Crestor Liver Function Impact: What Rosuvastatin Actually Does to Your Liver

Does rosuvastatin raise liver enzymes?

Yes, in a minority of patients. In the pooled placebo-controlled trials summarized in the Crestor label, transaminases above 3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin and 0.5% of those taking placebo [1]. The label also lists hepatitis and jaundice among postmarketing reports [1].

The 40 mg dose has the most direct trial data. METEOR randomized 984 low-risk adults with subclinical carotid atherosclerosis to rosuvastatin 40 mg or placebo [8]. In the label's safety data from that trial, 700 adults took rosuvastatin 40 mg and 281 took placebo for a mean of 1.7 years; ALT above 3 times the upper limit occurred in 2.2% versus 0.7% [1]. That 2.2% is the rate in this specific group, not a universal figure for the 40 mg dose.

The same trial also recorded creatine kinase elevation in 2.6% versus 0.7% [1].

What does the Crestor label say about liver testing?

The label says to consider liver enzyme testing before starting rosuvastatin and as clinically indicated afterward [1]. It carries no boxed warning [1].

The label's other liver statement is about severity rather than frequency: rare fatal and non-fatal hepatic failure has been reported with statins [1].

Is liver disease a contraindication?

The label's liver contraindication is narrow: acute liver failure or decompensated cirrhosis [1]. The other contraindication is hypersensitivity to rosuvastatin or an excipient, with rash, pruritus, urticaria and angioedema reported [1].

Pharmacokinetic studies in hepatic impairment are small but informative. In Child-Pugh A, peak concentration rose about 60% and total exposure about 5%; in Child-Pugh B, peak concentration rose about 100% and exposure about 21% [1].

How the liver handles rosuvastatin

Rosuvastatin is not a prodrug. More than 90% of the active plasma HMG-CoA reductase inhibitory activity comes from the parent compound, unlike simvastatin, which is a prodrug [1]. Peak plasma concentration is reached 3 to 5 hours after a dose, and the half-life is about 19 hours [1].

Metabolism is limited. About 10% of a dose is recovered as metabolites, mainly N-desmethyl rosuvastatin formed principally by CYP2C9, and about 90% is excreted in feces [1]. Clearance does not depend on CYP3A4 to a clinically significant extent: itraconazole 200 mg daily raised rosuvastatin exposure only about 1.4-fold [1]. The interactions that matter involve the transporters OATP1B1 and BCRP rather than CYP enzymes [1].

On genetics, the label is cautious: people carrying two reduced-function SLCO1B1 521 C alleles had higher concentrations in very small groups (n=3 to 5), the variant is under 5% in most groups, and its clinical impact has not been established [1].

Which drugs and conditions raise exposure most

• Cyclosporine. Rosuvastatin exposure rose about 7-fold and peak concentration about 11-fold in the label's data [1]. In a study of 10 stable heart transplant recipients taking cyclosporine, exposure was 7.1-fold higher and peak 10.6-fold higher than in 21 historical healthy controls, and rosuvastatin did not change cyclosporine levels [2]. The dose limit is 5 mg once daily [1].
• Gemfibrozil. In a randomized crossover study of 20 healthy volunteers, gemfibrozil 600 mg twice daily raised rosuvastatin exposure 1.88-fold and peak concentration 2.21-fold [4]. The label says avoid the combination, or if unavoidable start at 5 mg and do not exceed 10 mg daily [1].
• Hepatitis C and HIV antivirals. Label exposure ratios include sofosbuvir/velpatasvir/voxilaprevir 7.4-fold (avoid), atazanavir/ritonavir 3.1-fold, simeprevir 2.8-fold, elbasvir/grazoprevir 2.3-fold, glecaprevir/pibrentasvir 2.2-fold and lopinavir/ritonavir 2.1-fold, with 5 mg starting doses and 10 mg limits for most of these [1].
• Resmetirom. The Rezdiffra label limits rosuvastatin to 20 mg daily when the two are taken together (rosuvastatin exposure 1.4-fold and peak 1.8-fold higher) and asks for monitoring for liver test elevation, myopathy and rhabdomyolysis [5]. That limit comes from the resmetirom label, not the Crestor label's interaction table [5].
• Severe renal impairment. Exposure is about 3-fold higher when creatinine clearance is under 30 mL/min/1.73 m2; the label says start at 5 mg and do not exceed 10 mg daily [1].
• Asian patients. Exposure is about 2-fold higher, and the label says to start at 5 mg once daily [1]. In a single-dose study of 36 white, 36 Chinese, 35 Malay and 35 Asian-Indian subjects living in Singapore, exposure ratios versus white subjects were 2.31, 1.91 and 1.63 in the Chinese, Malay and Asian-Indian groups respectively [6].

What about fatty liver disease?

A 2010 review in Mayo Clinic Proceedings concluded that statin treatment is supported in patients at high cardiovascular risk whose elevated aminotransferases have no clinical relevance or are attributable to known stable chronic liver conditions, with the decision based on an individual assessment of risks and benefits [7].

How often is serious liver injury?

Swedish adverse drug reaction reports from 1988 to 2010 give a sense of scale. Statin-related drug-induced liver injury was reported in 1.2 per 100,000 users, and 73 reports had at least a possible relationship [3]. Among those 73, two patients died of acute liver failure, one had a liver transplant and 25 (34%) had jaundice [3]. Median duration of therapy before injury was 90 days, and most patients developed injury 3 to 4 months after starting [3]. Atorvastatin accounted for 30 of the 73 cases and simvastatin 28 [3]. Three patients were rechallenged with the same statin and developed a similar pattern of injury [3].

The U.S. Drug Induced Liver Injury Network adds detail from the other direction. Of 1,188 cases of drug-induced liver injury enrolled between 2004 and 2012, 22 were attributed to a statin; four of those patients developed evidence of hepatic failure and one died, and four had persistent or chronic injury [8]. Median time to onset was 155 days, with a range from 34 days to 10 years [8].