Zetia vs Praluent Side Effects: Ezetimibe vs Alirocumab Head-to-Head Comparison

Two different drugs, two different reaction lists

Ezetimibe blocks the sterol transporter NPC1L1 at the brush border of the small intestine; in a 2-week trial in 18 patients it inhibited cholesterol absorption by 54% compared with placebo [1]. Alirocumab is a human monoclonal antibody that binds PCSK9 [5].

Ezetimibe is a 10 mg tablet taken once daily, with or without food [1]. Alirocumab is injected; FDA records list Praluent as 75 mg and 150 mg injectable products approved on 24 July 2015 [3].

The percentages below come from separate trial programs with different comparators and durations, so they cannot establish which drug is better tolerated overall. ODYSSEY ALTERNATIVE did compare the two drugs directly over 24 weeks in people with statin intolerance [4].

What the Zetia label reports

In ten placebo-controlled trials of ezetimibe alone (2,396 on ezetimibe, 1,159 on placebo, median 12 weeks), the reactions at 2% or more and above placebo were upper respiratory infection 4.3% vs 2.5%, diarrhea 4.1% vs 3.7%, arthralgia 3.0% vs 2.2%, sinusitis 2.8% vs 2.2%, pain in extremity 2.7% vs 2.5%, fatigue 2.4% vs 1.5% and influenza 2.0% vs 1.5% [1].

Across 28 controlled trials in which ezetimibe was started with a statin or added to one, 11,308 people received ezetimibe plus a statin and 9,361 received a statin without ezetimibe; the common reactions were nasopharyngitis 3.7% vs 3.3%, myalgia 3.2% vs 2.7%, upper respiratory infection 2.9% vs 2.8%, arthralgia 2.6% vs 2.4%, diarrhea 2.5% vs 2.2% and back pain 2.4% vs 2.3% [1].

The Zetia label has no boxed warning [1]. Its warnings cover liver enzyme rises and muscle effects. Consecutive transaminase elevations of 3 times the upper limit of normal or more occurred in 1.3% of patients who started ezetimibe together with a statin, versus 0.4% on a statin alone; the label says to test liver enzymes as clinically indicated and to consider stopping ezetimibe if ALT or AST stays at 3 times the upper limit or higher [1]. Myopathy and rhabdomyolysis are listed as possible, and the label notes that in postmarketing reports most patients who developed rhabdomyolysis were also taking a statin or another agent such as a fibrate [1]. For ezetimibe alone, the contraindication is known hypersensitivity to ezetimibe or an excipient. When it is combined with a statin, fenofibrate, or another LDL-lowering therapy, the partner drug's contraindications also apply [1].

Postmarketing reports, for which the label says frequency cannot be estimated, include thrombocytopenia, pancreatitis, hepatitis, cholelithiasis, cholecystitis, elevated liver enzymes, myopathy/rhabdomyolysis, hypersensitivity reactions including anaphylaxis and angioedema, depression, dizziness, paresthesia, headache and erythema multiforme [1].

Three interactions are listed in the label. Cyclosporine increases ezetimibe and cyclosporine concentrations, and the label says to monitor cyclosporine levels when the drugs are used together [1]. With fenofibrate, cholecystectomy rates were 0.6% on fenofibrate alone versus 1.7% with ezetimibe added [1]. Cholestyramine lowers ezetimibe exposure, and the label says to take ezetimibe at least 2 hours before or 4 hours after a bile acid sequestrant [1].

What the alirocumab trials and label report

ODYSSEY LONG TERM randomized 2,341 people at high cardiovascular risk who had LDL cholesterol of 70 mg/dL or more on maximum tolerated statin therapy, in a 2:1 ratio, to alirocumab 150 mg every 2 weeks or placebo for 78 weeks [2]. Compared with placebo, alirocumab produced more injection-site reactions (5.9% vs 4.2%), myalgia (5.4% vs 2.9%), neurocognitive events (1.2% vs 0.5%) and ophthalmologic events (2.9% vs 1.9%) [2]. The placebo-corrected difference in LDL cholesterol at week 24 was -62 percentage points [2].

The Praluent label pools nine adult placebo-controlled trials (alirocumab 75 or 150 mg every 2 weeks, 2,476 people, vs placebo, 1,276 people, median 65 weeks). Injection-site reactions were 7% vs 5%, influenza 6% vs 5%, diarrhea 5% vs 4%, myalgia 4% vs 3%, muscle spasms 3% vs 2% and contusion 2% vs 1%. Discontinuation was 5.3% vs 5.1%, with allergic reactions (0.6% vs 0.2%) and elevated liver enzymes (0.3% vs under 0.1%) the leading causes [7]. In ODYSSEY OUTCOMES, myalgia was 6% vs 5% and injection-site reactions 3.8% vs 2.1% [7].

The Praluent label has no boxed warning. Its one warning is hypersensitivity, including hypersensitivity vasculitis and angioedema, and a serious hypersensitivity reaction to alirocumab or an excipient is a contraindication [7]. In studies with atorvastatin or rosuvastatin, statin concentrations did not change [7].

Injection-site reactions: the clearest split

Ezetimibe is a tablet, so there is no injection site to react [1]. In ODYSSEY LONG TERM, injection-site reactions were reported by 5.9% of people taking alirocumab 150 mg every 2 weeks, versus 4.2% of those taking placebo [2].

Muscle symptoms

With ezetimibe added to a statin, myalgia was 3.2% vs 2.7% with the statin alone [1]. In IMPROVE-IT, muscle, gallbladder and hepatic adverse effects and cancer were similar between the simvastatin-ezetimibe and simvastatin-placebo groups [6].

For alirocumab, myalgia was 5.4% vs 2.9% in ODYSSEY LONG TERM [2]. ODYSSEY ALTERNATIVE enrolled 361 people with statin intolerance who entered a four-week single-blind placebo run-in; continuing patients were then randomized 2:2:1 to alirocumab 75 mg every 2 weeks, ezetimibe 10 mg daily, or atorvastatin 20 mg daily for 24 weeks [4]. Skeletal muscle-related events were less frequent with alirocumab than with the atorvastatin rechallenge (hazard ratio 0.61, 95% CI 0.38-0.99, P=0.042) [4].

Liver enzymes with ezetimibe

The Zetia label reports the ezetimibe-plus-statin transaminase signal (1.3% vs 0.4%), and says ezetimibe is not recommended in moderate or severe hepatic impairment because exposure rises about 3- to 4-fold [1].

What the large outcomes trials reported

IMPROVE-IT enrolled 18,144 people hospitalized for an 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. The primary composite at 7 years was 32.7% vs 34.7% (hazard ratio 0.936, 95% CI 0.89-0.99, p=0.016), and muscle, gallbladder and hepatic adverse effects and cancer were similar between groups [6]. The Zetia label has no cardiovascular risk-reduction indication and does not mention that trial; its approved purpose is lowering LDL cholesterol and plant sterols [1].

ODYSSEY OUTCOMES enrolled 18,924 people who had an acute coronary syndrome 1 to 12 months earlier and were on high-intensity or maximally tolerated statin therapy. The primary composite was 9.5% vs 11.1% (hazard ratio 0.85, 95% CI 0.78-0.93), and all-cause death was 3.5% vs 4.1% (hazard ratio 0.85, 0.73-0.98), which the trial's prespecified testing method did not treat as statistically significant [5][7].