By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships relevant to this field of study.
SYNOPSIS: The addition of ezetimibe to statin therapy in stable patients who had suffered an acute coronary syndrome and who had LDL cholesterol levels already within guideline recommendations further lowers the risk of cardiovascular events.
SOURCE: Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397.
The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has been clearly demonstrated to reduce both low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events in patients with and without cardiovascular disease.1-4 Because of the residual risk of recurrent cardiovascular events and safety concerns associated with high-dose statin therapy,5 additional lipid-modifying therapies that would reduce LDL levels in patients who are on maximal statin therapy have been sought.6,7
Ezetimibe reduces the absorption of cholesterol from the intestine and, when added to statin drug therapy, has been demonstrated to reduce LDL cholesterol levels by an additional 23% to 24% on average.8,9 Because of the uncertainty as to whether further lowering of LDL cholesterol levels achieved with the addition of ezetimibe to statin therapy would lead to a benefit in clinical outcomes, representatives from the Thrombolysis in Myocardial Infarction (TIMI) study group and the Duke Clinical Research Institute (DCRI), in collaboration with an international steering committee, organized a large study in patients who receive standard medical and interventional treatment for acute coronary syndromes. Subjects were randomly assigned in a double-blind fashion to receive either simvastatin in a dose of 40 mg once daily or simvastatin/ezetimibe in doses of 40 mg and 10 mg, respectively.10 The study enrolled a total of 18,144 patients who were randomized at 1147 sites in 39 countries. The baseline characteristics of the patients in the two studies were well matched. Simvastatin increased to 80 mg for elevated LDL cholesterol levels in 27% of patients in the simvastatin-monotherapy group and in 6% of the patients in the simvastatin-ezetimibe group. The results demonstrated that the addition of ezetimibe to statin therapy in stable patients recovering from an acute coronary syndrome and who had LDL cholesterol levels within guideline recommendations further lowered LDL cholesterol levels and the risk of cardiovascular events. No adverse or toxic events were observed.
The results of the IMPROVE- IT trial in essence demonstrated that the combination of simvastatin and ezetimibe resulted in significantly lower LDL levels and a lower risk of cardiovascular events than occurred in patients who are treated with statin monotherapy.10 These findings directly support the conclusion that a non-statin lipid-lowering agent can also reduce cardiovascular risk and indirectly support the LDL hypothesis; that is, lowering LDL cholesterol leads to a reduction in cardiovascular events and the benefits occurred because the LDL cholesterol was lowered and not simply because patients were given a statin drug. The same relationship between reduction in LDL cholesterol levels and clinical benefits is seen even when different statins and/or different statin doses are administered.4 It is quite probable that even greater LDL-lowering benefits from ezetimibe therapy may have been seen if statins had not been initially used. Therefore, baseline LDL levels almost certainly would have been higher.
Other LDL cholesterol-lowering drugs for use with statin drugs are now being tested, such as PCSK9, an injectable drug that in early studies has been extremely effective in reducing LDL to very low levels with improvement in all cardiovascular outcomes. It should be clearly recognized that all patients in the IMPROVE-IT trial had been hospitalized for acute coronary syndrome within the preceding 10 days, and, therefore, the findings in this study cannot be extended to the vast population of patients who require LDL cholesterol-lowering to prevent the onset of symptomatic coronary artery disease. However, it seems logical to assume based on previously published data1-4 that intensive LDL cholesterol-lowering by any means would be an appropriate form of therapy for primary cardiovascular disease prevention to prevent the onset of symptomatic coronary artery disease, as well as for secondary prevention of cardiovascular disease.
- Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol-lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.
- Heart Protection Study Collaborative Group. MRC/BHF Hearts Protection Study of cholesterol-lowering with simvastatin in 20,536 high risk individuals: A randomized placebo-controlled trial. Lancet 2002;360:7-22.
- Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statin. Lancet 2005;366:1267-1278.
- Balgent C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet 2010;376:1670-1681.
- Preiss D, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis. JAMA 2011;305:2556-2564.
- Boden WE, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2014;371:203-212.
- Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:289-299.
- Ballantyne CM, et al. Efficacy and safety of ezetimibe coadministered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Card 2004;93:1487-1494.
- Morrone D, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: A pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012;223:251-261.
- Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397.