Statins and the Kidney

One in four patients 40 years or older in the United States reports using a statin medication in the past 30 days. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and therefore reduce endogenous hepatic cholesterol synthesis by inhibiting the mevalonate pathway. Chronic hepatic cholesterol synthesis inhibition results in increased hepatic uptake and degradation of low-density lipoprotein (LDL), decreased secretion of hepatic lipoproteins, and decreased hepatic scavenger receptor expression. According to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines and the 2014 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia, the following patient groups significantly benefit from chronic statin therapy: patients with a history of coronary artery disease, stroke, or peripheral vascular disease; patients with LDL cholesterol of at least 190 mg/dL; patients with diabetes mellitus type 1 or 2 who are 40 to 75 years old with LDL cholesterol of at least 70 mg/dL; and patients whose 10-year risk of atherosclerotic cardiovascular disease as estimated by a ACC/AHA-endorsed pooled cohort risk calculator is at least 7.5% or at least 5% and desire treatment after a benefit/risk discussion. In these patient populations, statin treatment reduces coronary, atherosclerotic peripheral vascular disease, and stroke events. These benefits are attributed primarily to statins' direct lowering of LDL cholesterol concentration; however, statins have been shown to have numerous additional biologic activities independent of cholesterol reduction.

By decreasing the synthesis of L-mevalonate, statins decrease protein prenylation. Protein prenylation controls posttranslational lipid modification of the cellular signaling proteins Rho, Ras, and Rac and affects cell motility, transcription factor activation, and membrane transport. Statin-associated cell signaling modifications produce antiinflammatory, antioxidant, and antithrombotic effects and improve endothelial function. Specifically, statin therapy reduces systemic inflammation by decreasing expression of tumor necrosis factor-α, interleukin-1β, and interleukin-12, by increasing expression of interleukin-10, by decreasing leukocyte adhesion molecule E-selectin expression, and by decreasing plasma levels of high sensitivity C-reactive protein. Statins have been shown to diminish oxidative stress by reducing vascular smooth muscle production of angiotensin II-induced free radicals and decreasing vascular superoxide generation. Improved endothelial function with statin therapy is the result of enhanced endothelial nitric oxide synthase mRNA stability and decreased caveolin-1 and oxidized LDL concentrations, which are known inhibitors of endothelial nitric oxidize synthase. These alterations lead to increased nitric oxide production. Because nitric oxide inhibits platelet aggregation on endothelium, this enhanced nitric oxide production also has antithrombotic actions. Furthermore, statins inhibit tissue factor activity and increase thrombomodulin concentration, stimulating the protein C fibrinolytic pathway. The clinical importance of these LDL-independent statin effects, which have been demonstrated primarily in in vitro and preclinical studies, remains unclear.

Statins are well tolerated by most patients, but several specific complications of chronic use have been observed. Rarely, statin therapy results in elevated liver transaminase levels, generally without clinically significant hepatic impairment. Statins also are known to affect the musculoskeletal system. Statin treatment is estimated to result in a 0.1% incidence of rhabdomyolysis compared with a 0.04% incidence in matched placebo groups. Statin-associated autoimmune myopathy, characterized by muscle cell necrosis and autoantibodies against HMG-CoA reductase, has been reported with an estimated incidence of 0.02% and often necessitates immunosuppressive therapy for symptom resolution. The most common muscle complaint associated with statin usage is myalgia, characterized by bilateral muscle pain and weakness involving large muscle groups, often without creatinine kinase elevation. Statin-associated myalgia is difficult to clinically differentiate from nonspecific myalgia because of the lack of a diagnostic test and validated clinical set of criteria. Statin therapy also is estimated to increase the risk of incidental diabetes by 9% because of increased insulin resistance, particularly in patients receiving a high dose of statin. In a recent meta-analysis of placebo-controlled trials involving more than 45,000 patients with a mean follow-up time of 3.2 years, no association between statin therapy and short- or long-term risk of serious adverse renal events was found.

Recently, the possibility of deleterious neurocognitive effects of statin use has concerned physicians and patients. Subgroup analyses within several randomized controlled trials (RCTs) demonstrated an increased incidence of intracerebral hemorrhage associated with statin treatment in patients with previous ischemic stroke. To investigate this finding, a meta-analysis of trials involving patients with a history of cerebrovascular disease was performed. No association between statin exposure and intracerebral hemorrhage was detected. In addition, studies have found no evidence that statin therapy is associated with cognitive impairment, worsening dementia, or memory deficits.