**5. Discussion**

After two decades of statin marketing, significant incidences of adverse drug reactions still presented during therapy. Number of studies of medications' ADRs always increased after first years of launching, but it found this matter is different with type of statin used20. Most of previous studies focused on serious ADRs of statin like muscle toxicity, elevation of liver enzymes, renal toxicity and polyneuropathy21,22. Although serious ADRs caused mortalities and death to patients, but their incidences are lower than other adverse reactions of statin

Predictors of the Common Adverse Drug Reactions of Statins 465

associated with fatigue. The dose of statins used did not have significant relationship with other symptoms of common ADRs. This result is consistent with other studies12,39. Finally, there was no significant relationship between combination therapy and ADRs. This relationship could not be seen possibly due to small number of patients receiving more than

The finding of this study showed that significant number of patients feel undesired effects of statin therapy and their predictors. Adjustment or manipulating of these preventable predictors such as to change type of statin used, reduce dose and duration are recommended to the prescribers. For example, based on the odd ratio, fatigue was the highest for patients who are alcohol consumers, followed by lovastatin dosage, duration and race. Therefore, steps needed to reduce the incidence of fatigue by avoiding or reducing the preventable predictors that related to these common ADRs like cessation of alcohol and

This paper explained that significant number of cardiac outpatients were experienced common ADRs related-statin through self-report approach and their predictors. Common ADRs of statin were fatigue, muscle pain, joint pain, back pain, insomnia and visual disturbances. The main predictors or contributing factors of common statin-related ADRs were gender, race, alcohol consumption, duration of statin used, renal induced-secondary dyslipidemia, subtype IIb of primary dyslipidemia and lovastatin dose. These predictors are useful in clinical practice to determine the likelihood of ADRs and to manage the common ADRs of statin in cardiac outpatients. Finding from this study was suggested appropriate dose and type of statin use and also adjustment of the preventable predictors may minimize common ADRs of statin in cardiac outpatients. Appropriate prospective study design with multicenter sites recommended determining the actual effects of these preventable

[1] Avorn J, Monette J, Lacour A, Bohn RL, Monane M, Mogun H, LeLorier J.(1998).

[3] Dewilde S, Carey IM, Bremner SA, Richards N, Hilton SR, Cook DG (2003). Evolution of statin prescribing 1994–2001: a case of agism but not of sexism? Heart 89:417–421 [4] National Cholesterol Education Program (NCEP) (2002). Expert panel on detection,

[5] Farahani P, Gaebel K, Lelorier J, Perrault S, Gillis J, Soon J, Levine M (2005). Assessment

of the American Medical Association 279:1458-1462 [2] National Cardiovascular Disease Database (NCVD) (2006), Malaysia

(Adult Treatment Panel III) final report 106:3143–3421

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evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults

of patient characteristics associated with statin use. The Canadian Journal of

one type of antilipidemic agent.

changing in type or dose of statin used.

predictors on common ADRs of statin.

**6. Conclusion** 

**7. References** 

symptomatic related ADRs. Kashani A. et al. 23 found that incidences of patients discontinued their therapy because of symptomatic ADRs of statin (5.6%) were higher than patients had rhabdomyolysis (0.2%), hepatotoxicity (1.4%), and creatine kinase (CK) elevations (0.9%). Therefore, self-reporting of ADRs are useful to determine and predict the toxicities induced by medication24. There are few studies done on the common statin-related ADRs that use patient self-report. There was a previous study that focused on the common ADRs during statin therapy and their predictors in cardiac outpatients. They reported the use of a self-report questionnaire form is suitable approach to assess the common undesired symptoms found during statin therapy25. In the real-life practice, doctors are more focusing on dyslipidemia and its complications than statin-related ADRs of their patients. Furthermore, self-report approach allows the patients to express directly their unwanted problems associated with statin therapy. In addition, patients sometimes feel uncomfortable or inappropriate telling their doctor about these undesired symptoms of statin26,27. The finding in this study showed a higher incidence of fatigue and muscle pain in this cardiac outpatients setting, which consistent with previous studies8,10.

In this study, females reported having back and joint pain significantly more than males did. Female patients are more sensitive to ADRs than males possibly because of pharmacokinetic and pharmacodynamic differences between genders28. Not all ADRs of statin related to gender, this finding supported by FDA, Bayer reports and previous studies29-32. When compared to other races, Indian patients had significantly higher incidence of some common ADRs (fatigue, muscle pain, back pain and visual disturbance). This is because genetics also has contributed in adverse drug reactions23. This result was supported by FDA reports in which ADRs were different among races7. Cigarette smokers had increased incidence of these ADRs than nonsmokers, however this finding was not statistically significant. Alcohol consumers had significant problems with fatigue, back pain and insomnia, and increased incidence of ADRs in general30. This is because alcohol causes mitochondrial dysfunction, which would increase the risk of muscle disorders caused by statins33. There was no relationship between age and ADRs, as shown in Table 2, which supported by Kucukarslan et al study34. There was a relationship between duration of statin used and ADRs in previous studies29,35,36. Their finding were consistent with this present finding, where the duration of statin therapy has related to fatigue, muscle pain and back pain.

Based on our knowledge, no previous studies reported the relationship between dyslipidemia types and the common ADRs. Significant relationship was found in this study between dyslipidemia type (primary and secondary) and common ADRs. Patients who had secondary dyslipidemia type had increase frequency of insomnia than with primary type. Patients with subtype IIb and renal induced dyslipidemia were significantly more likely to have back pain and insomnia than other subtypes.

Although statins differ in their pharmacokinetic properties37,38, there is no significant relationship found between statin types and common ADRs. However, simvastatin was more likely to cause fatigue, joint pain, back pain and visual disturbance than other statins. Although there is no significant relation found between atorvastatin and common ADRs. Atorvastatin found to cause muscle pain more often than other statin types, this finding also proved by Clearfield et al. and Golomb et al. 10,11. Patients on lovastatin therapy had higher incidence of insomnia than other types of statin. Higher doses for all types of statins have resulted in a higher incidence of ADRs. The higher dose of lovastatin (60 mg) significantly associated with fatigue. The dose of statins used did not have significant relationship with other symptoms of common ADRs. This result is consistent with other studies12,39. Finally, there was no significant relationship between combination therapy and ADRs. This relationship could not be seen possibly due to small number of patients receiving more than one type of antilipidemic agent.

The finding of this study showed that significant number of patients feel undesired effects of statin therapy and their predictors. Adjustment or manipulating of these preventable predictors such as to change type of statin used, reduce dose and duration are recommended to the prescribers. For example, based on the odd ratio, fatigue was the highest for patients who are alcohol consumers, followed by lovastatin dosage, duration and race. Therefore, steps needed to reduce the incidence of fatigue by avoiding or reducing the preventable predictors that related to these common ADRs like cessation of alcohol and changing in type or dose of statin used.
