CLEAR Outcomes study - bempedoic acid and cardiovascular outcomes in statin intolerant patients
Bempedoic acid is a first-in-class, small-molecule inhibitor of ATP-citrate lyase, a component of the cholesterol biosynthesis pathway that works upstream of beta-hydroxy beta-methylglutaryl-coenzyme A.
- Bempedoic acid is a prodrug that is activated by very-longchain acyl-CoA synthetase-1, an enzyme that is not present in skeletal muscle
- therefore bempedoic acid acts on the same pathway as statins - however lack of the activating enzyme in skeletal muscle may prevent the muscular adverse effects associated with statins (1)
- in phase 2 and phase 3 clinical trials, bempedoic acid significantly reduced atherogenic lipoproteins and high-sensitivity C-reactive protein (hsCRP) levels, and was associated with a low risk for adverse events typically associated with statins such as muscle-related symptoms and new-onset diabetes mellitus
Bempedoic acid - CLEAR Outcomes study (cardiovascular outcomes in statin intolerant patients)
- study design
- randomized, double-blind, placebo-controlled clinical trial
- included patients must have all of the following:
- (i) established atherosclerotic cardiovascular disease or have a high risk of developing atherosclerotic cardiovascular disease,
- (ii) documented statin intolerance, and
- (iii) an LDL-C >=2.6 mmol/l on maximally-tolerated lipid-lowering therapy
- randomized to treatment with bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy
- primary endpoint was 4-component MACE, defined as nonfatal MI, nonfatal stroke, coronary revascularization or CV death
- trial was designed to continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months (2)
- study results (3)
- total of 13,970 patients underwent randomization
- 6992 were assigned to the bempedoic acid group and 6978 to the placebo group
- median duration of follow-up was 40.6 months
- mean LDL cholesterol level at baseline was 3.5 mmol/l in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 0.75 mmol/l
- at 6 months, bempedoic acid reduced LDL-c by 21.7% and hsCRP (high sensitivity CRP) by 22.2%
- in comparison, a 0.6% reduction in LDL-c and an increase of 2.2% in hsCRP was observed in the placebogroup at 6 months
- incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; (absolute risk reduction of 1.6%) Number needed to treat (NNT) was 63
- hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P=0.004)
- the first 3 secondary endpoints were reduced as well by bempedoic acid:
- a 15% reduction in 3-component MACE (HR 0.85, 95%CI 0.76-0.96, P=0.006, ARR 1.3%),
- a 23% reduction in fatal or nonfatal MI (HR 0.77, 95%CI 0.66-0.91, P=0.002, ARR 1.1%) , and a
- 19% reduction in coronary revascularization (HR 0.81, 95%CI 0.72-0.92, P=0.001, ARR 1.4%).
- bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause
- incidences of gout (3.1% vs. 2.1%) Number needed to harm (NNH) = 100, cholelithiasis (2.2% vs 1.2%) NNH =100, renal impairment (11.5% vs. 8.6%) (NNH = 34), elevated hepatic-enzyme level (4.5% vs. 3.0%) (NNH=66) and hyperuricemia (10.9% vs. 5.6%) (NNH=19) were higher in the bempedoic acid group compared to the placebo group
- conclusion:
- CLEAR Outcomes study showed that among statin-intolerant primary and secondary prevention patients, bempedoic acid reduced the risk of the primary composite endpoint of nonfatal MI, nonfatal stroke, coronary revascularization or CV death
In a sub-analysis of bempedoic acid in primary prevention of cardiovascular disease in statin-intolerant patients (3):
- 4206 participants were enrolled with high cardiovascular risk but without a prior cardiovascular event. In this subgroup, bempedoic acid treatment, 180 mg daily, was associated with a significant reduction in major cardiovascular events (hazard ratio, 0.70)
- mean participant age was 68 years, 59% were female, and 66% had diabetes
- follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89] NNT=43; P=.002)
Reference: