Physicians' Academy for Cardiovascular Education

Common side effects observed with statin therapy

Thomson PD et al., JACC 2016

Statin-associated side effects

Thomson PD, Panza G, Zaleski A, et al.
JACC 2016;67:2395-2410


Statins are hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors that are well tolerated but are associated with various statin-associated symptoms (SAS) like statin-associated muscle symptoms (SAMS), diabetes mellitus (DM) and central nervous system (CNS) complaints. It is not clear whether statins are the direct cause of these symptoms. Nevertheless, they often result in reduction or discontinuation of therapy. SAS is favoured over the term statin intolerance because many patients with SAS can tolerate reduced doses of these drugs. A meta-analysis of 15 studies observed a 45% and 15% increase in all-cause mortality respectively CVD events in patients taking less than 80% of their prescribed statin versus patients who were more adherent [1]. Some patients tolerate one statin better than another.

Statin-associated muscle symptoms (SAMS)

SAMS are the most common SAS and are reported in 10-25% of statin-treated patients [2,3]. SAMS can occur without creatinine kinase (CK) elevations. Syndromes range from myalgia to marked CK elevations and/or clinical rhabdomyolysis. Several definitions of SAMS have been proposed [4-7], but these are useful for quantifying SAMS in clinical trials but less useful in clinical practice.

Diagnosis of SAMS

The diagnosis of SAMS is often subjective for patient and physician because there are no validated clinical tests or diagnostic criteria. The National Lipid Association (NLA) proposed a point/scoring system on the basis of observational studies, such as the PRIMO and STOMP studies [2,6,8]. Consensus maintains that muscle pain and aching (myalgia), cramps and weakness can be manifestations of SAMS. Symptoms are usually bilateral and involve large muscle groups. In contrast, cramping is usually unilateral and may involve small muscles of the hand and feet. Symptoms may be more frequent in physically active patients [2]. Symptoms often appear early after starting therapy or after increasing a dose and SAMS should usually resolve or reduce within weeks after discontinuation of therapy. Several clinical trials have been performed to identify SAMS but these illustrate the difficulty to recognize them [2,8-11]. This hampers also estimation of incidence and prevalence of SAMS.

Risk of SAMS

The risk of SAMS may be increased by increased serum statin concentrations (such as increased dose, affected statin intestinal absorption, catabolism or metabolism) or reduced body muscle mass. Furthermore, female sex, advanced age, physical disability and a lower body mass index are associated with lower plasma volumes and reduced muscle mass and are SAMS risk factors [12,13]. Also compounds such as alcohol affect muscles and may increase the risk of SAMS. Serious SAMS are more frequent with simvastatin than with other available statins and therefore the FDA recommend avoiding the 80 mg dose [14].

Statin-induced necrotising autoimmune myopathy

The only SAMS that do not directly disappear after cessation of therapy are statin-induced necrotising autoimmune myopathy (SINAM). This presents with proximal muscle weakness, markedly elevated CK levels and persistence of symptoms and CK elevations despite drug discontinuation [15]. Most patients harbour antibodies against HMG-CoA which can be detected with the enzyme-linked immunosorbent assay (ELISA) [16]. SINAM is associated with human leukocyte antigen (HLA) genotypes [17] and recognition of SINAM is important because therapy is required to prevent progression to sever and often irreversible muscle weakness.

Management of SAMS

Managing patients with possible SAMS and other SAS requires reassessing the benefit of statin therapy, making the tentative diagnosis, eliminating contributing factors, reassuring the patient, trying alternative statins and doses and prescribing alternative treatment strategies. CK measurements can be useful to exclude clinically threatening muscle injury and to assist with diagnosis [9]. It is important to exclude other potentially contributing factors. The authors of this paper consider it critical to reassure patients that statins are extremely safe and effective and that SAMS is reversible with drug cessation as may patients are concerned about the side effects. Medications other than statins, which may be out-of-favour, should also be considered, like niacin [18].

Possible mechanisms that produce SAMS

Statins inhibit HMG-CoA reductase, a rate-limiting enzyme of the mevalonate pathway. This pathway produces cholesterol, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) [19]. FPP and GGPP can activate a variety of small guanosine triphosphate (GTP)-binding regulatory proteins. Multiple mechanisms have been suggested as contributing to SAMS. These include reduced sarcolemmal or t-tubule cholesterol, affecting the phosphoinositide 3-kinase (PI3K)/AKT pathway and impairment of mitochondrial function [20-22].


Statins and diabetes mellitus

Contradicting results are reported by clinical trials regarding the relationship of statin therapy with diabetes mellitus (DM), but this affected by the patient inclusion criteria [23,24]. Two meta-analyses both reported a small increase in incidence related to statin treatment, and 1 additional case of DM per year would occur for every 498 patients treated with intense versus moderate statin therapy, which translates to the prevention of 3.2 CVD events for each new case of DM when using intense statin therapy [25,26]. The risk of DM during statin therapy increases with the usual DM risk factors, statin dose and ethnicity [26]. 
How statins increase the risk of DM is not clear, but the lower cholesterol levels produced by statins may contribute to the effect. High serum cholesterol levels are associated with a reduced risk of DM. Interestingly, the magnitude of LDL-C increase in FH patients varies with the genetic defect [27]. Patients with genetic defects blocking LDL receptor synthesis have LDL levels greater than in patients with a defective, but synthesized, LDL receptor. Consistent with the concept that increased LDL-C “protects” against DM, the prevalence of DM was lower in LDL receptor-negative patients than those with defective receptors than those with apoB defects. Similarly a meta-analysis demonstrated 2 single-nucleotide polymorphisms in the HMG-CoA reductase gene that reduced LDL-C levels and increased the risk of DM [25].

Statin effect on the central nervous system

Statins have possible adverse effects (AEs) on cognition. There are some reports of statin-associated memory loss or dementia that often resolve with cessation of statin therapy [28]. However, the number of reports is low but effects on memory may be easily overlooked or mistakenly attributed to aging or concurrent disease [29]. The statin-effect on cognition is controversial but strong evidence linking statins to AEs is lacking, as compared with a larger body of evidence supporting their safety.

Possible mechanisms for CNS effects by statins

Statins could affect the CNS directly by inhibiting the CNS cholesterol synthesis or indirectly by altering other substance involved in cognitive function. Directly inhibition seems unlikely due to the low turn-over of cholesterol in the brain [30]. As statins differ in their ability to cross the blood-brain barrier due to their lipophilic or hydrophilic characters, the possible effect of any statin probably depends on the statin itself as well as on its dose and duration of treatment.

Other SAS

After performing a Pubmed search for relevant meta-analyses and reviews, the authors suggest other possible statin-associated effects. These include liver failure, decreased renal function, tendon ruptures, haemorrhagic stroke, low testosterone, depression, interstitial lung disease and sleep.


1. Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:2940–8.
2. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage
statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005;19:403–14.
3. Cohen JD, Brinton EA, Ito MK, et al. Understanding Statin Use in America and Gaps in Patient
Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin
Lipidol 2012;6:208–15.
4. Pasternak RC, Smith SC Jr., Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40: 567–72.
5. Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol 2013;29:1553–68.
6. Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014;8:S58–71.
7. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36: 1012–22.
8. Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013;127:96–103.
9. Taylor BA, Lorson L, White CM, et al. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015;238:329–35.
10. Buettner C, Rippberger MJ, Smith JK, et al. Statin use and musculoskeletal pain among adults with and without arthritis. Am J Med 2012;125: 176–82.
11. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014;168:6–15.
12. Schech S, Graham D, Staffa J, et al. Risk factors for statin-associated rhabdomyolysis. Pharmacoepidemiol Drug Saf 2007;16:352–8.
13. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin Drug Saf 2015;14: 935–55.
14. FDA: Limit use of 80 mg Simvastatin. FDA Consumer Health Information, June 2011. U.S. Food and Drug Administration. 2011. Available at: Accessed March
12, 2016.
15. Grable-Esposito P, Katzberg HD, Greenberg SA, et al. Immune-mediated necrotizing myopathy
associated with statins. Muscle Nerve 2010;41:185–90.
16. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy.
Arthritis Rheum 2011;63:713–21.
17. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve 2013;48:477–83.
18. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients:
long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–55.
19. Cao P, Hanai J, Tanksale P, et al. Statininduced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. FASEB J 2009;23:2844–54.
20. Draeger A, Monastyrskaya K, Mohaupt M, et al. Statin therapy induces ultrastructural damage in
skeletal muscle in patients without myalgia. J Pathol 2006;210:94–102.
21. Hoffman EP, Nader GA. Balancing muscle hypertrophy and atrophy. Nat Med 2004;10:584–5.
22. Thompson PD, Parker B. Statins, exercise, and exercise training. J Am Coll Cardiol 2013;62:715–6.
23. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001;103:357–62.
24. Ridker PM, Danielson E, Fonseca FA, et al., JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207.
25. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015;385:351–61.
26. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a metaanalysis. JAMA 2011;305:2556–64.
27. Besseling J, Kastelein JJ, Defesche JC, et al. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015;313:1029–36.
28. Wagstaff LR, Mitton MW, Arvik BM, et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003;23:871–80.
29. Evans WJ, Cannon JG. The metabolic effects of exercise-induced muscle damage. Exerc Sport Sci Rev 1991;19:99–125.
30. Dietschy JM, Turley SD. Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004;45:1375–97.