Crestor vs Repatha Side Effects: Rosuvastatin vs Evolocumab Head-to-Head Safety Comparison

Do Crestor and Repatha cause the same side effects?

No. Their labels and trials report different patterns. Rosuvastatin blocks HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis [1]. Evolocumab binds PCSK9 so that more LDL receptors stay available to clear LDL from the blood [2]. Rosuvastatin is a tablet taken once daily, at any time of day, with or without food [1]. Evolocumab is injected under the skin every 2 weeks or once monthly, usually alongside a statin [2].

Rosuvastatin's label carries precautions for myopathy and rhabdomyolysis, liver enzymes, and proteinuria and hematuria at 40 mg. The only Warning and Precaution in the current Repatha label is hypersensitivity, including angioedema [1][2]. Neither drug has a boxed warning [1][2].

The figures below come from each drug's own label and separate trials, not from a head-to-head comparison.

Muscle symptoms with rosuvastatin

The Crestor label warns about myopathy and rhabdomyolysis, with risk factors of age 65 or older, uncontrolled hypothyroidism, renal impairment, certain interacting drugs and higher dose; myopathy risk is greater at 40 mg daily than at lower doses, and a rare immune-mediated necrotizing myopathy has been reported [1].

In pooled placebo-controlled trials of up to 12 weeks, myalgia was reported by 2.8% of patients on Crestor and 1.3% on placebo [1]. In JUPITER, which randomized 17,802 people to rosuvastatin 20 mg or placebo, myalgia was 7.6% vs 6.6% and arthralgia 3.8% vs 3.2% over a mean of 2 years [1][3]. In METEOR, 700 adults on rosuvastatin 40 mg vs 281 on placebo over a mean 1.7 years, myalgia was 12.7% vs 12.1%, arthralgia 10.1% vs 7.1%, and raised creatine phosphokinase 2.6% vs 0.7% [1][4].

Muscle symptoms with evolocumab

In the Repatha label's 52-week placebo-controlled trial (599 patients on evolocumab 420 mg monthly, 302 on placebo), myalgia was reported by 4.0% vs 3.0% [2]. Discontinuation was 2.2% vs 1.0%, and myalgia was the most common single reason (0.3% vs 0%) [2]. The FOURIER investigators reported no significant difference in adverse events between evolocumab and placebo except injection-site reactions, which were 2.1% vs 1.6% [5].

GAUSS-3 studied people with muscle-related statin intolerance. In its first phase, 491 adults with a history of intolerance to two or more statins took atorvastatin and placebo in a crossover, and 209 (42.6%) had muscle symptoms on atorvastatin but not on placebo [6]. In the second phase, 218 people were randomized: 199 came from the first phase and 19 entered directly because of elevated creatine kinase. Of these, 145 received evolocumab 420 mg monthly and 73 received ezetimibe 10 mg daily; LDL-C fell 54.5% vs 16.7% at weeks 22 to 24 [6]. The trial's coprimary endpoints were LDL-C changes, not muscle-symptom rates.

Injection-site and allergic reactions

Rosuvastatin is a tablet, so injection-site reactions do not apply. The Repatha label reports injection-site reactions in 5.7% vs 5.0% on placebo in the 52-week trial and 3.2% vs 3.0% across eight pooled controlled trials, mostly erythema, pain and bruising, with 0.1% discontinuing [2]. Hypersensitivity reactions were 5.1% vs 4.7% in the pooled trials, including rash 1.0% vs 0.5%, eczema 0.4% vs 0.2% and urticaria 0.4% vs 0.1% [2]. Angioedema appears among post-marketing reports [2].

Serious hypersensitivity reactions, including angioedema, have occurred with Repatha, and a history of a serious hypersensitivity reaction to evolocumab or an excipient is a contraindication [2]. Some autoinjector and syringe presentations have a needle cover containing dry natural rubber, which can cause reactions in latex-sensitive people; latex-free presentations exist [2].

Antibodies to evolocumab were binding in 0.3% (48 of 17,992) of adults; none were neutralizing, and there was no evidence of an effect on pharmacokinetics, response or safety [2]. In OSLER-1, which treated patients for up to 5 years, 2 standard-care and 2 evolocumab patients developed new, transient binding antibodies, and no neutralizing antibodies were seen [7].

For rosuvastatin, hypersensitivity to the drug or an excipient is a contraindication, and rash, pruritus, urticaria and angioedema have been reported [1].

Liver enzymes

The Crestor label reports transaminases above 3 times the upper limit of normal in 1.1% of patients on rosuvastatin vs 0.5% on placebo in pooled placebo-controlled trials [1]. In METEOR, ALT above 3 times the upper limit was 2.2% vs 0.7% [1]. The Crestor label says to consider liver enzyme testing before starting and as clinically indicated, and notes rare fatal and non-fatal hepatic failure with statins; acute liver failure or decompensated cirrhosis is a contraindication [1].

The Repatha label lists no hepatic warning or precaution [2].

Blood sugar and diabetes

The Crestor label states that HbA1c and fasting glucose can rise on rosuvastatin, in some cases past the threshold for a diabetes diagnosis [1]. In JUPITER, diabetes mellitus was reported in 2.8% on rosuvastatin vs 2.3% on placebo, and mean HbA1c was 0.1% higher on rosuvastatin [1].

In FOURIER, diabetes mellitus was reported in 8.8% on evolocumab vs 8.2% on placebo, and among the 16,676 participants without diabetes at baseline, new-onset diabetes was 8.1% vs 7.7% [2].

Memory and thinking

In the EBBINGHAUS cognitive substudy of FOURIER, the label lists 1,974 patients enrolled; the published analysis followed 1,204 patients for a median of 19 months [2][8]. Evolocumab was non-inferior to placebo on the spatial working memory strategy index of executive function (mean change -0.21 vs -0.29, non-inferiority P<0.001), and the label adds that it was also non-inferior on selected other cognitive domains [2][8].

The Crestor label lists rare cognitive impairment among post-marketing reports [1]. That is a spontaneous-report list rather than a rate measured in a controlled trial.

Drug interactions

The Repatha label has no drug interactions section [2]. Adults on a high-intensity statin had about 20% lower Cmax and AUC of evolocumab, which the label calls not clinically meaningful; evolocumab is eliminated by target binding and proteolysis [2]. No dose adjustment is needed for renal impairment or mild to moderate hepatic impairment [2].

Rosuvastatin has a longer interaction list:

• Cyclosporine: the Crestor label limits the dose to 5 mg once daily; in 10 heart transplant recipients compared with historical healthy controls, rosuvastatin AUC rose about 7-fold and Cmax about 10.6-fold [1][9].
• Gemfibrozil: the label advises avoiding the combination; when it is unavoidable, it specifies a 5 mg starting dose and a 10 mg daily maximum. In 20 healthy volunteers given a single 80 mg rosuvastatin dose, gemfibrozil raised rosuvastatin AUC 1.88-fold and Cmax 2.21-fold [1][10].
• Warfarin: rosuvastatin significantly increased INR, and the label asks for INR checks before starting and often enough after starting, titration or stopping [1].
• Aluminum/magnesium hydroxide antacid taken at the same time cut rosuvastatin AUC by about 50%; the label says to take Crestor at least 2 hours before the antacid [1].
• Several antivirals raise exposure: atazanavir/ritonavir 3.1-fold and simeprevir 2.8-fold, where the label specifies a 5 mg start and a 10 mg ceiling, and sofosbuvir/velpatasvir/voxilaprevir (7.4-fold), which the label says to avoid [1].

The label also specifies lower dosing in two groups. Asian patients start at 5 mg once daily because of higher rosuvastatin plasma concentrations; the label reports about 2-fold higher median exposure than in White controls, and a study of 36 White, 36 Chinese, 35 Malay and 35 Asian-Indian subjects found a similar difference [1][11]. Severe renal impairment (creatinine clearance under 30 mL/min/1.73 m2, not on dialysis) starts at 5 mg with a 10 mg maximum; exposure is about 3-fold higher [1].

Using the two together

FOURIER tested evolocumab added to statin therapy in 27,564 patients with atherosclerotic cardiovascular disease, 69% of them on a high-intensity statin [5]. Investigators reported no significant difference in adverse events versus placebo except injection-site reactions (2.1% vs 1.6%) [5]. LAPLACE-2 enrolled 1,896 patients with hypercholesterolemia who were on background atorvastatin, rosuvastatin or simvastatin and reported LDL-C differences rather than a safety comparison: -71% versus placebo with 140 mg every 2 weeks and -63% with 420 mg monthly [2].