A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

Abstract

Background/Aims There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known. In this systematic review we aimed to address pharmacokinetics (PK), safety, and effects on cardiovascular (CV) outcomes of statins in cirrhosis. Methods Our systematic search in several electronic databases and repositories of two regulatory bodies up to 2020-06-11 yielded 22 articles and 2 drug monographs with relevant data. Results Rosuvastatin and pitavastatin showed minimal PK changes in Child–Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study. Atorvastatin showed pronounced PK changes in cirrhosis. No PK data was found for simvastatin, the most commonly used statin in cirrhosis trials. There was insufficient data to assess CV effects of statins in cirrhosis. Clinical trials in cirrhosis were limited to simvastatin, atorvastatin, and pravastatin. In patients taking simvastatin 40 mg, pooled frequency of rhabdomyolysis was 2%, an incidence 40-fold higher than that reported in non-cirrhosis patients, while this was no rhabdomyolysis observed in patients on simvastatin 20 mg, atorvastatin 20 mg, or pravastatin 40 mg. Drug-induced liver injury was of difficult interpretation due to co-existence of muscle damage. No overt liver failure was reported. Conclusions Simvastatin 40 mg should be avoided in decompensated cirrhosis. Safety data on simvastatin 20 mg or other statins are based on small study sample size. This rarity of evidence combined with lack of data in dose adjustment methods in cirrhosis is a barrier for using statins for CV indications or for investigational use for liver indications.

Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans

“…The PBPK model developed in this study can be used to extend dosing regimens and predict drug–drug interactions and population-related alterations in the pharmacokinetic profiles of enavogliflozin in humans. For example, some marketed drugs require their dosing regimen to be adjusted or are not recommended for patients with hepatic or renal impairment [ 12 , 41 , 42 , 43 ]. Additionally, researchers involved in new drug development may need to predict the expected exposure or concentration profiles of the agent before clinical observation.…”

The Link between Magnesium Supplements and Statin Medication in Dyslipidemic Patients

“…Patients with compensated liver disease could use pravastatin and rosuvastatin, because compared to other statins, they are only partially metabolized by the liver. Statins are contraindicated in patients with acute liver failure or decompensated cirrhosis [ 87 , 90 , 91 ].…”

Management of NAFLD in primary care settings

“…66 However, cardiovascular benefits are unclear in patients with cirrhosis, and statin plasma area under the curve and Cmax levels are higher in people with Child-Pugh class B compared with class A. 67 Thus, around 2% of patients with Child-Pugh class B and C, but not class A, cirrhosis may develop rhabdomyolysis when receiving simvastatin at 40 mg/ day. 67 Finally, statins, metformin and aspirin have been reported to potentially reduce the risk of HCC and cirrhotic complications, 68,69 though metformin should be avoided in patients with Child-Pugh class B and C disease because of the risk of lactic acidosis.…”

“…67 Thus, around 2% of patients with Child-Pugh class B and C, but not class A, cirrhosis may develop rhabdomyolysis when receiving simvastatin at 40 mg/ day. 67 Finally, statins, metformin and aspirin have been reported to potentially reduce the risk of HCC and cirrhotic complications, 68,69 though metformin should be avoided in patients with Child-Pugh class B and C disease because of the risk of lactic acidosis.…”

“…In a recent meta‐analysis including 121 058 patients with chronic liver disease, treatment with statins was associated with a nearly 50% reduction in hepatic decompensation and overall mortality 66 . However, cardiovascular benefits are unclear in patients with cirrhosis, and statin plasma area under the curve and Cmax levels are higher in people with Child–Pugh class B compared with class A 67 . Thus, around 2% of patients with Child‐Pugh class B and C, but not class A, cirrhosis may develop rhabdomyolysis when receiving simvastatin at 40 mg/day 67 .…”