Efficacy and Safety of Ezetimibe Added to Atorvastatin Versus Atorvastatin Uptitration or Switching to Rosuvastatin in Patients With Primary Hypercholesterolemia

Study Questions:

What is the relative efficacy/safety of adding ezetimibe to low-dose atorvastatin compared to doubling the dose or switching to rosuvastatin 10 mg?


Hypercholesterolemic patients (n = 1,547) at high atherosclerotic cardiovascular disease risk with low-density lipoprotein cholesterol (LDL-C) levels ≥100 and ≤160 mg/dl while treated with atorvastatin 10 mg/day entered a multicenter, randomized, double-blind, active-controlled clinical trial using two 6-week study periods. Period I compared the efficacy/safety of: 1) adding ezetimibe 10 mg (ezetimibe) to stable atorvastatin 10 mg, 2) doubling atorvastatin to 20 mg, or 3) switching to rosuvastatin 10 mg. Subjects in the latter two groups who persisted with elevated LDL-C levels after period I, entered period II; subjects on atorvastatin 20 mg had ezetimibe added to atorvastatin 20 mg, or uptitrated their atorvastatin to 40 mg; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe, or uptitrated rosuvastatin to 20 mg.


At the end of period I, ezetimibe plus atorvastatin 10 mg reduced LDL-C more than atorvastatin 20 mg or rosuvastatin 10 mg (22.2% vs. 9.5% or 13.0%, respectively; p < 0.001). At the end of period II, ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg (17.4% vs. 6.9%; p < 0.001); switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg (17.1% vs. 7.5%, p < 0.001). Relative to comparative treatments, ezetimibe added to atorvastatin 10 mg (period I) or atorvastatin 20 mg (period II) produced greater percent attainment of LDL-C targets <100 or <70 mg/dl, and significantly greater percent reductions in total cholesterol, non–high-density lipoprotein cholesterol, and most ratios. Reports of adverse experiences were generally similar among groups.


Treatment of hypercholesterolemic subjects at high cardiovascular risk with ezetimibe added to atorvastatin 10 or 20 mg produced significantly greater improvements in key lipid parameters and significantly greater attainment of LDL-C treatment targets than doubling atorvastatin or switching to (or doubling) rosuvastatin at the compared doses.


The novel contribution is that the study was a ‘real-life’ treat-to-target design. The results support the well-recognized evidence that ezetimibe reduces the LDL-C by about 18% and doubling the dose of statins reduces LDL-C by an additional 6-7%. While adding ezetimibe to statins appears safe, the cost-benefit and true value of the combination is awaiting a definitive cardiovascular disease outcome trial.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Fluorobenzenes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pyrimidines, Lipoproteins, Risk Factors, Heptanoic Acids, Hypercholesterolemia, Pyrroles, Cholesterol, Dyslipidemias, Azetidines, Cardiology, Cardiovascular Diseases, Sulfonamides

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