The following are key points to remember about statin-associated side effects:

1. Statins are generally well tolerated, but can be associated with skeletal muscle, metabolic, central nervous system complaints, and possibly other side effects. “Statin-associated symptoms” (SAS) are favored by some over “statin intolerance” because many patients can tolerate reduced statin doses.
2. Statin-associated muscle symptoms (SAMS) including myalgia, cramps, and aching are reported in 10-25% during treatment, and 60% of former statin users report SAMS. There is a marked increase in cardiovascular (CV) events in patients taking <80% of recommended doses compared to those who are more adherent.
3. SAMS most often occur without an elevation of creatine kinase (CK) and range from myalgia with normal CK to marked elevations and/or rhabdomyolysis (CK about 2000 U/L or >10x upper limit of normal ULN]), suggesting gradations of the same pathway. When weakness accompanies myalgia and an elevated CK, it is considered myositis. The incidence of rhabdomyolysis with clinically available statins ranges from 0.6 to 1.2 per 10,000 person-years.
4. In the placebo-controlled study of statin-naïve persons (STOMP), statin myalgia was predominantly aching, cramps, or fatigue in thigh and calf muscles, while placebo was associated with generalized fatigue, pain in areas of prior injury, and the groin. Time from active drug to onset of pain was 35 ± 31days compared to 61 ± 33 days on placebo. Onset <4 weeks is more likely statin related and persistence >2 months after cessation suggests nonstatin causes or underlying muscle disease provoked by statins. Symptom reappearance with a rechallenge and disappearance with cessation strongly infers SAMS.
5. In the STOMP study, only 9.4% of atorvastatin and 4.6% of placebo-treated patients had SAMS, suggesting background noise is about 5%, and 5% is true SAMS. However, such trials may underestimate SAMS because they enroll younger persons, limit intense exercise, last for a limited time, and avoid potential for drug interactions and conditions that increase statin myalgia. Statins can magnify exercise-induced marked elevation of the CK.
6. Risk factors for SAMS include increasing serum concentration of statins or reduced body muscle mass, both of which increase muscle concentration; enhanced absorption and hepatic uptake, which may be genetic regulated; and rate of entry and exit from muscle. Major factors leading to SAMS include drugs that interfere with the metabolism via CYP3A4, higher doses, elderly, female sex, physical disability, and low body mass index (BMI). Nearly 40% of medications are metabolized by the CYP3A4 isoenzyme, which competes for catabolism with the statins. Many of these are commonly used in patients on statins including antifungals, macrolide antibiotics, tricyclic antidepressants, calcium channel blockers, amiodarone, cyclosporine, sildenafil, and warfarin. Pravastatin, fluvastatin, pitavastatin, and rosuvastatin have less risk of drug interactions.
7. SAMS with or without CK elevation generally resolve within a few weeks. If not, consideration should be given to statin-induced necrotizing autoimmune myopathy (SINAM) (1/100K and very high CK) that presents with proximal muscle weakness, markedly elevated CK, and persistence of symptoms despite stopping the statin. Antibodies against hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase are found in 94% of those with SINAM. Immunosuppressive therapy can prevent progression to irreversible muscle weakness.
8. If low vitamin D levels, hypothyroid, and drug interactions are eliminated, and the statin is stopped until symptoms disappear; statins with a long half-life (atorva, rosuva, pitava) given low dose and less often can result in over 90% of patients with SAS being able to tolerate a statin. Low-dose statin + ezetimibe can reduce low-density lipoprotein cholesterol (LDL-C) almost to the level of high-intensity statins. There is no proven benefit of co-enzyme Q-10 in patients with SAMS.
9. Statins appear to impair mitochondrial function, which may explain statin-associated weakness, and statins have been shown to reduce the benefit of exercise training on maximal oxygen uptake.
10. Data suggesting that statins increase the risk for diabetes mellitus (DM) are not consistent. But regardless, two additional diabetics occur while there are 6.5 fewer CV events with intense statins over 1,000 patient-years. The risk of DM from statins is related to the number of risk factors for DM including increase in BMI, fasting blood sugar >100 mg/dl, age, women, and Asians.
11. In 2012, the Food and Drug Administration required a label regarding statins: “memory loss and confusion have been reported with statin use…..generally not serious and went away once drug was no longer taken.” Studies and meta-analysis designed to assess the effect of statins on cognitive function found little to no evidence, which prompted the National Lipid Association to conclude that statins are not associated with adverse effects on memory or cognition.
12. There is little to no evidence that statins cause serious liver damage, reduce renal function, induce clinical testosterone deficiency, or cause interstitial lung disease, tendon rupture, or impaired sleep. Low LDL-C and statins have been associated with depression, but the evidence is inconclusive. Statins appear to increase the risk of hemorrhagic stroke in persons with prior ischemic strokes.

Keywords: Antidepressive Agents, Tricyclic, Calcium Channel Blockers, Cholesterol, LDL, Creatine Kinase, Cytochrome P-450 CYP3A, Depression, Diabetes Mellitus, Drug Interactions, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Immunosuppressive Agents, Muscle Cramp, Muscle Weakness, Myalgia, Myositis, Pravastatin, Primary Prevention, Rhabdomyolysis, Risk Factors, Stroke, Vitamin D Deficiency, Warfarin

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