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Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients
Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.
We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.
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.
Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).
Disclosure statements are available on the authors' profiles:
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant PatientsN. Engl. J. Med 2023 Mar 04;[EPub Ahead of Print], SE Nissen, AM Lincoff, D Brennan, KK Ray, D Mason, JJP Kastelein, PD Thompson, P Libby, L Cho, J Plutzky, HE Bays, PM Moriarty, V Menon, DE Grobbee, MJ Louie, CF Chen, N Li, L Bloedon, P Robinson, M Horner, WJ Sasiela, J McCluskey, D Davey, P Fajardo-Campos, P Petrovic, J Fedacko, W Zmuda, Y Lukyanov, SJ Nicholls
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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The problem of statin intolerance, typically myalgias, represents one of the most challenging and frustrating clinical problems encountered by physicians and other caregivers who treat patients with preexisting cardiovascular disease or those at high risk for a first event. Despite explaining the benefits of lowering LDL-C levels with statins, some patients will decline treatment, thereby placing themselves at a high risk for cardiovascular morbidity and mortality. Bempedoic acid is not active in peripheral tissues when administered orally, requiring conversion in the liver to an active moiety. This property results in a low incidence of statin-associated muscle symptoms. The CLEAR Outcomes trial demonstrated that administration of bempedoic acid, compared with placebo, resulted in a significant reduction in the primary four-component major adverse cardiovascular event endpoint and several key secondary endpoints, including three-component major adverse cardiovascular events, myocardial infarction, and coronary revascularization but not cardiovascular death. These findings establish bempedoic acid as a safe and effective alternative in patients unable or unwilling to take statins.
Protecting statin-intolerant patients with Bempedoic Acid
Statin-intolerant patients are basically left unprotected from CVD that is driven by LDL cholesterol. Statins block the HMG-CoA reductase enzyme, which is a critical step in the production of cholesterol in the liver. When this is blocked, the liver cells can not make cholesterol; therefore, the liver cells increase the number of LDL receptors on its surface so that they can grab LDL particles and pull them into the liver to use their cholesterol. This means fewer LDL particles in the blood, which means less chance of these LDL particles entering the walls of the blood vessels and forming plaques.
In statin-intolerant patients, the statin causes issues in muscle cells, which is never the intended target. The target is the liver cells. So far, there are no liver-specific statins.
Bempedoic acid blocks the ATP citrate lyase, which is the enzyme that is one step before the HMG CoA reductase in the cholesterol production cascade. This means that bempedoic acid would also lead to reduced cholesterol production in the liver, and hence would cause the liver to increase the LDL receptors and pull in more LDL particles. Effectively, it will cause the same effects as statin therapy.
However, the main difference is that bempedoic acid is a pro-drug that is activated in liver cells but not in muscle cells. This selective activation means that there is no effect on cholesterol metabolism in the muscle cells. This means that it could be used in statin-intolerant patients to lower their LDL cholesterol. However, we still need to prove that this would help reduce cardiovascular events.
This CLEAR Outcomes trial enrolled 13,970 patients and tested bempedoic acid versus placebo, with a median follow-up time of 40.6 months. The LDL cholesterol reduction was a modest 21.1% from baseline. However, there were significant reductions in cardiovascular events.
The primary outcome of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization was reduced by 13% (HR 0.87; 95% CI: 0.79–0.96; P = .004). Myocardial infarction was reduced on its own by 23% (HR 0.77; 95% CI: 0.66–0.91; P = .002). Coronary revascularization on its own was reduced by 19% (HR 0.81; 95% CI: 0.72–0.92; P = .001).
There were no significant effects on stroke or death endpoints. There was a slight increase in gout and cholelithiasis (3.1% vs 2.1% and 2.2% vs 1.2%, respectively), and there were some small increases in serum creatinine, uric acid, and hepatic enzyme levels.
The bottom line is that bempedoic acid is now a good option for patients who cannot take statins. But remember, statins should still be our first choice due to their strong evidence of benefit. We should not be thinking, “let's use bempedoic acid for all our patients because it has fewer muscle side effects”. No — we should continue to use statins for all and reserve bempedoic acid for the patients that have true statin intolerance.