CLEAR (Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen) OUTCOMES: a role for bempedoic acid in statin-intolerant high-risk patients

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Macrovascular Residual Risk Studies

6 July 2023

Lowering low-density lipoprotein cholesterol (LDL-C) with bempedoic acid reduced major adverse cardiovascular events in high-risk patients unable to tolerate statin therapy.

Nissen SE, Lincoff AM, Brennan D et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023; DOI: 10.1056/NEJMoa2215024

STUDY SUMMARY

Objective:

To investigate the effects of bempedoic acid on adverse cardiovascular events in patients for whom primary or secondary prevention is clinically indicated but who were unable or unwilling to take guideline-recommended doses of statin therapy

Study design:

This was a double-blind, randomized, placebo-controlled trial.

Study population:

Secondary prevention patients or high-risk primary prevention patients who were unwilling or unable to take statin therapy. All patients provided documented information that they were statin intolerant. Other lipid lowering therapies (ezetimibe, niacin, bile acid resins, fibrates, or proprotein convertase subtilisin–kexin type 9 inhibitors) were permitted.

Main study variables:

• Primary end point: four-component composite of major adverse cardiovascular events (MACE), defined as death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization
• Key secondary end points: three-component composite of death from cardiovascular causes, nonfatal stroke, or nonfatal MI; fatal or nonfatal MI; coronary revascularization; fatal or nonfatal stroke; death from cardiovascular causes; and death from any cause.

Methods:

Eligible patients who completed a 4-week run-in phase (single-blind placebo) were randomized to oral treatment with bempedoic acid (180 mg once daily) or matching placebo. At 6 months, the central laboratory informed the investigator if the patient’s LDL C was 25% or higher than the baseline value. The patient was counselled on healthy dietary guidelines and reminded to take all lipid-regulating medications. If the LDL-C level still remained above this threshold on repeat testing, the investigator was permitted to adjust the lipid lowering regimen according to the standard of care and local guidelines.

Results:

The study randomized 13,970 patients to treatment with bempedoic acid (n= 6992) or placebo (n=6978). The two groups were similar in baseline characteristics (mean age 65.5 years, 48% women, 46% with diabetes and 70% with a prior cardiovascular event). Overall, 3174 (23%) were taking a statin, and 1612 (11.5%) were receiving ezetimibe. Mean LDL-C at baseline was 139 mg/dL (3.59 mmol/L).

Patients were followed for a median of 40.6 months, with a similar duration of treatment in each group.

Treatment with bempedoic acid lowered LDL-C by 21.1% or 29.2 mg/dL (corrected for placebo) at 6 months, and was associated with significant reductions in the relative risk of MACE, the key 3-point outcome of cardiovascular death, nonfatal stroke and nonfatal MI; fatal or nonfatal stroke; and coronary revascularization (Table 1). Treatment with bempedoic acid did not significantly reduce the risk of fatal or nonfatal stroke, death from cardiovascular causes, or all-cause death. Bempedoic acid was well tolerated with a similar incidence of discontinuation due to adverse events, including adverse musculoskeletal effects, as with placebo.

Table 1. Effect of bemepdoic acid on primary and key secondary outcomes

Outcome, n (%)	Bempedoic acid	Placebo	Hazard ratio (95% CI)	p-value
Primary	819 (11.7%)	927 (13.3%)	0.87 (0.79 to 0.96)	0.004
Key secondary end points
Cardiovascular death, nonfatal stroke, or nonfatal MI	575 (8.2%)	663 (9.5%)	0.85 (0.76 to 0.96)	0.006
Fatal/nonfatal MI	261 (3.7%)	334 (4.8%)	0.77 (0.66 to 0.91)	0.002
Coronary revascularization	435 (6.2%)	529 (7.6%)	0.81 (0.66 to 0.91)	0.001

Authors’ conclusion:

Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of MACE (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization).

COMMENT

Statin therapy is first-line for the management of high-risk patients with elevated LDL-C levels, based on proven efficacy and reduction of cardiovascular events (1,2). However, a proportion of high-risk patients are unable to tolerate a statin (even at low doses), which impacts their clinical outcome (3,4). Bempedoic acid, an inhibitor of ATP-citrate lyase, is a pro-drug which is activated in the liver but not skeletal muscle, thereby lowering the risk of muscle-related adverse events (5). In previous studies, treatment with bempedoic acid was shown to lower LDL-C levels by up to 28% (6-9). However, it was uncertain whether this LDL-C lowering would translate to reduction in cardiovascular events.

The results of CLEAR-OUTCOMES demonstrate that bempedoic acid significantly reduces cardiovascular events in statin-intolerant patients with elevated LDL-C levels. The findings of this trial therefore inform guideline groups by confirming bempedoic acid as an evidence-based oral treatment alternative for the management of elevated LDL-C levels in high-risk patients unable or unwilling to tolerate statin therapy.

References

1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation 2019; 139: e1082-e1143.
2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188.
3. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel statement on assessment, aetiology and management. Eur Heart J 2015; 36: 1012-1022.
4. Serban MC, Colantonio LD, Manthripragada AD, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017:69:1386-1395.
5. Biolo G, Vinci P, Mangogna A, et al. Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome. Front Cardiovasc Med 2022;9:1028355.
6. Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol 2015; 9: 295-304.
7. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-1032.
8. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA 2019; 322: 1780-1788.
9. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019; 8: e011662-112.

Key words

bempedoic acid; statin intolerance; CLEAR OUTCOMES; cardiovascular events