Does statin (HMG-CoA reductase inhibitor) reduce calcified atherosclerosis?

From the Guidelines

Statin therapy reduces calcified atherosclerosis.

Mechanism of Action

The beneficial effect of statins on ischemic stroke is most likely related to their capacity to reduce progression or induce regression of atherosclerosis 1.

• Statins inhibit the HMG-CoA reductase enzyme, the rate-limiting step in cholesterol biosynthesis, and are powerful drugs for lowering LDL-C 1.
• High-intensity statin therapy appears to confer incremental clinical benefit compared with less intensive therapy, producing a highly significant 15% further reduction in major vascular events, driven by reductions in coronary death or non-fatal MI, coronary revascularization, and ischemic stroke 1.

Clinical Evidence

• A meta-analysis of 26 trials that included >90,000 patients found that statins reduced the risk of all strokes by ≈21% (95% CI, 15–27) 1.
• Another meta-analysis of randomized trials of statins in combination with other preventive strategies that included 165,792 individuals showed that each 1-mmol/L (39-mg/dL) decrease in LDL cholesterol was associated with a 21.1% (95% CI, 6.3–33.5; P=0.009) reduction in stroke 1.
• The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends treatment of patients ≤75 y of age who have clinical atherosclerotic cardiovascular disease (including those with MI) with high-intensity statin 1.

Key Points

• Statin therapy should be individualized in persons >75 y of age according to the potential for ASCVD risk-reduction benefits, adverse effects, drug-drug interactions, and patient preferences 1.
• The intensity of statin therapy depends on the drug and the dose, with examples including lovastatin at 20 mg/d (low-intensity therapy) and atorvastatin at 80 mg/d (high-intensity therapy) 1.

From the FDA Drug Label

Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40 to 80 years of age (mean of 63 years; 19% female; 95% White, 3% Black or African American, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p=0. 0005 Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). The FDA drug label does not answer the question.

From the Research

Statin Effects on Calcified Atherosclerosis

• The use of statins has been associated with an increase in calcified atherosclerotic plaques in some studies 2, 3, 4, 5.
• A study published in the International Journal of Cardiology found that statin treatment was associated with a higher presence of calcification in carotid atherosclerotic plaques 2.
• Another study published in Frontiers in Cardiovascular Medicine found that statins slowed down the progression of coronary artery calcification, but did not reduce or enhance it 6.
• A narrative review published in Reviews in Cardiovascular Medicine suggested that statins may promote a "favorable" atherosclerotic calcification, suppressing atherosclerotic lesion expansion and their vulnerability 3.
• A study published in JAMA Cardiology found that statin therapy was associated with greater rates of transformation of coronary atherosclerosis toward high-density calcium, which was associated with less plaque progression 4.
• The PARADIGM study published in JACC: Cardiovascular Imaging found that statins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features 5.

Key Findings

• Statins may increase the presence of calcified atherosclerotic plaques, but this may be associated with a more stable plaque phenotype 2, 3, 4, 5.
• The progression of coronary artery calcification may be slowed down by statin therapy, but the overall effect on cardiovascular outcomes is still unclear 6.
• Statins may promote a phenotypic transformation of atherosclerotic plaques, leading to a more stable and less vulnerable plaque type 3, 4, 5.