By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
August, 2012
Statins are a class of cholesterol lowering medications that act by inhibiting a key enzyme in cholesterol metabolism in the liver known as HMG-CoA reductase. Lovastatin was the first drug in this class that became available in 1987. Since then, numerous other statins, including atorvastatin and simvastatin, have been developed and released on the market. In 2003, atorvastatin manufactured by Pfizer and marketed, as Lipitor became the best-selling drug in history with sales reaching over $10 billion. The main indication for statin use is hypercholesterolemia. In fact, statins generally reduce blood cholesterol levels by 40-50% when taken at the maximum recommended dose. Importantly, this reduction in cholesterol levels reduces mortality from cardiovascular disease, which is common in the general population especially among adults over 60 years of age and the leading cause of death in the western world. Clearly, statins have made a significant contribution to world health over the past 25 years.
In addition to their cholesterol lowering properties, statins may have other beneficial health effects. However, it should be noted that non-cardiovascular benefits of statins have typically been observed as associations in observational studies rather than being endpoints of randomized controlled trials. This always raises the possibility that an undetected confounding variable may bias the results. In one study, the use of statins was associated with an almost 50% reduction in the risk of Alzheimer disease. This may be attributable to cholesterol metabolism in the brain and the processing of amyloid protein or a reduction in the risk of small strokes. However, it is also possible that patients with early Alzheimer were not started on a statin or that those with progressive dementia were taken off statins because of their co-morbidities. Similarly, there are conflicting results on the potential relationship between statins and cancer. Early animal studies suggested that very high doses of statins may increase the risk of liver cancer in rodents. This has not been detected in multiple long-term clinical studies in humans. In contrast, some observational studies have suggested that statins may reduce the risk of cancer, while others have found no beneficial effect of statins on cancer. In fact, several meta-analyses that combine data from multiple randomized controlled trials to increase sample size and follow-up time found no beneficial effect of statins on the risk of cancer.
In lung transplantation, there has been some interest in the potential protective effects of statins against rejection. Some animal and experimental studies suggest that statins may have anti-inflammatory and immunomodulatory effects. As a result, multiple groups have investigated the potential effect of statins on chronic rejection after lung transplantation. Importantly, patients in these studies were prescribed statins for hypercholesterolemia, and the analyses were performed retrospectively. The first study from the University of Pittsburgh examined the outcomes of 39 patients who were treated with statins to 161 patients who were not. Those treated with statins were less likely to have acute rejection, and none of those who were started on statins in the first year developed chronic rejection. In addition, the statin group had better lung function and better long-term survival than the group who was not treated with statins.
We performed a similar retrospective study at Washington University and compared the outcomes of 51 patients treated with statins to 101 patients who were not treated with statins. Unlike the results from the University of Pittsburgh, there was no difference in the development of chronic rejection or in survival between the two groups at our center. However, in a recent study from Hannover, Germany, patients who were treated with statins had better lung function, were less likely to develop chronic rejection, and had better survival than those who were not. It is difficult to reconcile the conflicting results from these three studies, but it is important to note that all of these studies had important limitations inherent to their design and none are conclusive.
Additionally, although statins are generally considered safe, they do have some potentially serious side effects. There is an increased risk of muscle injury. This can range in severity from myalgias (muscle pain) to severe rhabdomyolysis (an acute muscle injury that can result in kidney failure. When statins are taken alone, the risk of muscle injury is very low, however, concurrent treatment with cyclosporine increases the risk of muscle injury significantly. Pravastatin has the lowest risk of muscle injury and is the only statin approved by the Food and Drug Administration (FDA) for use in combination with cyclosporine. Furthermore, statins have been associated with an increased risk of new onset diabetes and impaired glucose control in diabetics, and this risk is dose dependent.
Overall, statins are very effective lowering blood cholesterol levels and reducing cardiovascular risk. Furthermore, they are generally safe. However, their impact on non-cholesterol associated diseases is dubious, and their role in preventing lung transplant rejection is uncertain. Ideally, a randomized controlled trial of statins in lung transplantation should be conducted to better understand their role in this setting.