Assessing Severity of Statin Side Effects: Fact Versus Fiction

High low-density lipoprotein cholesterol (LDL-C) is one of the most common modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD), affecting 78 million US adults (37% of the American adult population) in 2011-2012 according to the Centers for Disease Control and Prevention. Statins are a class of drug that inhibit one of the first steps in cholesterol synthesis, in turn upregulating LDL receptors and lowering LDL-C generally by 25-50%. Since lovastatin was first approved in 1987 in the US, statins have become the leading pharmacologic treatment for high LDL-C and non-HDL-C.

Since 1900, ASCVD has been the leading cause of death every year in the US (except for 1918, the year of the influenza pandemic). With the decline of smoking, LDL-C control has become an even more important way to decrease the risk for ASCVD events (heart attacks and strokes). Patients with high cholesterol develop plaque in their blood vessels, which can limit blood flow and lead to ASCVD events.

Robust data show that reducing LDL-C through statin therapy leads to a reduction of ASCVD risk. The Cholesterol Treatment Trialists' (CTT) meta-analysis using 27 large-scale trials demonstrated that each ~40 mg/dL (1 mmol/L) reduction in LDL-C with statin therapy decreases risk of major vascular events by ~25% each year after the first year; there was a more modest 10-12% reduction in the first year. An ~80 mg/dL (2 mmol/L) reduction over five years with low-cost statin therapy appears to prevent a major vascular event in about 500 out of 10,000 patients who have not yet had a vascular event (primary prevention) and 1,000 out of 10,000 patients who already have ASCVD (secondary prevention). The number of events prevented will continue to grow past five years since statin therapy further reduces ASCVD risk during each year it continues to be taken.

Statins clearly help to lower the risk for future ASCVD events in patients at risk. In general, statins are very well tolerated and about 85-90% of patients report no side effects. However, there are a few side effects that tend to raise concern among patients when considering the need for one these medications. Three of the most common concerns include muscle-related issues, new-onset diabetes and increased incidence of hemorrhagic stroke.

The most common complaints with statin use are muscle-related, with reported rates ranging widely between 0.3 to 33%. The broad range in rates reflects differences in study populations and is likely in part caused as well by differing categorizations for muscle symptoms. Statin-induced myopathy is typically defined as muscle pain, weakness and/or cramps with blood creatine kinase (CK) levels at least ten times the normal upper limit. Creatine kinase, an essential enzyme for muscle function, is a marker for muscle damage when found in elevated levels in the blood.

The mechanism of statin-induced myopathy is not completely understood and may be caused by decreased synthesis of mevalonic acid from statin use leading to decreased energy generation, which may lead to muscle injury. For patients on standard statin doses, symptomatic adverse events like muscle pain and weakness may occur in 50-100 patients per 10,000 treated over five years. However, in routine practice, much of the symptomatic adverse events attributed to statin therapy represent misattribution, as demonstrated by placebo-controlled trials.

Since patients who take statins are often asked to watch out for muscle problems, the clinical incidence of muscle complaints is likely higher than its true value. The "nocebo" effect occurs when a patient who has been told that a drug has a particular side effect reports that side effect even when they are actually taking a placebo instead of the drug; this effect has been demonstrated to occur with statin-related muscle symptoms in several clinical studies, most notably the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and in Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3).

Statins have also been shown to be environmental triggers for anti-HMG-CoA reductase necrotizing autoimmune myositis, a rare disorder characterized by severe muscle cell death caused by an autoimmune response against the enzyme that statins target. This disorder likely only develops in individuals with an existing genetic susceptibility, but its severity and need for immediate treatment with immunosuppressants highlight the importance of familiarity with this disorder.

Another side effect associated with statin usage is new-onset diabetes. The Crestor 20 mg Versus Placebo in Prevention of Cardiovascular (CV) Events (JUPITER) trial found 25% more cases of newly diagnosed diabetes in the statin group compared to placebo (270 vs. 216, out of 17,603 total). The occurrence of new-onset diabetes went up when patients had one or more pre-existing risk factors for diabetes. However, this non-dose dependent possible side effect should not be a reason to avoid prescribing a statin--for every 54 newly diagnosed case of diabetes in the JUPITER trial, 134 vascular events or deaths were prevented.

While lipid-lowering with statins decreases risk for ischemic stroke (when blood flow is obstructed to tissues), risk for a hemorrhagic stroke (a brain aneurysm or blood vessel leak) is associated with lower LDL-C according to some observational studies. The Lipitor In The Prevention Of Stroke, For Patients Who Have Had A Previous Stroke (SPARCL) trial found a slight increase in hemorrhagic strokes in the statin group, while a meta-analysis of CTT found a slight increase that was not statistically significant. Out of 10,000 patients treated for five years, only 5-10 patients may have a hemorrhagic stroke, which pales in comparison to the reduction in ischemic stroke seen with LDL-C reduction.

In addition to increased statin dosage, several other medications, age and genetic factors can put patients at higher risk of having an adverse effect. Some medications (e.g., cyclosporine, gemfibrozil, antifungal azoles, macrolide antibiotics and protease inhibitors) lead to higher levels of statins by decreasing their rate of breakdown and can result in a higher risk of side effects. Age and a mutation in the SLCO1B1 gene can also slow statin breakdown.

For patients concerned about statin side effects, it is important to consider the strongest evidence and to talk with well-versed clinicians. It is important to note the large risk reduction in ASCVD events offered by lowering LDL-C while the incidence of side effects is comparatively low. Health care providers can take the opportunity to highlight the importance of lifestyle changes to lower LDL-C because reduction through lifestyle means less of a need for reduction through statin therapy.

There are several lifestyle changes that can help reduce LDL-C. A healthy diet with reduced saturated fat and trans fat, like the Mediterranean diet, can help lower LDL-C. The American Heart Association recommends moderate to vigorous exercise for 40 minutes at least three times a week. For those with high triglyceride levels or large waistlines, reducing weight can also help reduce risk of vascular events.

While the side effects of statins are important to keep in mind, overall, the benefits of lowering LDL with statins far outweigh the low likelihood of an adverse effect for the vast majority of adults at elevated risk for ASCVD. Fear of adverse effects should not prevent a healthcare provider from prescribing a statin, though it is important to be alert for a severe reaction to a statin and take it seriously. Providers should also be careful of factors that can increase the risk of side effects presenting in a patient, especially interacting medications. Ultimately, lowering LDL-C is incredibly important when it comes to improving heart health, and with only 55% of US adults needing cholesterol medicine currently taking it, statins are still a great way to prevent vascular events.

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, LDL, Gemfibrozil, Mevalonic Acid, Midazolam, Macrolides, Lovastatin, Risk Factors, Myalgia, Pandemics, Cyclosporine, Muscle Cramp, Secondary Prevention, Diet, Mediterranean, Immunosuppressive Agents, Influenza, Human, Protease Inhibitors, Genetic Predisposition to Disease, Nocebo Effect, Autoimmunity, Intracranial Aneurysm, Brain Ischemia, Cause of Death, Hypercholesterolemia, Hydroxymethylglutaryl CoA Reductases, Muscular Diseases, Myocardial Infarction, Myositis, Primary Prevention, Diabetes Mellitus, Risk Reduction Behavior, Mutation, Smoking, Cell Death, Anti-Bacterial Agents, Creatine Kinase, Receptors, LDL, Triglycerides

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