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Bempedoic Acid and Cardiovascular
Outcomes in Statin-Intolerant Patients
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Download the PDF here
Download the PDF here
Download the PDF here
Results
A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid.
The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P=0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P=0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P=0.001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.
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Bempedoic acid, sold under the name Nexletol, was designed specifically to treat statin-intolerant patients. The FDA approved it for this purpose in 2020, but the effects of the drug on heart health had not been fully assessed until this large trial. The new study was funded in part by Esperion Therapeutics, the maker of Nexletol.
"Statins are the gold standard. They are the cornerstone. The purpose of this study was not to replace statins, but to allow an alternative therapy for people who simply cannot take them," Nissen said.
"We continue to see that if we can lower your LDL significantly, we improve people's cardiovascular health. And so we need as many different arrows in our quiver to try to get that done," Patel said. providers are already prescribing bempedoic acid for some patients, but with this new research, he thinks they will quickly be used with more statin-intolerant patients.
Statins are considered safe and effective, but there are millions of people who cannot or will not take them. For some people it causes intense muscle pain. Past research has shown anywhere between 7% and 29% of patients who need to lower cholesterol do not tolerate statins, according Dr. Steven Nissen, a cardiologist and researcher at the Cleveland Clinic and co-author of the new study.
"I see heart patients that come in with terrible histories, multiple myocardial infarction, sometimes bypass surgery, many stents and they say, 'Doctor, I've tried multiple statins, but whenever I take a statin, my muscles hurt, or they're weak. I can't walk upstairs. I just can't tolerate these drugs,' " Nissen said. "We do need alternatives for these patients."
Doctors have a few options, including ezetimibe and a monoclonal antibody called a proprotein convertase subtilisin/kexin type 9, or PCSK9 inhibitors for short.
"Both groups primary and secondary prevention got benefit, which I think is impressive with the modest amount of LDL reduction," Weintraub said.
https://www.cnn.com/2023/03/04/health/bempedoic-acid-heart-statin-intolerance-study/index.html
EDITORIAL
It is premature, however, to consider bempedoic acid as an alternative to statins.
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.
Fortunately, alternative LDL cholesterol-lowering therapies, such as ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, and bempedoic acid, are available.5-7 Ezetimibe has a modest effect in lowering the LDL cholesterol level and the risk of cardiovascular events, and PCSK9 inhibitors, although they are highly effective at lowering the LDL cholesterol level, require parenteral administration and are expensive. Bempedoic acid, an inhibitor of ATP citrate lyase, works upstream of statins in the same mechanistic pathway and reduces the LDL cholesterol level when used alone or in combination with ezetimibe in statin-intolerant patients or with statins or ezetimibe in patients with familial hypercholesterolemia.8-10 Bempedoic acid is a prodrug that is metabolized to its active metabolite in the liver but not in peripheral tissues and thus has few, if any, muscle-related side effects.9 What has been lacking to date is high-quality evidence that bempedoic acid reduces the risk of clinical events.
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.4 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.8
Two observations from the CLEAR Outcomes trial warrant further exploration. First, given the pathobiology of atherosclerosis, the suggestion of a greater effect of bempedoic acid in the primary-prevention cohort than in the secondary-prevention cohort is probably due to chance. It is plausible, however, that patients benefit more from bempedoic acid administered early in the course of atherosclerotic disease or that concomitant therapies diminished the benefit of bempedoic acid in the secondary-prevention cohort. Second, bempedoic acid had no observed effect on mortality. As the investigators note, this finding could be due to effective concomitant therapy, treatment and observation periods that were too short, or the actual absence of an effect of bempedoic acid on mortality. 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. 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.
EDITORIAL #2
In an article now published in the Journal, Nissen and colleagues report the results of the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, which tested the effect of bempedoic acid in patients with or at increased risk for cardiovascular disease.1 Patients who were unable or unwilling to take high-intensity statins because of unacceptable adverse effects ("statin-intolerant" patients) were the target trial population; statins are typically used as first-line agents to prevent cardiovascular events in patients at high cardiovascular risk. Nissen et al. found that the percent reduction in the LDL cholesterol level was 21 percentage points greater with bempedoic acid than with placebo. This reduction in cholesterol level corresponded to a 13% lower risk of major adverse cardiovascular events, defined as a four-component composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. These results are discussed in an accompanying editorial2 and are welcome news for a patient population in which it is otherwise very challenging to achieve meaningful reductions in cholesterol levels and the risk of cardiovascular events.
Currently, statins have an enviable track record in preventing both first and subsequent occurrences of cardiovascular disease. It is generally accepted that contemporary statins produce a 22% reduction in the risk of vascular events for each reduction in the LDL cholesterol level of 39 mg per deciliter (1 mmol per liter) and that this response is roughly linear.3 It is also accepted that high-intensity statin treatment (i.e., ≥20 mg of rosuvastatin or ≥40 mg of atorvastatin) should yield a reduction in the LDL cholesterol level of approximately 50%. Thus, it is clear that a considerable reduction in the risk of cardiovascular events can be achieved with statin monotherapy.
Bempedoic acid monotherapy lowers the LDL cholesterol level up to 28%,5 and this effect is attenuated to approximately 16% in patients receiving the maximum tolerated dose of statins.6 Although we do not have specific cardiovascular outcome data with bempedoic acid monotherapy, it is associated with a reduction in the level of C-reactive protein, a well-established biomarker for future cardiovascular events. The CLEAR Outcomes trial also showed that bempedoic acid, used in addition to modest cholesterol-lowering therapy, led to a reduction in the LDL cholesterol level that exceeded that with placebo by 29 mg per deciliter (0.75 mmol per liter), a finding that corresponded to a 13% lower risk of cardiovascular disease. This correspondence between a reduction in the LDL cholesterol level and a reduction in the risk of cardiovascular events is on par with that observed for statins. However, determining whether bempedoic acid is preferable to statins would require a direct-comparison trial, which is unlikely to be realized with patients who are able to receive statins, given that it would be unethical to withhold statin treatment from them. Rather, the most likely situation in which a choice would need to made between bempedoic acid and statins would be for the treatment of patients with statin-associated adverse effects such as myopathy or diabetes, which could, in theory, be avoided with bempedoic acid.
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