1. Maenne Okunola Pharm D. Candidate: University of Georgia June 2012 Preceptor: Dr. Ali Rahimi

2. Level of Evidence

3. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analyisis Authors: Athyros, Tziomalos, Gossios, Griva, Anagnostis, Kargiotis, Pagourelias, Theocharidou, Karagiannis, Mikhalidis All MDs Lancet 2010; 376:1916-1922 Unsponsored non-funded study This study looks at the role of statin therapy in patients with non-alcoholic fatty liver disease (NAFLD) who have elevated liver enzymes up to three times the upper limit.

4. Background Information Statin treatment has been used to decrease the frequency of cardiovascular events by maintaining a persons lipid profile. More research needed to evaluate safety and efficacy versus risk of statin treatment in patients with abnormal liver tests due to NAFLD. NAFLD is the most common cause of abnormal liver tests in the developed world. Past studies suggests: NAFLD and non-alcoholic steatohepatitis, a more advanced stage of NAFLD, may be independent risk factors for cardiovascular disease. Raised liver enzymes due to NAFLD may be improved with statins.

5. Design Prospective, randomized, open label, intention to treat, survival study, post-hoc analysis Duration of study: 3 years

6. Setting /Patients 1600 patients with coronary heart disease in GREACE study: 437 had abnormal liver tests 227 on statin therapy median dose: Atorvastatin 24 mg 210 not on statin therapy 56% of patients of patients with metabolic syndrome had abnormal liver function tests. 71% of patients with DM had abnormal liver function tests. Patients with liver abnormalities: Majority male, BMI 28-29, ex-smokers, metabolic syndrome, DM, central obesity, raised blood pressure with mean age 60-61 Hippokration University Hospital, Thessaloniki, Greece

7. Methods Patient in treated group given a starting dose of 10 mg of Atorvastatin and dose was modified every 6 weeks up to 80 mg to achieve LDL goals of less than 2.6 mmol/L. Patient visits occurred at baseline, at the sixth treatment week, then every 6 months for three years. ALT, AST, and GGT measured at this time.

8. Inclusion/Exclusion Inclusion LDL cholesterol serum concentration greater than 2.6mmol/L (100mg/dL) Triglyceride serum concentration of less than 4.5 mmol/L (394.73mg/dL) Non alcoholic fatty liver disease ultrasonographic diagnosis Coronary heart disease Age less than 75 years Exclusion Increase of liver enzymes three times the upper limit Alanine Aminotransferase 8-40 IU/L (>120 IU/L) Aspartate aminotransferase 15-40 IU/L (>120 IU/L) Gamma glutamyl transpeptidase 2-30 IU/L (>90 IU/L) Alcohol misuse Liver Disease Wilsons disease Chronic Hepatitis B or C Autoimmune hepatitis

9. Clinical Endpoints Primary endpoint: Occurrence of any cardiovascular event: all cause mortality, coronary heart disease mortality or morbidity, or stroke in patients treated with statins versus untreated with statins Secondary endpoints: effects of statin treatment on liver tests.

10. Results-Primary Endpoint: Cardiovascular Events in Selected Populations Normal liver enzymes Abnormal liver enzymes Statin therapy90/653=14%22/227= 10% No statin therapy117/510=23%63/210=30% Relative Risk Reduction ([14-23]/23)= 39%: p<0.0001 ([10-30]/30)= 68%: p<0.0001 Absolute Risk Reduction 23%-14%= 9%30%-10%=20% Number needed to treat (NNT) (1/0.09)=12(1/0.2)=5

11. Results- Secondary Endpoint: Liver Enzyme Comparison A - Patients on statin treatment (n=227) B - Patients not on statin treatment (n=210) * -Time when differences became statistically significant

12. Results Patients did not have considerable increases of bilirubin or alkaline phosphatase. BMI did not change with statin therapy. Improved labs: total cholesterol, LDL, HDL, Triglycerides, ALT, AST, GGT, eGFR all statistically significantly improved in patients in statin group with baseline liver abnormalities (P-value<0.05) Worsened labs: ALT, AST and GGT all statically significantly worse in ptnts not on statin therapy with baseline liver abnormalities (P-value <0.05) 7/880 receiving a statin had to discontinue therapy due to liver related adverse effects. Median dose of statins Atorvastatin 25 mg Simvastain 22mg Pravastatin 29mg Fluvastatin 40mg

13. Conclusion Statin therapy proves to be effective in preventing cardiovascular events in patients with non-alcoholic fatty liver disease who are less than 75 years of age with LDL levels greater than 100mg/dL and TG levels less than 394.73 mg/dL. Statin therapy also proves to be effective in decreasing liver enzymes in up to three months in patients who have baseline liver enzyme levels of less than three times the upper limit.

14. Importance to Health Care Professionals A more active diagnosis of NAFLD and non-alcoholic steatohepatitis to be adopted possibly targeting the patient with diabetes mellitus ore metabolic syndrome. Look further into the benefit to patients with liver enzymes more than three times the upper limit. NAFLD patients have a 69% higher all-cause mortality than the general population which may be due to cardiovascular disease versus liver disease.

15. Additional Thoughts Statin therapy proves to be an effective therapy in patients with non-alcoholic liver disease. Further research in patients greater than 75 years of age to be determined. The role of other lipid lowering agents to decrease cardiovascular events and improve liver enzyme tests. Open label- worry about bias and adherence issues Higher doses of statins were not used so incorporating this into therapy for selected patients may result in less concern of adverse effects.