The Food and Drug Administration (FDA) considers a side effect serious if it is life-threatening, requires a hospital stay, or causes permanent damage or disability.1 The FDA requires medication guides to be issued when, in its view, serious side effects could occur while taking a medication. There are no medication guides issued for statin monotherapy.2
Package inserts for the seven statins licensed for use in the US warn against the small (<0.1%) risk of developing severe myopathy, defined as muscle pain or tenderness with creatinine kinase (CK) levels ten times the upper limit of normal (ULN) while taking statins. They also warn against rhabdomyolysis, a condition that results from the breakdown of damaged skeletal muscle.3–9 The risk is increased in older people (≥65), people with hypothyroidism and kidney disease, and people taking statins at the same time as CYP34A inhibitors. The risk of severe myopathy increases with increasing dosages of a statin. Based on a clinical trial database (n=41,050), the risk of severe myopathy with simvastatin was 0.02% at 20 mg/d, 0.08% at 40 mg/day, and 0.53% at 80 mg/day.7 Similar dose-response effects are reported for other statins. In most cases, muscle symptoms resolved and CK levels returned to normal when the statin was discontinued.
Graham et al. identified a cohort of statin users (n=252,460) from a large health insurance database from 11 managed care plans in the US to estimate the risk of rhabdomyolysis.10 Per year of statin monotherapy, 22,727 people were needed to observe one case of rhabdomyolysis.
In clinical trials, elevations in liver enzymes in excess of three times ULN have been reported in 0.2% to 4.9% of patients taking statins.3–9 This risk also appears to increase with increasing dosages. Discontinuation of the statin typically results in the liver enzymes returning to pretreatment levels. There were very few reports of clinical signs or symptoms of liver problems in pre-clinical trials. Liver failure has been reported in patients taking statins, but these case reports are rare.3–9,11,12 Twenty-two cases of drug-induced liver injury over a nine-year period were attributed to statin use by the US Drug-Induced Liver Injury Network, of which four developed liver failure and one died.12 Because the incidence of liver failure in patients taking statins is so rare, it is difficult to attribute the liver failure to the use of statins, but the Liver Expert Panel of the National Lipid Association considers liver failure to be a plausible, but extremely rare, reaction to statins.11
Statins may increase the risk of diabetes in some patients, an effect that may vary by the statin type and dosage used.13–15 Package inserts for most statins except pravastatin report an increased risk of elevated glucose, HbA1C, and, in some cases, new-onset diabetes compared to placebo.3–9 The effect is particularly true for those with metabolic syndrome and on high-dose statin therapy who were at higher baseline risk of diabetes before statins were initiated.16,17 Ridker et al. conducted a randomized double-blind study comparing the incidence of cardiovascular endpoints and incident physician-reported diabetes in patients taking rosuvastatin 20 mg (n=8,901) versus placebo (n=8,901).16 Study inclusion criteria included the presence of elevated hs-CRP, which is a marker for insulin resistance. Forty-one percent of study participants had metabolic syndrome. The number of people with new-onset diabetes was 0.6% higher in patients taking rosuvastatin compared to placebo. People with diabetes risk factors (metabolic syndrome, impaired fasting blood glucose, BMI >30 kg/m2, or HbA1c >6%) on rosuvastatin had a 28% increase in incident diabetes compared to those with risk factors taking placebo. There was no increase compared to placebo in incident diabetes in individuals without risk factors. The authors also calculated the cardiovascular benefit among those on statins. For individuals with diabetes risk factors, 134 vascular events were avoided for every 54 new cases of diabetes.
According to 2018 American Heart Association/American College of Cardiology guidelines for the management of blood cholesterol,18 if statin-associated side effects are not severe, statin dosage may be modified or an alternate statin may be tried to lessen the adverse effects. CK levels and liver enzymes may need to be monitored when patients develop signs or symptoms of muscle or liver toxicity, but routine measurements of these enzymes have not been shown to be useful.
References
- Food and Drug Administration. What is a serious adverse event? https://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm. Accessed August 12, 2019.
- Food and Drug Administration. Medication guides. https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Accessed August 12, 2019.
- Pravastatin[package insert]. Princeton, NJ: Bristol Myers Squib.
- Pitavastatin [package insert]. Tokyo, Japan: Kowa Pharmaceuticals, 2012
- Fluvastatin [package insert]. East Hanover NJ: Novartis Pharmaceuticals, 2012.
- Lovastatin [package insert]. Morgantown WV: Mylan Pharmaceuticals.
- Simvastatin [package insert]. Cramlington UK: Merck, Sharpe & Dohne, LTD, 2010.
- Atorvastatin [package insert]. Dublin Ireland: Pfizer Parke-Davis, 2009.
- Rosuvastatin [package insert]. Wilmington DE: AstraZeneca Pharmaceuticals, 2010.
- Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2019; 292(21):2585-2590.
- Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97(8A):77C-81C.
- Russo MW, Hoofnagle JH, Gu J, et al. Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014; 60(2):679-686.
- Preiss D, Welsh P, Murphy SA, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy. JAMA 2011; 305(24):2556-2564.
- Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ 2013;346: f2610.
- Navarese EP, Buffon A, Andreotti F, et al. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am J Cardiol 2013;111(8):1123-1130.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008;359(21):2195-2207.
- Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol 2013;61(2):148-152.
- Grundy S, Stone N, Beam C, Birtcher KK, Harm PD. 2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019;73(24):e285-e350.
