CLEAR Outcomes study - bempedoic acid and cardiovascular outcomes in statin intolerant patients

Last edited 03/2023 and last reviewed 03/2023

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

Commentary (4):

"The CLEAR Outcomes provides evidence of cardivascular benefit for the use of bempedoic acid in patients with high risk of cardiovascular disease or established atherosclerotic cardiovascular disease who are "statin intolerant". The evidence of cardiovascular benefit for a lipid lowering therapy adds to the options of the armoury of evidence based lipid lowering treatments of statins, ezetimibe, PCSK9 inhibitors and icosapent ethyl.

The absolute benefit risk reduction of the primary end point (4-component MACE, defined as nonfatal MI, nonfatal stroke, coronary revascularization or CV death) achieved in the CLEAR Outcomes Study was 1.6% which reflects a number needed to treat (NNT) of 63. Also of note is that the p value for significance was p=0.004 because of the trial design and not p=0.001.

Of the six prespecified secondary end-points (secondary end-points are not powered by the study to be causal but only "points of interest") three were significantly achieved with bempedoic acid - the 3-component MACE, defined as nonfatal MI, nonfatal stroke or CV death; fatal or nonfatal MI, coronary revascularization. Bempedoic acid however had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.

Bempedoic acid showed significant reductions in LDL-cholesterol (LDL-c) and high sensitivity CRP (hs CRP) and at 6 months, bempedoic acid reduced LDL-c by 21.7% and hsCRP by 22.2%. The ability to significantly reduce hsCRP has been shown by statins but not by PCSK9 inhibitors or ezetimibe and may contribute to the cardiovascular risk reductions seen in the CLEAR Outcomes Study despite a relatively small LDL-C reduction compared with for example atorvastatin 20mg per day which achieves an approximate 44% LDL-C reduction.

The incidences of some adverse effects was higher with bempedoic acid than placebo

  • 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)
  • hyperuricemia (10.9% vs. 5.6%) (NNH=19)

So in conclusion, this is good news. Another lipid lowering agent with evidence based effect. Bempedoic acid has evidence of benefit in patients with high cardiovascular risk who are "statin intolerant". Also bempedoic acid significantly reduces hsCRP and this anti-inflammatory property may contribute to the cardiovascular benefits seen in the CLEAR Outcomes study. There are increased adverse effects associated with bempedoic acid use and the balance of potential benefits and harms must be considered when using this - or any other - pharmaceutical agent in our patient population."

Reference:

Related pages:

bempedoic acid