PRACTICE CHANGER
Treat patients with hyperlipidemia and presumed nonalcoholic fatty liver disease with atorvastatin to reduce the risk of cardiovascular events.1
STRENGTH OF RECOMMENDATION
B: Based on a single prospective randomized controlled trial (RCT).
Athyros VG, Tziomalos K, Gossios TD, et al. 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 analysis. Lancet. 2010; 376:1916-1922.
ILLUSTRATIVE CASE
An obese 58-year-old man with type 2 diabetes comes to your office for follow-up. His low-density lipoprotein cholesterol (LDL-C) is 130 mg/dL; triglycerides, 300 mg/dL; alanine transaminase (ALT), 110 units/L; and aspartate transaminase (AST), 120 units/L. The patient’s work-up for chronic hepatitis B and C, autoimmune hepatitis, hemochromatosis, and Wilson’s disease are negative, and you rule out alcohol misuse based on his medical history. An ultrasound of the patient’s liver reveals hepatic steatosis, and you diagnose nonalcoholic fatty liver disease (NAFLD). Should you start him on a statin?
Patients with central obesity, diabetes, hypertension, hyperlipidemia, and metabolic syndrome are at high risk of developing NAFLD. These conditions have increased in prevalence, and NAFLD is now the most common cause of liver disease in the United States.2 In Western industrialized countries, approximately 30% of the general population and 70% to 90% of patients with diabetes will develop NAFLD.3 Although most patients are asymptomatic, their liver enzymes are elevated. To diagnose NAFLD, it is necessary to rule out alcoholic hepatitis with a medical history, and viral hepatitis, hereditary hemochromatosis, Wilson’s disease, and autoimmune hepatitis with laboratory testing. Ultrasound reveals fat accumulation in the liver.
Treatment for NAFLD has little evidence of benefit
Patients with NAFLD have a much higher mortality rate than that of the general public, primarily because of cardiovascular disease.4-6 Increased physical activity and weight loss is the only therapy that has solid evidence of a benefit,7 although other treatments, such as insulin-sensitizing drugs (metformin or pioglitazone), may be beneficial.8 Surprisingly, atorvastatin has been found to reduce aminotransferase levels in patients with NAFLD,9,10 but clinicians are often concerned about prescribing a statin for patients with elevated liver enzymes. In one study, 50% of primary care physicians said they would not prescribe statins for patients whose liver enzymes are 1.5× the upper limit of normal (ULN).11
STUDY SUMMARY: Statins lower risk of cardiovascular morbidity and mortality
The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study was a randomized, prospective open-label, intention-to-treat trial involving 1600 patients. All had established coronary heart disease (CHD), were younger than 75 years, and had triglycerides <400 mg/dL and LDL-C >100 mg/dL. The study reviewed here—evaluating the risk-to-benefit ratio of using a statin to treat hyperlipidemia in patients with NAFLD—was a post hoc analysis of the GREACE study.1
Participants were randomized to either usual care or structured care with atorvastatin, starting at 10 mg/d and adjusted to 80 mg/d to bring the LDL-C level below 100 mg/dL. In the usual care group, treatment included lifestyle changes plus necessary drug treatments (only 30% of those in the usual care group received hyperlipidemia drugs). Patients were followed after medication dose titration, then every 6 months for 3 years. Serum ALT and AST were measured at baseline, at 6 weeks, and every 6 months.
At baseline, mild-to-moderate increases (<3× ULN) in ALT/AST were noted in 437 of the 1600 patients. For these patients, alcoholic hepatitis, chronic hepatitis B and C, Wilson’s disease, and autoimmune hepatitis were excluded by history, laboratory tests, and ultrasound, and the elevated liver enzymes were attributed to NAFLD.
The primary endpoints were the first occurrence of any cardiovascular event, including nonfatal myocardial infarction, revascularization, unstable angina, heart failure, and stroke; all-cause mortality; and CHD mortality. The relative risk (RR) for such events was calculated for the 437 patients with elevated liver enzymes, compared with that of patients without abnormal liver tests. Elevated liver enzymes and liver-related adverse events were secondary endpoints.
A cardiovascular event occurred in 10% (22/227) of the patients with elevated liver enzymes who received a statin, and 30% (63/210) of patients who had elevated liver enzymes but did not receive a statin.