Data from a phase 2, double-blind, placebo-controlled study, showed a higher dose of simvastatin was associated with greater liver and muscle toxicity compared with a lower dose for patients with decompensated cirrhosis.
Data from a phase 2, double-blind, placebo-controlled study, showed a higher dose (40 mg/day) of simvastatin (Zocor, Merck) was associated with greater liver and muscle toxicity compared with a lower dose of 20 mg/day for patients with decompensated cirrhosis.
“There have been no specific studies evaluating safety of statins in decompensated cirrhosis. The aim of the current study was to investigate the safety and tolerability of 2 different doses in simvastatin,” the study authors wrote.
With liver transplantation as the only curative option currently available for this patient population, recent trials have shown that simvastatin may have beneficial effects to prevent the progression of decompensated cirrhosis by decreasing systemic and hepatic inflammation, improving the altered hepatic microcirculation, decreasing portal hypertension, and reducing fibrosis progression.
In the multicenter, European study, 44 patients with decompensated cirrhosis (Child-Pugh B [n = 34] and Child-Pugh C [n = 10]) were randomized 1:1:1 to receive either simvastatin 20 mg/day or 40 mg/day plus rifaximin (Xifan) 1200 mg/day, or matching placebo of both drugs for 12 weeks. Patient characteristics were balanced between the 3 arms.
The primary endpoints of the trial were liver and muscle toxicity, as estimated by changes in enzyme levels. Patients treated with simvastatin 40 mg/day had significantly higher aspartate aminotransferase (ASD) and alanine aminotransferase (ALT) levels (181 UI/L and 91 UI/L, respectively) compared with those treated with simvastatin 20 mg/day (20 UI/L and 23 UI/L, respectively; P = .01 and P <.01).
Patients in the placebo arm had ASD and ALT levels of 55 UI/L and 32 UI/L, respectively.
Creatinine kinase levels were also notably higher in the simvastatin 40 mg/day cohort, compared with the lower-dose simvastatin and placebo cohorts (984 UI/L versus 109 UI/L versus 112 UI/L, respectively). Three of the 16 patients who received the higher dose of simvastatin developed clinically significant rhabdomyolysis compared with 0 patients in the other 2 arms.
“These results suggest that simvastatin 20 mg/day should be preferred to 40 mg/day in clinical trials investigating the effects of statins in patients with decompensated cirrhosis,” the investigators concluded.
Based on the results of this trial, a follow-up phase 2 study will assess the efficacy of the combination of rifaximin-extended intestinal release 400mg every 8 hours plus simvastatin 20 mg/day for a 12-month period to reduce acute on chronic liver failure (ACLF) in patients with decompensated cirrhosis.
“The expected impact of [these studies] is to halt progression to ACLF liver failure, the main cause of death, to decrease complications of the disease, to reduce hospital readmissions and to improve the cost-effectiveness of therapies,” the investigators wrote.
The study, “Safety and tolerability of two doses of simvastatin associated with rifaximin in patients with decompensated cirrhosis. A double-blind, randomized, placebo-controlled trial,” was presented at the 2018 American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 9-13, 2018, in San Francisco, California.