Oxidation injury in patients receiving HMG-CoA reductase inhibitors: occurrence in patients without enzyme elevation or myopathy.
BACKGROUND
Myopathy in its severe forms including rhabdomyolysis is a very rare adverse effect occurring during monotherapy with the HMG-CoA reductase inhibitors ('statins') and is associated with pronounced signs of oxidation injury. This has been found at a local (muscle) as well as at a systemic level (blood). Several lines of evidence indicate that even mild forms of myopathy during statin treatment may be associated with in vivo oxidation injury. In contrast, statin therapy has been shown to be associated with a decrease in oxidation injury.


OBJECTIVE
The aim of this study was to investigate whether patients with heterozygous familial hypercholesterolaemia who did not exhibit any symptoms or abnormalities in safety parameters during 6 months of treatment with various statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin) did exhibit a change in oxidation injury as assessed by the isoprostane levels.


METHODS
Blood (plasma and serum) as well as urine was tested before and 1, 3 and 6 months after starting statin therapy.


RESULTS
Out of 111 treated patients (63 males, 48 females; aged 19 to 58 years) who did not experience any adverse effects during statin treatment, 11 (seven males, four females; aged 24 to 51 years) showed a pronounced increase in 8-epi-prostaglandin (PG) F(2alpha) in all the compartments examined. In the remaining 100 patients (56 males, 44 females; aged 19 to 58 years) there was either no change in or even an apparent decrease in 8-epi-PGF(2alpha). This increase was monitored with all the statins administered. If elevated, the increase in 8-epi-PGF(2alpha) remained without change throughout the entire follow-up period. No sex difference or differential response between smokers and nonsmokers was observed.


CONCLUSIONS
These findings indicate that in the absence of other clinically observable adverse effects, in some of the patients, for an as yet unknown reason, statin therapy may be associated with increased oxidation injury. The fact that changing to another statin is apparently not necessarily associated with an identical response raises the question of a specific predisposition for certain compounds in a given patient. These data add a further piece of evidence that mild adverse effects of statins that are difficult to assess might be much more prevalent than widely considered. The clinical relevance and consequence of these findings still remains to be assessed.
Sinzinger
Helmut
H
Wilhelm Auerswald Atherosclerosis Research Group (ASF), Vienna, Austria. helmut.sinzinger@akh-wien.ac.at
Chehne
Fahdi
F
Lupattelli
Graziana
G
D000328:Adult; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced; D010084:Oxidation-Reduction / Q000187:drug effects; D012907:Smoking
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D006903:Hydroxymethylglutaryl CoA Reductases