Crestor vs Zetia: Head-to-Head Efficacy Compared

How much does each drug lower LDL cholesterol?

Rosuvastatin inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and more than 90% of its circulating enzyme-blocking activity comes from the parent drug rather than a metabolite [3]. In JUPITER, 17,802 apparently healthy adults with LDL-C under 130 mg/dL and high-sensitivity C-reactive protein of 2.0 mg/L or higher took rosuvastatin 20 mg daily or placebo; LDL-C fell 50% [1]. In METEOR, 984 adults with subclinical carotid atherosclerosis took rosuvastatin 40 mg or placebo for two years, and mean LDL-C dropped from 155 to 78 mg/dL, a 49% reduction [5].

Ezetimibe works at the intestinal brush border, blocking the NPC1L1 sterol transporter, so less cholesterol reaches the liver and LDL receptors increase [2]. In two pooled 12-week placebo-controlled trials in 1,719 adults, ezetimibe 10 mg lowered LDL-C by 18% versus a 1% rise on placebo, and total cholesterol by 13% versus 0% [2]. Maximal response generally arrived within about two weeks [2].

What does ezetimibe add when a statin is already in place?

In an 8-week trial of 769 patients already taking a statin and still above their LDL goal, adding ezetimibe lowered LDL-C by 25% versus 4% when placebo was added, and total cholesterol by 17% versus 2% [2]. LDL reductions were consistent across the statins used, which were mainly atorvastatin (40% of patients) and simvastatin (31%) [2].

When ezetimibe was started at the same time as a statin rather than added later, the combination of ezetimibe with atorvastatin 10 mg lowered LDL-C by 53% versus 37% with atorvastatin 10 mg alone [2].

What do the cardiovascular outcomes trials show?

JUPITER is the rosuvastatin outcomes trial. The primary endpoint of myocardial infarction, stroke, arterial revascularization, unstable angina hospitalization or cardiovascular death occurred at 0.77 versus 1.36 per 100 person-years (hazard ratio 0.56, 95% CI 0.46 to 0.69) [1]. The trial was stopped early after a median follow-up of 1.9 years [1]. The Crestor label reports 142 versus 252 events in JUPITER, a 44% relative risk reduction and a 1.2% absolute risk reduction [3].

IMPROVE-IT is the ezetimibe outcomes trial, and it tested a combination. It enrolled 18,144 patients hospitalized for acute coronary syndrome within the previous 10 days and compared simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg plus placebo, over a median of 6 years [4]. Mean on-treatment LDL-C was 53.7 versus 69.5 mg/dL, and the 7-year event rate for the primary composite endpoint was 32.7% versus 34.7% (hazard ratio 0.936, 95% CI 0.89 to 0.99, p=0.016) [4].

Put plainly, the two trials answered different questions in different populations. JUPITER tested a statin against placebo in apparently healthy people with elevated high-sensitivity C-reactive protein. IMPROVE-IT tested whether adding ezetimibe to a statin helps people who had just had an acute coronary syndrome.

What each label is actually approved for

The Crestor label lists an indication to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, arterial revascularization) in adults at increased risk, alongside LDL-C lowering in primary hypercholesterolemia, slowing progression of atherosclerosis, heterozygous familial hypercholesterolemia from age 8, homozygous familial hypercholesterolemia from age 7, dysbetalipoproteinemia and hypertriglyceridemia [3].

The Zetia label is narrower: it is indicated, in combination with a statin or alone when additional LDL-C lowering therapy is not possible, to reduce elevated LDL-C in adults with primary hyperlipidemia including heterozygous familial hypercholesterolemia, with a statin in children 10 and older with that condition, with fenofibrate in mixed hyperlipidemia, with a statin and other LDL-lowering therapies in homozygous familial hypercholesterolemia, and for sitosterolemia from age 9 [2]. It contains no cardiovascular risk-reduction indication and no mention of IMPROVE-IT [2].

Side effects: what the labels report

In ezetimibe monotherapy trials (2,396 patients on ezetimibe 10 mg versus 1,159 on placebo, median 12 weeks), the reported rates were upper respiratory infection 4.3% versus 2.5%, diarrhea 4.1% versus 3.7% and arthralgia 3.0% versus 2.2% [2]. With a statin, myalgia was 3.2% versus 2.7% on the statin alone [2]. The ezetimibe label warns that it may cause myopathy and rhabdomyolysis, and that in postmarketing reports most patients who developed rhabdomyolysis were also taking a statin or another agent such as a fibrate; consecutive transaminase rises of at least three times the upper limit of normal occurred in 1.3% with ezetimibe plus a statin versus 0.4% with a statin alone [2].

For rosuvastatin, short placebo-controlled trials of up to 12 weeks reported myalgia in 2.8% of patients receiving rosuvastatin versus 1.3% receiving placebo, and transaminases above three times the upper limit of normal in 1.1% versus 0.5% on placebo [3]. In JUPITER, myalgia was 7.6% versus 6.6%, diabetes mellitus reported 2.8% versus 2.3%, and mean HbA1c was 0.1% higher on rosuvastatin [3]. In METEOR, myalgia was 12.7% versus 12.1% and increased creatine phosphokinase 2.6% versus 0.7% [3]. The rosuvastatin label lists myopathy and rhabdomyolysis as a warning, with higher risk at the 40 mg dose and in people aged 65 or older, with uncontrolled hypothyroidism, or with renal impairment [3].

The ezetimibe label states that adverse reaction rates from different clinical trials cannot be directly compared, because the trials ran under different conditions [2].

Taking rosuvastatin and ezetimibe together

Ezetimibe is labeled for use in combination with a statin [2]. The Crestor label does not list ezetimibe among the drugs that carry a rosuvastatin dose cap (such as cyclosporine, gemfibrozil and certain antivirals) [3]. Ezetimibe 10 mg daily raised rosuvastatin exposure (AUC) 1.2-fold, with a 90% CI of 0.9 to 1.6, meaning no clear change [3]. When the two are used together, the ezetimibe label defers to the statin's own prescribing information for the combination's risks [2].