Inflammation At Least As Important As Cholesterol for Predicting CV Risk in Statin-intolerant Patients

A collaborative analysis of three randomized, controlled trials (n=31,245) published in The Lancet showed that among patients receiving statin therapy, high-sensitivity C-reactive protein (hsCRP) more strongly predicted future cardiovascular risk, especially cardiovascular death, than low-density lipoprotein cholesterol (LDLC).

Now, Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, and colleagues have published similar results from a large cohort of patients not taking statins. In Circulation, they say inflammation assessed by hsCRP predicted cardiovascular events and death at least as strongly as LDLC in the CLEAR-Outcomes trial, which compared bempedoic acid with placebo in statin-intolerant patients.


CLEAR-Outcomes was conducted at 1,250 sites in 32 countries. 13,970 patients with LDLC >100 mg/dL were randomly assigned to receive 180 mg of bempedoic acid or placebo between December 2016 and August 2019.

Eligible participants either had a previous cardiovascular event (n=9,764, 70%) or were at high risk of cardiovascular events and were unable or unwilling to use a statin because of an adverse effect that started or increased during statin therapy and resolved or improved after discontinuation. At trial entry, the median hsCRP was 2.3 mg/L, and the median LDLC was 135 mg/dL.

The primary endpoint was the composite of future myocardial infarction, stroke, coronary revascularization, and cardiovascular death. Patients were followed for a median of 41 months (maximal follow-up five years).

Individual Effects of Inflammation and Cholesterol

Baseline hsCRP quartile (highest vs. lowest) was significantly associated with:

  • The primary composite endpoint—adjusted HR (aHR), 1.43; P<0.0001
  • Cardiovascular mortality—aHR, 2.00; P<0.0001
  • All-cause mortality—aHR, 2.21; P<0.0001

The relationship of baseline LDLC quartile to future cardiovascular events was of smaller magnitude for the composite endpoint (aHR, 1.19; P=0.01) and nonsignificant for cardiovascular mortality (aHR, 0.90; P=0.44) and all-cause mortality (aHR, 0.95; P=0.60).

Joint Effects of Inflammation and Cholesterol

Regardless of LDLC strata, risks were significantly higher for study participants with above-median hsCRP than those who had below-median hsCRP:

LDLC ≥130 mg/dL and hsCRP <2 mg/L

  • Primary composite endpoint—aHR, 1.16; P=0.06 vs. LDLC <130 mg/dL and hsCRP <2 mg/L
  • Cardiovascular mortality—aHR, 0.84; P=0.26
  • All-cause mortality—aHR, 0.86; P=0.21

LDLC <130 mg/dL and hsCRP ≥2 mg/L

  • Primary composite endpoint—aHR, 1.25; P=0.004
  • Cardiovascular mortality—aHR, 1.37; P=0.02
  • All-cause mortality—aHR, 1.51; P=0.0001

LDLC ≥130 mg/dL and hsCRP ≥2 mg/L

  • Primary composite endpoint—aHR, 1.46; P<0.0001
  • Cardiovascular mortality—aHR, 1.54; P=0.0009
  • All-cause mortality—aHR, 1.63; P<0.0001

Benefits of Bempedoic Acid

Compared with placebo, bempedoic acid:

  • Reduced median hsCRP by 22% at six months
  • Reduced mean LDLC by 21% at six months
  • Reduced the incidence of the composite endpoint by 13% (HR, 0.87; 95% CI, 0.79–0.96)

Among the 4,206 patients with no history of cardiovascular disease, those who used bempedoic acid had a 30% reduction in the risk of first major adverse cardiovascular events (HR, 0.70; P=0.002).

Guidance for the Clinic

Both LDLC and hsCRP need to be measured to quantify the risk of cardiovascular events and inform the choice of medication. For example, it’s worth noting that in June 2023, the FDA approved low-dose colchicine as the first anti-inflammatory therapy for primary or secondary prevention of cardiovascular events and death. Combination regimens that aggressively lower both LDLC and hsCRP may be optimal.

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