Statin associated muscle symptoms (SAMS): strategies for prevention, assessment and management

Figures & data

Table 1. Proposed mechanisms of SAMS.

Proposed mechanism	Pathophysiology and evidence		Recommendations	Level of evidence 1–6*
Gene regulation and single nucleotide polymorphisms	- Genetic basis for SAMS investigated in candidate gene studies, GWAS, multi-omic networks [31,32] -Genetic variants coding for proteins involved in statin uptake, metabolism, elimination: CYPs, UGTs, SLCO1B1, ABCB1, ABCG2, COQ1, RYR1, LILRB5, UGT1A, GATM [33–35]		- Data to support clinical validity of genetic testing remains limited although, in some cases, genotyping may address concerns about perceived statin risks and optimizing medication adherence [36–38] − Clinical implementation of pharmacogenetic testing not routinely recommended − Attempt alternative statin	1–2
	SLCO1B1: regulates hepatic uptake of statins CYPs: CYP450 is the main pathway for statin metabolism, affect metabolizing rate (i.e. rapid vs poor) ABC transporter genes: ABCB1 (impaired efflux, longer statin half-life), ABCG2 (altered statin pharmacokinetics) CPT: essential role in transfer of FAs from cytosol to mitochondria; CPT2 deficiency (myalgia, rhabdomyolysis with statin + exercise, infection, cold exposure)
Statin-associated autoimmune myopathy (SAAM)	Mechanism: -autoantibodies anti-HMGCR with immune-mediated-necrotizing myopathy. Incidence 2–3/100,000; variable symptom onset -statins upregulate muscle HMGCR expression in anti-HMGCR (+) myopathy patients➔ anti-HMGCR induce muscle atrophy Necrotizing myopathy [28,29] -Extreme CK elevation (90% > 2000 IU/L) -Progressive, symmetrical proximal muscle weakness -Positive anti-HMG-CoA reductase antibodies -Muscle biopsy: necrosis + macrophage infiltration		- Immediate statin discontinuation [39]. Initiate non-statin LLT - In some cases, myopathy does not revert after drug discontinuation - Immunosuppressive therapy (eg glucocorticoids) [40] − Rechallenging with another statin proven to be unsuccessful and should be avoided	1
Neuromuscular conditions	-Exacerbate underlying neuromuscular disorders: myasthenia gravis, derma/polymyositis, inclusion body myositis, motor neuron disease, MELAS, hypothyroid myopathy [41] -Metabolic myopathies sometimes identified once statin started (CPT2/AMPD1/GAA/V deficiency) [42]		- Discontinuation of statin or treatment of underlying disorder [43–45]	4–5
Mitochondrial dysfunction −direct cellular and subcellular effects	Mechanism: Impaired muscular mitochondrial oxidative capacity (increased ROS) + decreased mitochondrial respiration + increased apoptosis [46–48] CPT1 & CPT2 involved in FA oxidation in mitochondria -CPT2 deficiency = autosomal recessive disease, increased risk of SAMS [48]		− No routine recommendations	3–4
HMG-CoA reductase pathway-mediated effects	-Perturbation of mevalonate pathway: altered energy metabolism [49] ➔ decreased intermediates of cholesterol synthesis (dolichol, squalene, ubiquinone/CoQ10, prenylated proteins, electron transport chain proteins)	-Decreased post-translational protein modification (prenylation) Mechanism: reduction of farnesyl and geranylgeranyl pyrophosphate reduces ATP and prenylation of GTPases (Ras, Rac, Rho) [50] ➔ activation of caspases ➔ apoptosis	− No data on routine recommendation for geranylgeranyl supplementation	5–6
		-Decreased CoQ10 levels Mechanism: −CoQ10 cofactor in mitochondrial energy metabolism -Mitochondrial dysfunction by reduced electron transport, Ca release and ATP synthesis ➔ caspase activation and apoptosis ➔ muscle damage [51] -Statins reduce CoQ10 in muscle tissue of humans & rodents [52,53] with structural abnormalities in muscle biopsies [54]	- CoQ10 supplementation proposed for SAMS prevention/treatment but RCT data regarding its efficacy is mixed [55–57]	2
			- RCT meta-analysis shows CoQ10 supplements do not reduce SAMS [58]	1
		Cholesterol depletion may lead to cell membrane instability and lysis [54]		5–6
- Impaired Ca homeostasis and signaling	Mechanism: -Abnormal RYR1/3 Ca-mediated release from SR ➔ increased Ca transients in muscle inducing pro-apoptotic signaling activation [59] -Muscle biopsies: increased expression of RYR3, structural changes in SR [54] -Increased RYR1 variants in patients with statin-induced myopathy [54,60]		− Routine supplementation with calcium to prevent SAMS not recommended	4–5
Atrogin-1 upregulation	-F-box protein, atrogin-1 (muscle-specific E3 ubiquitin ligase) plays a role in inducing proteolysis and muscle atrophy by ubiquitin proteasome pathway [61] -Increased expression in muscle biopsies [62]			5–6
Vit D deficiency	-Role of statin on Vitamin D levels controversial [63] -Vitamin D deficiency known to cause muscle weakness/myopathy independently of statin use [64] -In largest meta-analysis of 2420 statin-treated patients from 7 studies, low vit D levels associated with myalgias/SAMS [65,66] Mechanism: Vitamin D deficiency may reduce: − transcription of Vitamin D receptor -synthesis of proteins for T-tubular system repair & prevention of SR rupture −CYP3A4 availability for statin metabolism		- In recent subgroup analyses of randomized studies Vitamin D supplementation does not seem to prevent SAMS or statin discontinuation [67]	2
			- Observational studies reported Vitamin D supplementation reduces SAMS in patients with previous reported statin intolerance [68,69]	4
Physical exercise	Statins may increase incidence of exercise-related myalgia but do not consistently reduce muscle strength, endurance or overall exercise performance [20,70].		− Animal studies suggest that gradual training may improve muscle tolerance to statin exposure	5–6

Note: SR, sarcoplasmic reticulum; Ca, Calcium; Vit D, Vitamin D; mtDNA, mitochondrial DNA; SLCO1B1, solute carrier organic anion transporter family member 1B1; ABCB1, ATP-binding cassette sub-family B (MDR/TAP) member 1; ABCG2, ATP-binding cassette subfamily G member 2. CYP, cytochrome; CPT1/2, carnitine palmitoyl transferase 1/2; RYR, ryanodine receptors; CoQ, coenzyme Q10; RCT, randomized controlled trials; AMPD1, adenosine monophosphate deaminase; GAA, acid alpha-glucosidase; ROS, reactive oxygen species.

Legend – Level of evidence.

1. Systematic review and meta-analysis.

2. Randomized controlled trial(s).

3. Non-randomized controlled trial (eg quasi-experimental or pre-post intervention study).

4. Observational studies (eg case control or cohort).

5. Qualitative studies (case report or case series, narrative review, expert opinion).

6. Animal and laboratory studies.

Table 2. Components and concepts endorsed by international societies pertaining to establishment of a statin intolerance syndrome. SAMS = statin-associated muscle symptoms, CK = creatine kinase, R = rosuvastatin, a = atorvastatin, S = simvastatin, Pr = pravastatin, L = lovastatin, F = Fluvastatin, Pi = pitavastatin.

	National Lipid Association [15]	National Health Service [81]	Canadian Consensus Working Group [22,82–84]	Taiwan Society of Lipids and Atherosclerosis [85]	Luso-Latin American Consortium [86]	European Atherosclerosis Society [19]	International Lipid Experts Panel [87]
Guideline-defined indication for statin			✓
Symptoms and/or biomarkers	✓	✓	✓	✓	Focus on SAMS, CK	Focus on SAMS, CK	✓
Challenge, de-challenge, re-challenge	✓	✓	✓	✓	✓	✓	✓
Number of statins	Minimum of 2, one at lowest approved daily dose	Emphasis on use of A and R	Minimum of 2, including A and R	Minimum of 2, one at lowest approved daily dose	2 statins at any dose or inability to tolerate doses higher than R 5 mg, A 10 mg, S 20 mg, Pr 20 mg, L 20 mg, F 40 mg, Pi 2 mg		Minimum of 2, one at lowest approved daily dose
Exclusion of drug-drug interactions	✓	✓	✓		✓		✓
Exclusion of relevant co-morbidities	✓	✓	✓		✓		✓
Lack of achievement of guideline-defined goal	Failure to meet therapeutic objective defined by shared decision making		✓
Concept of complete/partial statin intolerance	✓		✓	Focus on complete statin intolerance			✓

Figure 1. General approach to statin-associated muscle and other statin-associated symptoms.

Table 3. Selected non-statin alternative therapies.

Agent	Drug class	Customary dose	Usual incremental LDL-C reduction	CV outcome RCTs	RCTs in statin intolerance
Ezetimibe	cholesterol absorption inhibitor targeting NPC1L1	10 mg daily by mouth	15–25%	yes; positive	no
Evolocumab	anti-PCSK9 monoclonal antibody	140 mg q 2 weeks or 420 mg q 4 weeks subcutaneously	55–70%	yes; positive	yes; positive
Alirocumab	anti-PCSK9 monoclonal antibody	75 mg or 150 mg q 2 weeks or 300 mg q 4 weeks subcutaneously	55–70%	yes; positive	yes; positive
Inclisiran	anti-PCSK9 short interfering RNA	284 mg on day 0, day 90 and q 6 months thereafter subcutaneously	44–55%	expected by 2024	no
Bempedoic acid	inhibitor of ACLY	180 mg daily by mouth	15–30%	yes; positive	yes; positive
Lomitapide	Inhibitor of MTP	5 to 60 mg daily by mouth	40–55%	no	no
Evinacumab	Inhibitor of ANGPTL3	15 mg/kg q 4 weeks intravenously	50–60%	no	no

Abbreviations: ACLY, adenosine triphosphate (ATP) citrate lyase; ANGPTL3, angiopoietin like 3 protein; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-Pick C1-like 1 protein PCSK9, proprotein convertase subtilisin kexin type 9; RCTs, randomized controlled trials.

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