Bempedoic Acid/Ezetimibe Combo Lowers LDL Cholesterol in High-Risk Patients
Bempedoic acid, if priced right, could find a role as an alternative to expensive PCSK9 inhibitors in this subgroup, say experts.
MAASTRICHT, the Netherlands—Use of a fixed-dose combination of bempedoic acid and ezetimibe in statin-treated patients at high risk for cardiovascular disease significantly lowers LDL cholesterol levels, according to results from a new study.
Following 12 weeks of treatment, patients who received bempedoic acid and ezetimibe (180/10 mg) had a 36.2% reduction in LDL cholesterol and a 35.1% reduction in high-sensitivity C-reactive protein (hs-CRP). These reductions were significantly larger than those observed in patients treated with bempedoic acid or ezetimibe alone.
Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), who presented the results at the European Atherosclerosis Society (EAS) Congress 2019, pointed out that study investigators enrolled patients with atherosclerotic cardiovascular disease (ASCVD) and/or familial hypercholesterolemia (FH) with LDL cholesterol levels of 100 mg/dL or greater: the patient population eligible for the PCSK9 inhibitors alirocumab (Praluent; Regeneron/Sanofi) or evolocumab (Repatha; Amgen). They also enrolled patients with multiple cardiovascular risk factors and LDL levels of 130 mg/dL or greater, a high-risk primary prevention population.
“Basically, to get a PCSK9 inhibitor, you have to be high-risk secondary prevention or FH,” he told TCTMD. “But what about all these people out there who have multiple risk factors, diabetes, high calcium scores, and you need further LDL reduction but they can’t take a statin? They’re out of luck right now. I think [bempedoic acid/ezetimibe] would be a nice fit, particularly for primary prevention. It’s a lot better for someone that’s not getting anything.”
He called the observed reduction in LDL cholesterol with the combination “pretty good,” noting that physicians and researchers have been slightly spoiled by the larger reductions seen with the PCSK9 inhibitors.
Absolute Reduction of Nearly 60 mg/dL
Several phase III studies testing bempedoic acid have emerged in recent months. In March, the CLEAR Wisdom and CLEAR Harmony studies, which included slightly different high-risk patient populations, both showed that adding bempedoic acid to maximally tolerated statin therapy modestly reduced LDL cholesterol by approximately 18%. Few patients in both trials were taking ezetimibe, however.
In the new study, patients were randomized to the bempedoic acid/ezetimibe combination (n = 81), bempedoic acid alone (n = 88), ezetimibe alone (n = 86), or placebo (n = 41). In total, 61.6% of patients had existing ASCVD/FH and 38.4% were secondary-prevention patients with multiple risk factors for ASCVD. Mean LDL cholesterol and hs-CRP levels were high at approximately 150.0 mg/dL and 3.0 mg/dL, respectively. In terms of background treatment, just one-third of patients were taking high-intensity statins and more than 35% were taking no statin at all.
The absolute reduction in LDL cholesterol levels with bempedoic acid/ezetimibe from baseline to week 12 was 1.5 mmol/L, or approximately 58.0 mg/dL. Treatment with bempedoic acid alone and ezetimibe alone lowered LDL cholesterol by 17.2% and 23.2%, respectively (absolute reductions of 27.1 mg/dL and 38.67 mg/dL). The fixed-dose combination also lowered non-HDL cholesterol and apolipoprotein B levels.
“You’ve got a drug that inhibits ATP citrate lyase, so it’s a cholesterol synthesis inhibitor, but it’s upstream of HMG-CoA reductase in the cholesterol synthesis pathway,” Ballantyne told TCTMD. “It’s converted to the active drug in the liver. When you put it together with ezetimibe, which blocks cholesterol absorption, you have different mechanisms of action. It ends up you get about a 40% reduction with the combination.”
Adverse events were evenly distributed across the four treatment groups, but there were no reported cases of gout, a side effect that was observed in earlier trials. Frederick Raal, PhD (University of the Witwatersrand, Johannesburg, South Africa), who wasn’t involved in the trial, noted that uric acid is pro-inflammatory, so it’s difficult to understand why uric acid increases and yet hs-CRP decreases. In response, Kausik Ray, MD (Imperial College, London, England), who is involved in clinical trials testing bempedoic acid, pointed out that bempedoic acid and uric acid are both excreted by the kidneys and compete for the renal transporters.
“Basically, as soon as you come off drug [uric acid] normalizes,” said Ray. “It’s a direct competitive mechanism, rather than to do with any on-target effects of the drug.”
A Cheaper Alternative to PCSK9 Inhibitors
To TCTMD, Ballantyne said he believes bempedoic acid can find a niche in light of some pushback stemming from the high cost of the PCSK9 inhibitors. Although the PCSK9 inhibitors costs less today than they did when first approved, there are still challenges with respect to patient access.
Earlier in the week, Ballantyne presented data from nearly 50,000 patients in the PINNACLE Registry with LDL cholesterol levels 190 mg/dL or greater. There, just 58.5% of patients were treated with a statin and only 32% were treated with a high-intensity statin. Combination therapy was used even less frequently, with only 6.2% of patients treated with a statin and ezetimibe and 0.7% treated with a statin and PCSK9 inhibitor.
For bempedoic to be an effective alternative to PCSK9 inhibitors will likely come to price, said Ballantyne. Esperion, the maker of bempedoic acid, said they plan to price the drug, assuming it’s cleared for market, cheaper than the PCSK9 inhibitors and are currently seeking approval for the agent as a standalone therapy and a fixed-dose combination therapy with ezetimibe.
Speaking with the media, Chris Packard, MD, PhD (University of Glasgow, Scotland), noted that physicians previously had just a single tool and one goal—to treat patients with the most effective statin dose to lower LDL cholesterol levels. “If you got to the top dose and you didn’t get to goal, the doctor and patient sort of looked at each other and said, ‘What do we do now?’” he told TCTMD. “I think we’ve moved into a new era of combination therapy, and I think we’re moving from monotherapy to combination therapy on a routine basis. You’ll find that combinations make it much easier to reach the target.”
Commenting on the emerging treatments, EAS President Lale Tokgozoglu, MD (Hacettepe University, Ankara, Turkey), said that while these new drugs are exciting, it’s the clinical outcome studies that will really interest the practicing physician. “It won’t be too long before we have the outcome studies,” she said. “We will have a huge therapeutic range of drugs if they make it to the clinical [setting].”
The CLEAR Outcomes study is currently underway, with investigators testing bempedoic acid in patients with ASCVD (or those are high risk for ASCVD) intolerant to statin therapy. Full results from the 12,000-patient trial are not expected until 2022.
Ballantyne C. Efficacy and safety of bempedoic acid plus ezetimibe fixed-dose combination in patients at high CVD risk and with elevated LDL cholesterol receiving maximally tolerated statin therapy. Presented at: European Atherosclerosis Society Congress 2019. May 27, 2019. Maastricht, the Netherlands.
- Ballantyne repots grant/research support to his institution from Abbott Diagnostic, Akcea, Amgen, Esperion, Novartis, Regeneron, Roche Diagnostics, Sanofi-Synthelabo, National Institutes of Health, American Diabetes Association, and American Heart Association. He reports consulting for Abbott Diagnostic, Akcea, Amarin, Amgen, Arrowhead, AstraZeneca, Boehringer Ingelheim, Denka Seiken, Esperion, Intercept, Janssen, Matinas Biopharma, Merck, Novartis, Novo Nordisk, Regeneron, Roche, and Sanofi-Synthelabo.