What is the effect of statins (HMG-CoA reductase inhibitors) on calcified atherosclerosis?

From the Guidelines

Statins have no direct effect on calcified atherosclerosis, but they do demonstrate mortality and CV event reduction in patients with peripheral arterial and aortic diseases, including those with calcified atherosclerosis 1.

Key Points

• Statins significantly improve CV outcomes in patients with PAD, reducing major adverse limb events (MALE) and improving walking distances 1.
• There is mixed evidence suggesting statins may mitigate AAA and TAA growth, but most patients with AAA or TAA present with associated CV risk factors, and liberal use of lipid-lowering treatment should be considered on an individualized basis 1.
• Statin use was associated with a mean AAA growth rate reduction and risk of rupture, but no benefit on AAA or TAA growth rate was shown with fenofibrate therapy 1.
• For calcific aortic stenosis (AS), statin therapy is not indicated for prevention of hemodynamic progression in patients with mild-to-moderate calcific valve disease, as 3 large well-designed RCTs failed to show a benefit either in terms of changes in hemodynamic severity or in clinical outcomes 1.

Clinical Implications

• Statins should be used to reduce CV risk in patients with calcified atherosclerosis, but not specifically to slow the progression of calcification.
• Treatment of associated CV risk factors, such as hypertension and hypercholesterolemia, is essential in patients with calcified atherosclerosis.
• The use of statins in patients with calcific AS should be guided by the presence of concurrent CAD or other CV risk factors, rather than the intention to slow AS progression.

From the Research

Effect of Statins on Calcified Atherosclerosis

• The use of statins has been associated with an increase in atherosclerotic plaque calcification in peripheral arteries, such as the carotids, after long-term therapy 2, 3.
• Despite this increase in calcification, statins have been shown to promote a "favorable" atherosclerotic calcification, suppressing atherosclerotic lesion expansion and their vulnerability 2.
• Studies have found that statins disrupt the complex between Rac1 and its inhibitor RhoGDI, leading to increased active Rac1 in primary monocytes/macrophages, which can increase atherosclerotic calcification 4.
• The PARADIGM study found that statins were associated with a slower rate of overall plaque volume progression, but more rapid progression of calcified plaque volume 5.
• A systematic review and meta-analysis found that statins slowed down coronary artery calcification progression mildly, but with statistical significance in populations with a baseline calcification score >400 6.

Plaque Composition and Stability

• Statin treatment has been associated with a higher presence of calcification and a lower presence of lipid core in carotid plaques 3.
• The presence of calcification in plaques has been associated with higher plaque stability, reducing the risk of consequent adverse events 2, 3.
• Statins have been shown to induce phenotypic plaque transformation, with increased plaque calcification and reduction of high-risk plaque features 5.

Cardiovascular Outcomes

• The relationship between coronary artery calcification progression under statin therapy and cardiovascular outcomes is still unclear, with some studies suggesting that baseline calcification score has more decisive effects on cardiovascular outcomes 6.
• Despite the increase in calcification, statins have been shown to reduce the risk of major adverse cardiovascular events 2, 5.