Modest LDL Cholesterol Reduction With Bempedoic Acid in Among High-Risk Patients: CLEAR Wisdom
The reduction in LDL is on top of statin therapy, leaving investigators hopeful bempedoic acid might be useful as an add-on therapy.
NEW ORLEANS, LA—The addition of bempedoic acid (Esperion) to maximally tolerated statin therapy significantly lowered LDL cholesterol in individuals at high risk for cardiovascular disease in a new phase III trial testing the investigational agent.
Presented earlier this week at the American College of Cardiology 2019 Scientific Session, the CLEAR Wisdom trial showed that bempedoic acid cut LDL cholesterol by 15.1% at 12 weeks, as well as lowered total cholesterol, apolipoprotein B, non-HDL cholesterol, and C-reactive protein levels. Although the study wasn’t powered for clinical events, major adverse cardiovascular events were reduced in the patients treated with bempedoic acid.
Anne Goldberg, MD (Washington University School of Medicine, St. Louis, MO), who presented the results during a late-breaking clinical trial session, said that despite the small size of the study, which was not powered to address hard clinical outcomes, the 1-year results nevertheless showed a 2% absolute difference in the risk of cardiovascular death, nonfatal MI, and nonfatal stroke favoring bempedoic acid (2.7% vs 4.7% in the placebo arm). There also was a 2% absolute reduction in the risk of an expanded composite endpoint that included coronary revascularization and hospitalization for unstable angina.
“This is actually a hypothesis-generating finding essentially, but there is a cardiovascular outcomes study already started,” she said. Results from CLEAR Outcomes are not expected until 2022.
Nonetheless, the early data suggest that bempedoic acid “looks like an additional therapeutic option, potentially, to lower LDL cholesterol in high-risk patients with elevated LDL cholesterol levels treated with maximally tolerated statins or other therapies,” said Goldberg. “It would be an add-on to statins, something else in armamentarium to get LDL lower since most of us believe that lower is better.”
Valentin Fuster, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), said physicians and researchers “have to pay attention to this drug” given that its mechanism of action is part of the same pathway for statins. Bempedoic acid is an inhibitor of ATP citrate lyase (ACL), a key enzyme involved in the cholesterol biosynthesis pathway. Fuster was surprised that the amount of LDL-lowering with bempedoic is not greater, although he doesn’t consider this problematic when used in high-risk patients for the prevention of recurrent ischemic events.
“It reminds me of ezetimibe when it came to market,” said Fuster. “The results weren’t very striking. Then, once it was looked at for the [prevention] of subsequent [cardiovascular] events, we became aware that this was a good drug to use. Preventing the train of events is important.”
Nearly 95% With Atherosclerotic CVD
The CLEAR Wisdom investigators randomized 779 patients at high risk for cardiovascular events 2:1 to bempedoic acid 180 mg or placebo. All patients were taking maximally tolerated statin therapy, including 53.3% who were taking a high-intensity regimen, such as rosuvastatin 40 mg or atorvastatin 80 mg. One-third of patients were taking a moderate-intensity statin, and the remainder were taking a low-intensity agent or no statin at all. Nearly 95% of patients in the trial had atherosclerotic CVD, 84% had hypertension, and one third had diabetes.
At week 12, patients treated with bempedoic had a 15.1% reduction in LDL cholesterol while those treated with placebo had a 2.4% increase, translating into a 17.4% placebo-corrected difference between treatments (P < 0.001). From baseline, LDL cholesterol levels declined from 122.8 mg/dL to 97.6 mg/dL, and this reduction was maintained at 1 year. Patients treated with a moderate- and high-intensity statin had 14.9% and 14.4% reductions in LDL cholesterol from baseline, respectively, while those untreated with statins had a 24.6% reduction in LDL cholesterol from baseline.
“Since bempedoic acid acts in the same pathway as HMG-CoA reductase, when you add it on to a statin you get a nice effect, more than the effect of doubling the dose of a statin,” said Goldberg. “You do see a bigger effect if you take a person who is not on any statin since this works at a step before HMG-CoA reductase.”
The researchers stressed that the role for bempedoic will be as an additional lipid-lowering agent in patients with LDL cholesterol levels still too high and not as a solo first-line agent. “The statin effect trumps everything,” Goldberg told TCTMD.
They observed no worsening of glycemic measurements in patients with a history of diabetes in the trial. Goldberg said there was no significant difference in total adverse events or serious adverse events between placebo and bempedoic acid, but that the investigators are still analyzing the results. In a similar phase III study published last week, the incidence of gout and elevations in uric acid were higher with bempedoic acid.
‘Big Wide World of People Out There’
Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who was one of the discussants during the session, agreed that physicians are watching bempedoic with interest because there is a need for an additional safe and effective lipid-lowering agent. He questioned whether investigators stratified the reduction in LDL cholesterol with bempedoic acid based on starting LDL cholesterol levels, which is a critical analysis. Goldberg agreed, but said this work has not yet been completed.
Speaking during a morning press conference, William White, MD (University of Connecticut School of Medicine, Farmington), said the addition of another agent for physicians would be beneficial given the heterogeneity of patients they see in clinical practice. Some can’t take a statin because of side effects, while others can’t or won’t take a dose high enough to achieve sufficient LDL-lowering. And while the PCSK9 inhibitors are indicated for CVD event reduction, an expensive, injectable monoclonal antibody isn’t for everybody, said White.
“It’s a big wide world of people out there with hypercholesterolemia and it’s not necessarily one size fits all,” said White.
Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), said that he’d be nervous substituting bempedoic acid for ezetimibe, alirocumab (Praluent; Regeneron/Sanofi), or evolocumab (Repatha; Amgen) when there are long-term outcome data for these agents, and since ezetimibe is available as a generic drug. “I believe in the LDL hypothesis and I think outcome trials [with bempedoic acid] will be positive, but I would be a bit cautious,” said Bhatt.
Esperion, the maker of bempedoic acid, has already announced plans to price the drug, assuming efficacy and regulatory approval, cheaper than the PCSK9 inhibitors. The company also has a bempedoic acid/ezetimibe combination pill in the works and plans to see US Food and Drug Administration approval for this combo at the same time as its new drug application for the stand-alone medication.
Goldberg AC, on behalf of the CLEAR Wisdom investigators. Efficacy and safety of bempedoic acid added to maximally tolerated statins in patients with hypercholesterolemia and high cardiovascular risk: the CLEAR Wisdom trial. Presented at: ACC 2019. March 18, 2019. New Orleans, LA.
- CLEAR Wisdom was sponsored and funded by Esperion Therapeutics.
- Goldberg reports grant/research support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS; and honoraria from the National Lipid Association, Esperion, Novartis AKCEA, Regeneron/Sanofi, 23andMe, and Merck.