Inflammation plays a central role in the pathogenesis of atherosclerosis and cardiovascular disease.¹ Atherosclerosis in particular is an inflammatory process that involves endothelial dysfunction, leukocyte adhesion, plaque formation and eventual rupture.² T-lymphocytes contribute by degrading fibrous caps and reducing collagen synthesis. These inflammatory mechanisms drive atherosclerosis progression and elevate the risk of cardiovascular events such as myocardial infarction (MI) and coronary artery disease (CAD).

High-sensitivity C-reactive protein (hsCRP), the most studied and validated biomarker of systemic inflammation, is a particularly strong predictor of cardiovascular risk.² Elevated hsCRP is associated with future MI, stroke and cardiovascular disease death in both primary and secondary prevention populations, based on evidence from randomized controlled trials (RCTs) and observational studies.^3-11

In primary prevention of atherosclerotic cardiovascular disease (ASCVD), an hsCRP ≥2 mg/L is considered a risk-enhancing factor in current guidelines.¹² hsCRP also predicts major adverse cardiovascular events (MACE) over the life course with 20 to 30 years of follow-up.^11,13 In patients with established ASCVD, elevated hsCRP is a marker of residual inflammatory risk and is a better predictor of future cardiovascular events and death than LDL-C.^14,15

This body of evidence highlights the utility of hsCRP testing in cardiovascular risk assessment and management. The recently released ACC Scientific Statement on Inflammation and Cardiovascular Disease now recommends universal screening of hsCRP in both primary and secondary prevention populations.

A Modifiable Risk Enhancer

It should be emphasized that hsCRP is modifiable and often can be lowered through behavioral and lifestyle interventions.¹⁵ Smoking cessation reduces systemic inflammation. One study reported a 0.40 mg/L reduction in individuals with established CVD,¹⁶ where improvements in inflammation were observed the longer an individual remained smoke-free.¹⁷ A meta-analysis showed that aerobic exercise reduces hsCRP by 0.59 mg/L in healthy adults and 0.34 mg/L in patients with cardiovascular disease.¹⁸ These reductions were independent of BMI and relative adiposity, but greater reductions were observed when both decreased concurrently with exercise intervention.¹⁹

Weight loss studies report a 0.25 mg/L decrease per 6.4 kg and an average reduction of 0.13 mg/L per kg.^16,20 Surgical weight loss interventions have resulted in some of the largest reductions of inflammation.²⁰

The American Heart Association's Life's Essential 8 (LE8) emphasizes the cumulative impact of multiple lifestyle and modifiable risk factors on cardiovascular health.²¹ Multiple studies show that suboptimal LE8 metrics are associated with higher hsCRP levels.^22,23 For example, patients with a low LE8 score are nearly six-times more likely to have an hsCRP level >3 mg/L.²⁴

Heart-healthy dietary patterns can lower hsCRP. A meta-analysis of RCTs of the Mediterranean diet reported a 0.98 mg/L decrease in hsCRP.²⁵ High-risk patients had lower CRP levels on the diet plus olive oil than controls in PREDIMED.²⁶ A vegan diet was associated with a 0.54 mg/L reduction in hsCRP vs. a diet with plant plus animal products.²⁷ In EVADE CAD, patients randomized to a vegan diet had a 32% lower hsCRP.²⁸ Both high-fiber DASH and fiber-supplemented diets reduce CRP levels.²⁹ Another RCT showed that a high-fiber diet reduced hsCRP by 28%, comparable to treatment with lovastatin (20 mg/d).³⁰

Drugs to Reduce hsCRP

Statins reduce hsCRP to varying degrees.^31,32 For example, a study comparing simvastatin (40 mg/d) and atorvastatin (80 mg/d) reported hsCRP reductions of 4.3 mg/L and 3.7 mg/L, respectively.³² Similar effects were reported with rosuvastatin and pravastatin.^31,33 Initiation or intensification of statin therapy should be considered in patients with persistently elevated hsCRP, irrespective of LDL-C level.¹⁵ Bempedoic acid (BA) can also reduce hsCRP.⁹ BA lowered LDL-C by 22.5% and hsCRP by 23.2% in patients with obesity (> BMI 30 kg/m2).³⁴ Though ezetimibe alone does not lower serum CRP concentrations,^33,35 ezetimibe plus BA lowered hsCRP by 26-38%.³⁵

Colchicine is known to reduce hsCRP, and recent meta-analyses showed that low-dose colchicine reduces MACE in patients with established cardiovascular disease.^36-38 However, in other RCTs low-dose colchicine did not reduce CV risk in patients after acute MI or stroke, and therefore may not be beneficial at the time of acute ischemia.^39-41 Even so, low-dose colchicine is now approved by the U.S. Food and Drug Administration and has a class 2b recommendation for secondary prevention in patients with CAD, and can be considered specifically for patients with chronic stable CAD.^15,42–44 Use of colchicine is generally safe but may cause mild diarrhea which typically resolves quickly, and is contraindicated in patients with estimated GFR <45 mL/min/1.73m2 or hepatic dysfunction.^15,38,42,45

GLP-1 RAs reduce inflammation and cardiovascular risk.⁴⁶ The SELECT trial found a 20% risk reduction in MACE, 28% in MI and all-cause mortality by 19% with semaglutide.⁴⁶ Semaglutide lowered inflammation in patients with type 2 diabetes and overweight or obese.^47,48 In patients with heart failure with preserved ejection fraction and obesity, it reduced inflammation by 43.5% vs. 7.3% in the control group.⁴⁹

In summary, universal screening of hsCRP in both primary and secondary prevention patients is now recommended.¹⁵ Clinicians should consider hsCRP ≥2 mg/L as a risk enhancer when assessing ASCVD risk in primary prevention and may be particularly useful when a patient is deemed at intermediate risk.^12,15 For patients with persistently elevated hsCRP, initiate or intensify lipid-lowering therapy regardless of their LDL-C level. Consider colchicine for patients with chronic stable CAD to help treat residual inflammatory risk. Use of hsCRP testing can also help guide lifestyle recommendations and other pharmacologic interventions.

References

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Clinical Topics: Dyslipidemia, Prevention, Nonstatins, Novel Agents, Statins

Keywords: Cardiology Magazine, ACC Publications, Primary Prevention, Atherosclerosis, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors