Bempedoic acid and ezetimibe – better together

“Alone we are strong. Together we are stronger”

Low density lipoprotein cholesterol (LDL-C) is a primary therapeutic target for atherosclerotic cardiovascular disease (ASCVD) risk reduction.^1,2 Meta-analyses of clinical trials and Mendelian studies have reaffirmed the principle of “lower is better” for LDL-C reduction for ASCVD prevention.^3,4 However, the cardiovascular benefits of LDL-C lowering might be limited to therapies which reduce LDL-C levels by mechanisms which ultimately upregulate LDL receptors, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.^4,5 Thus, it is logical to consider that intensification of therapy by combining drugs which act on different targets but ultimately share the same mechanism of LDL-C clearance would be synergistic when used together.^2,4,5

Bempedoic acid, a pro-drug which gets activated in liver, targets the same cholesterol synthesis pathway as do statins. Its mechanism of action is by inhibition of ATP-citrate lyase, which is upstream of HMG-CoA reductase, to enhance LDL-C clearance via up-regulation of LDL receptors. In their trial published in this issue of the European Journal of Preventive Cardiology, Ballantyne and colleagues evaluated 301 patients at high risk for ASCVD who were receiving maximally tolerated statin therapy (with approximately one-third of patients respectively on high-intensity statin, other intensity statin, or no statin) but who had residual hypercholesteremia (mean baseline LDL-C of 3.87 mmol/L (149.8 mg/dL)).⁶ Participants were randomized to fixed dose combination (FDC) treatment (bempedoic acid 180 mg+ ezetimibe 10 mg), bempedoic acid 180 mg alone, ezetimibe 10 mg alone, or placebo.⁶ At 12 weeks, the FDC significantly reduced LDL-C levels (–36.2%) compared with bempedoic acid (–17.2%), ezetimibe (–23.2%), and placebo (1.8%) (p < 0.001 for all). In other words, the benefit of the combination (bempedoic acid + ezetimibe) together was better than either drug alone. These reductions were consistent across patients taking varying intensity of statin therapy.

Also very notable was a 35.1% reduction in high-sensitivity C-reactive protein (hsCRP) with FDC, which was greater than ezetimibe alone (8.2% reduction) or placebo (21.6% increase). Elevations of the inflamma-tory biomarker hsCRP are associated with increased ASCVD risk even among statin-treated individuals.⁷ Thus, the hsCRP-lowering effect of bempedoic acid is particularly encouraging, as other therapies, such as canakinumab, conferring reductions in hsCRP, have translated into cardiovascular outcome benefit.⁸

The degree of LDL-C lowering shown by bempedoic acid in this study is consistent with prior trials.^6,9,10 In the CLEAR Harmony trial (n = 2230), bempedoic acid reduced LDL-C levels by 18% at 12 weeks.⁹ Similarly, the CLEAR WISDOM trial (n = 779) presented at the 2019 American College of Cardiology (ACC) meeting, showed a 15.1% LDL-C reduction with bempedoic acid compared with a 2.4% increase in placebo group at 12 weeks.¹⁰

So where might FDC fit into current medical management? The first target population would be secondary prevention patients who remain at high residual ASCVD risk due to persistent LDL-C elevation. The 2018 American Heart Association/ACC Cholesterol Guidelines recommend that in patients at very high ASCVD risk an LDL-C threshold ≥70 mg/dL would prompt consideration of addition of ezetimibe to a maximally tolerated statin, and if LDL-C still remained above 70 mg/dL, then PCSK9 inhibitors could be added next.^2,11 In this present study, the investigators attempted to maximize LDL-C lowering by using FDC of bempedoic acid + ezetimibe. While the magnitude of reduction of LDL-C with FDC was not as great as what would be expected by PCSK9 inhibitors (~60% reduction in LDL-C), the high price tags of PCSK9 inhibitors might limit their use among many potential recipients.^2,12 Furthermore, the appeal of FDC lies in its oral form and lower expected price, while ensuring an impressive ~36% LDL-C reduction.

The second population where FDC would likely have the most utility is in individuals at elevated ASCVD risk who have statin intolerance. Current practice guidelines favor ezetimibe or other non-statin drugs, such as bile acid sequestrants, for patients with statin intolerance. Bempedoic acid does not precipitate in skeletal muscles and there has been no increased risk of adverse muscle symptoms reported; thus, this drug appears to be a useful alternative option in patients with statin associated muscle symptoms.

Reassuringly, the safety profile of FDC appears very favorable when added to maximally tolerated statin therapy. There was a significant elevation in uric acid, as has been noted in other studies of bempedoic acid, but the clinical implications of this remain uncertain as this was not accompanied by new gout cases in this study, although a small increase in gout was seen in CLEAR Harmony.⁹ The incidence of upper respiratory tract infection or nasopharyngitis was non-significantly higher in groups receiving bempedoic acid compared with ezetimibe or placebo, which is consistent with prior studies.^9,10

The biggest uncertainty, however, is whether or to what extent the LDL-C lowering potential of FDC or bempedoic acid monotherapy translates into ASCVD risk reduction. While none of the clinical trials was powered to assess the cardiovascular efficacy of bempedoic acid, the rates of major adverse cardiovascular events (MACEs) were numerically lower than or comparable to bempedoic acid versus placebo in CLEAR Harmony: non-fatal myocardial infarction (MI) (1.3% vs. 1.8%), non-fatal stroke (0.3% vs. 0.3%), coronary revascularization (2.6% vs. 3.2%), death from cardiovascular causes (0.4% vs. 0.1%).⁹ In CLEAR Wisdom, MACEs (6.1% vs. 8.2%) and non-fatal MI (1.1% vs. 3.5%) were also numerically lower with bempedoic acid versus placebo. This smaller study by Ballantyne et al., of only 301 patients followed for 12 weeks, is inadequate to discern any effects on ASCVD events, although the incidence of acute MI was 1.2% vs. 2.3% vs. 3.5% vs. 0% among the FDC, bempedoic acid, ezetimibe, and placebo groups.⁶

Based on the totality of these data, one can assume encouraging results regarding benefit and safety of bempedoic acid in on-going large trials powered for cardiovascular outcomes. There will be an extension of CLEAR Harmony, and the CLEAR Outcomes study will examine whether bempedoic acid can reduce cardiovascular events among 12,600 patients with clinical ASCVD or high ASCVD risk who are statin intolerant (NCT02993406). In the meantime, we can at least conclude that in patients requiring intensive LDL-C lowering, who cannot afford PCSK9 inhibitors, or have statin intolerance, bempedoic acid and ezetimibe are stronger together and can serve as an alternative approach for lipid management in ASCVD prevention.