic acid is a novel, first-of-class drug that can help lower residual CVD risk as (i) add-on therapy to maximally tolerated statin and/or ezetimibe in patients with high-risk or very high-risk ASCVD and (ii) patients with statin intolerance.

Bempedoic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) (Esperion Therapeutics Inc, Ann Arbor, MI) is a prodrug that is absorbed quickly in the small intestine and rapidly forms CoA thioester in the liver, which competitively inhibits ATP-citrate lyase, an enzyme in the cholesterol synthesis pathway upstream of HMG CoA (inhibited by statins).(23) Bempedoic acid thereby reduces hepatic cholesterol biosynthesis, resulting in upregulated LDL receptors and an increase in clearance of LDL particles from systemic circulation.(24,25)

Because bempedoic acid is a prodrug that requires activation by very-long-chain acylcoenzyme A synthetase-1 (an enzyme that is present in the liver but absent in skeletal muscle (25) ), it has similar LDL-C lowering efficacy to statins without the associated muscle-related adverse events. Multiple trials have shown that bempedoic acid (i) results in significant reductions in LDL-C, (ii) is not associated with increased muscle-related adverse events compared to placebo (26), (iii) offers LDL-C lowering independent of baseline statin use (27), and (iv) does not result in higher rates of hyperglycemia or diabetes compared to placebo.

Initial phase 2 randomized controlled trials showed that bempedoic acid at a dose of 120mg daily in patients off all lipidlowering therapy prior to inclusion resulted in significant LDL-C reduction (-42.9% and -26.6% for bempedoic acid compared to -4.0% and -2.1% for placebo).(28,29) In both trials, these reductions were irrespective of baseline plasma triglyceride and LDL-C levels. The latter study evaluated the efficacy of bempedoic acid in patients with hypercholesterolemia and type 2 diabetes and found that the LDL-C reductions were accomplished without worsening glycemic control – an important finding given the association of statins with hyperglycemia and new-onset diabetes. In fact, 24-hour continuous glucose monitoring showed a nonsignificant trend towards improved glycemic control in the bempedoic acid group.

Thompson et al. completed two studies on bempedoic acid alone (30) and bempedoic acid plus ezetimibe in statin-intolerant patients.(31) These studies found a 32% and 30% reduction in LDL-C, respectively. Intriguingly, the lipid-lowering effect with the addition of ezetimibe in the latter study was additive, with LDL-C reductions of 48% in the bempedoic acid + EZE group.(31) In both studies, musclerelated adverse events occurred in similar frequency in the bempedoic acid and placebo groups and less frequently in the bempedoic acid group compared to the EZE group. LDL-C reductions were similar to those in statin-tolerant and statin-intolerant patients (31) – a notable finding given the higher baseline risk for cardiovascular disease in the statin-intolerant cohort.

Recently, two phase 3 randomized controlled trials – The Cholesterol Lowering via Bempedoic Acid, and ACLInhibiting Regimen (CLEAR) Tranquility and the CLEAR Serenity trials – gave further support to the safety and efficacy of bempedoic acid in lowering LDL-C.(32,33)

The CLEAR Tranquility was a multicenter, double-blind placebo-controlled trial that studied bempedoic acid plus ezetimibe in statin-intolerant patients. Patients had to be unable to tolerate more than a low-intensity statin for inclusion – 69% of patients were not on any statin therapy. The authors found a 28.5% LDL-C reduction compared to placebo, a reduction maintained through follow-up at 12 weeks. Rates of treatment-emergent adverse events were similar between the groups. Both trials noted elevations in uric acid more commonly in the group that received bempedoic acid, though mean uric acid elevations remained stable after four weeks of treatment and were not accompanied by new or worsening gout in the CLEAR Tranquility Trial. The frequencyof transaminase elevations was similar to the trials of statins.(34)

The CLEAR Serenity trial evaluated the safety and efficacy of bempedoic acid alone in patients with statin intolerance and found similar results.(33) At baseline, 93% of patients reported a history of SAMS. The placebo-controlled difference in LDL-C was -21.4% at 12 weeks. Myalgias and new-onset or worsening diabetes was seen less frequently in the bempedoic acid than the placebo group. More patients in the placebo group discontinued the drug due to muscle-related symptoms.

A pooled analysis of four double-blind phase 3 trials, including patients on stable lipid-lowering therapy and high CVD risk or hypercholesterolemia with statin intolerance showed similar results. Among patients with high ASCVD risk or heterozygous FH or both, the mean LDL-C percent change from baseline was -16% with patients on bempedoic acid (-17.8% compared to placebo); patients with statin intolerance had a 12-week LDL-C percent change of -23% (-24.5% compared to placebo). These were sustained in long-term follow-up in both groups.(35) Treatment-emergent adverse events included increased blood uric acid level (2.1% vs. 0.5% for placebo), gout (1.4% vs. 0.4%), and increased hepatic enzymes (2.8% vs. 1.3%).

Despite the promising results of bempedoic acid in LDL- reduction, the trials thus far have been short-term and powered for lipoprotein reduction. Larger trials with long-term follow-up are needed to evaluate the incidence of adverse events and the effect of bempedoic acid on long term cardiovascular events. Promising results may lie ahead in the ongoing CLEAR Outcomes Trial investigating the influence of bempedoic acid on ASCVD risk.

In summary:

1. Cardiovascular disease risk decreases in proportion to LDL-C reduction.
2. Statins are the mainstay of therapy for both primary and secondary prevention but have a significant rate of muscle-related adverse events. Non-statin options for LDL-C lowering are limited.
3. Bempedoic acid is effective and well-tolerated as both add-on therapy for statin tolerant patients with high-risk ASCVD or patients with statin-intolerance.

The ongoing CLEAR Outcomes Trial is evaluating whether the use of bempedoic acid in statin-intolerant patients reduces adverse cardiovascular events.

Disclosure statement:
Dr. Buda has no financial disclosures to report. Dr. Gopal has no financial disclosures to report.

References: 

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