Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials.
OBJECTIVE
We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer.


BACKGROUND
Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated.


METHODS
Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression.


RESULTS
In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23).


CONCLUSIONS
Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.
Alsheikh-Ali
Alawi A
AA
Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Maddukuri
Prasad V
PV
Han
Hui
H
Karas
Richard H
RH
D056486:Chemical and Drug Induced Liver Injury; D008078:Cholesterol, LDL / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D007211:Indoles / Q000009:adverse effects; D008107:Liver Diseases / Q000201:enzymology; D008148:Lovastatin / Q000009:adverse effects; D009369:Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D017035:Pravastatin / Q000009:adverse effects; D012206:Rhabdomyolysis / Q000139:chemically induced*; D019821:Simvastatin / Q000009:adverse effects
D008078:Cholesterol, LDL; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin