A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3 placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, myocardial infarction (MI), stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well-tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steve Nissen, MD, Cleveland Clinic, Ohio, concluded.
Nissen presented the CLEAR Outcomes trial on March 4 at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023.
The study was simultaneously published online in the New England Journal of Medicine (NEJM). Topline results were previously reported in December 2022.
Nissen pointed out that while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction — that’s about the same as 40 mg simvastatin or 20 mg atorvastatin — without giving a statin. And I think that’s where I see the potential of this therapy,” he commented.
Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a pro-drug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary end point (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs 9.5%; hazard ratio, 0.85; P = .006).
Fatal or nonfatal MI was reduced by 23% (3.7% vs 4.8%; hazard ratio, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs 7.6%; hazard ratio, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group vs 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs 2.1%) and cholelithiasis (2.2% vs 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors point out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline-eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative non-statin therapies are needed to manage the LDL cholesterol level in these patients,” they write.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding, “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL hypothesis.
She added that: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, North Carolina, writes, “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warns, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects,” he writes.
Alexander also points out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he notes that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Alexander concludes. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr, MD, Brigham and Women’s Hospital, says the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautions that “These data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Keaney notes that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16 to 26% reduction in the LDL cholesterol level,” he adds. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Nissen reports grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen, and Glenmark Pharmaceuticals.
American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023. Joint American College of Cardiology/ Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented March 4, 2023.
N Engl J Med. Published online March 4, 2023. Full text, Editorial 1, Editorial 2
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