Rethinking Statin Dosage in Coronary Disease

The management of risk factors and timely revascularisation continues to reduce the morbidity and mortality from cardiovascular disease. Despite good evidence for reduced mortality on statins and decades of promotion, population uptake globally is less than 3%, and only around 10% even in the United Kingdom and the United States. Statins remain the only cholesterol-lowering drug class shown to improve survival, albeit only in symptomatic coronary patients and on mid-range doses. Population studies have consistently shown that coronary events and mortality are lower the lower the serum total cholesterol concentration. However, below 5 mmol/L (low-density lipoprotein, LDL, cholesterol around 3.5 mmol/L), the population studies show that total mortality begins to rise. Statin research and competitive marketing have advanced to where a wide range of dosages has been approved in many countries. No specific target cholesterol concentration that maximizes survival has been demonstrated in appropriately designed randomized controlled trials (RCTs). As with any enzyme inhibitor, the efficacy of statins plateaus above mid-range doses, but toxicities continue to increase manyfold. In the six largest RCTs that compared high versus mid-range statin doses in coronary patients, a higher statin dose achieved marginally greater reductions in coronary events, in some studies, but without appreciable reduction in mortality. Newer drugs, which reduce PCSK9, and ezetimibe, have similarly not been shown to lower mortality. It is widely acknowledged that a sufficient statin dose is important in the management of symptomatic coronary disease, along with weight reduction and appropriate antithrombotic, blood pressure, and diabetes pharmacotherapy. Mid-range statin doses have been shown to achieve the maximum improvements in total mortality and have the advantage of greater tolerability because of fewer adverse events and interactions.