Table IV.

Risk Factors for Statin Adverse Effects (AEs)

Risk Factor	Considerations
Dose (or Potency; see Table II)36, 37, 163, 176, 178, 180, 185, 334	- As discussed in the text (section ‘Dose Response’), many statin AEs are dose dependent. - Although some literature advises “the lower the better” with regard to LDL-C and aggressive statin use,191, 192 the US FDA states “all statins…should be prescribed at the lowest dose that achieves the goals of therapy (e.g., target LDL-C level).”180
Other Interacting Drugs (see Table III) 36, 163, 180 and Polypharmacy341	- As discussed in the text (section ‘Drug Interactions’), many drug interactions functionally increase dose. In some cases, interacting drugs may, in addition, cause/compound mitochondrial toxicity (e.g. amiodarone;283-288 HIV protease inhibitors335, 336), and may themselves conduce to rhabdomyolysis.300 - Use of CYP3A4 inhibitors were associated with a 6.0-fold increase in hospitalizations for myopathy including rhabdomyolysis in patients on lipid therapy (95% CI 2.1-17.4), and a 2.3-fold increase in hospitalizations for renal AEs (95% CI 1.6-3.2) based on administrative claims data, matching controls to cases on age, sex, geographic region, length of follow-up, and time of index drug fill.167
‘Frailty’ or Small Body Frame94, 325, 337	Small size and frailty may signal higher mg/kg dose (and also lower clinical or cellular reserve).
Surgery94, 338-340	- Intraoperative or perioperative rhabdomyolysis. - Surgery may increase energy demands, which may be a problem in settings of marginal supply if mitochondrial effects that are otherwise subclinical are present. Surgery may also be associated with use of interacting drugs. Surgery may worsen oxidative stress, aggravating risk in those subjects for whom statins increase lipid peroxidation markers.51-53, 342 - Coenzyme Q10 has reportedly improved surgical outcomes and reduced reperfusion injury in some human and animal studies343-346 (statins reduce coenzyme Q10 concentrations). - However, while animal studies have suggested worsening of myocardial stunning with statin pretreatment,347 in a range of human studies, statins have apparently improved surgical outcomes for vascular and heart surgery,348-350 possibly via statin antioxidant effects that predominate in many people.51
Infection351-354	- One possible mechanism is that infection may increase energy demands, which may be a problem in settings of marginal supply if statin mitochondrial effects occur that might otherwise be subclinical. Infection may also be associated with use of drugs that interact with statins, such as macrolide antibiotics. - Some evidence suggests statin users may have lower incidence of sepsis. However, confounding (by indication [i.e. if high LDL-C rather than statins drives the protection] or by socioeconomic status,355-357 for instance) cannot be excluded as a basis of such findings.
Exertion94, 351, 358	- Exertion may increase energy demands, which may be a problem in settings of marginal supply if mitochondrial effects that are otherwise subclinical are present. - Treadmill exercise increased incidence and severity of statin damage in Type 2 fiber-predominant muscles.60 - Statins alter gene expression selectively with exercise.62
‘Elderly’ or Older Age: >65, >70, >75, >80 Years in Different Sources34, 94, 163, 180, 325, 340, 359	- A nested case control study of a cohort of 252,460 new users of lipid-lowering medications found the odds of rhabdomyolysis for those over age 65 relative to those under were 4.36 (95% CI 1.5-14.1).360 - In subjects assigned to simvastatin 80mg (SEARCH trial), age ≥65 at baseline was linked to increased “definite or incipient myopathy” with a relative risk of 2.2 (95% CI 1.4 -3.4) overall (n=98); and 2.3 (95% CI 1.3-4.1) in the first year (n=56).186 a (The relative risk was 2.0 in later years, 95% CI 1.1-3.9, n=42.) - Older age signals both higher effective dose (through impaired clearance, increased polypharmacy with more potential drug interactions,361 and sometimes smaller body frame), and pre-existing mitochondrial vulnerability (since DNA mutations rise with age362, 363).
Asian Ethnicity (Japanese or Chinese)36, 180	Asian ethnicity has been associated with elevated blood levels (higher functional dose, reduced clearance) for rosuvastatin.364
Female Gender337, 340, 359	- A nested case control study of a cohort of 252,460 new users of lipid-lowering medication found a trend to increased odds of rhabdomyolysis in females (OR 2.53; 95% CI 0.91-7.3).360 - The risk-benefit balance of statins, as indexed by the available objective metric (total mortality), appears less favorable in women than in men, for those major clinical trials for which data are available.8, 9, 365, 366 - In subjects assigned to simvastatin 80mg (SEARCH trial), female gender at baseline was linked to increased “definite or incipient myopathy” with a relative risk of 1.8 (95% CI 1.1-2.8) overall (n=98); and 2.0 (95% CI 1.0-3.9) after the first year (n=42).186 a (The relative risk was 1.6 in the first year, 95% CI 0.9-3.0, n=56.) Possible considerations include: - Smaller body size for the same dose may imply a higher effective dose for the same milligram dose. Whether for this and/or other reasons, greater statin-induced reductions in lipids have been reported in women.367 - Women have increased AEs to many medications and vaccinations.368 - If statins modestly lower estrogens (a product of cholesterol) as they have been found to lower testosterone,15, 369 they may diminish levels of an essential antioxidant mediator for women that affords key mitochondrial protection.370
Renal Insufficiency36, 94, 180, 340, 359	- In subjects assigned to simvastatin 80mg (SEARCH trial), low glomerular filtration rate (<60 mL/min/1.73m2) was linked to increased “definite or incipient myopathy” with a relative risk of 2.5 (95% CI 1.6-3.9) overall (n=98); and 2.6 (95% CI 1.3-5.1) after the first year (n=42).186 a (The relative risk was 2.4 in the first year, 95% CI 1.3-4.3, n=56.) - In subjects assigned to simvastatin 80mg (SEARCH trial), elevated Creatinine (≥85μmol/L; i.e. 1.0mg/dL) was linked to increased “definite or incipient myopathy” with a relative risk of 2.0 (95% CI 1.3-3.1) overall (n=98); and 2.5 (95% CI 1.4 -4.6) in the first year (n=56).186 a (The relative risk was 1.5 after the first year, 95% CI 0.8-2.8, n=42.) - A number of case reports describe complications of statins arising with renal insufficiency.371 - A nested case control study of a cohort of 252,460 new users of lipid-lowering medication found increased odds of rhabdomyolysis, testing the joint effect of high statin dose and renal disease (p=0.022).360
Hepatic Dysfunction94, 163, 340	- May increase drug levels by impaired hepatic clearance; for instance, fatty liver is reportedly associated with reduced CYP3A activity.372 - May in some instances signal mitochondrial dysfunction, at least in the liver (e.g. with fatty liver i.e. hepatic steatosis, whether or not of alcohol origin373-375).
Alcohol Abuse36, 94	Potential mechanisms (same as for drug interactions) include the following factors: - Alcohol may increase drug levels if hepatic function is impaired. - Alcohol is a mitochondrial toxin.376
Hypertension167	- Hypertension was associated with a 5.1-fold increase in hospitalizations for myopathy including rhabdomyolysis in patients on lipid therapy (95% CI 2.4- 10.9), a 7.0-fold increase in hospitalizations for renal AEs (95% CI 3.7-13.4), and a 2.6-fold increase in hospitalizations for hepatic events (95% CI 1.8–3.7) based on administrative claims data, matching controls to cases on age, sex, geographic region, length of follow-up, and time of index drug fill.167 - Essential hypertension is strongly tied to mitochondrial dysfunction, with an estimated 55% (95% CI 45%-65%) of hypertension cases associated with mitochondrial DNA mutations.377
Diabetes Mellitus167, 340, 341	- Diabetes mellitus was associated with a 2.8-fold increase in hospitalizations for renal AEs in patients on lipid therapy (95% CI 2.4-3.3), and a 1.8-fold increase in hospitalizations for hepatic events (95% CI 1.5-2.3) based on administrative claims data, matching controls to cases on age, sex, geographic region, length of follow- up, and time of index drug fill.167 - In subjects assigned to simvastatin 80mg (SEARCH trial), diabetes mellitus at baseline was linked to increased “definite or incipient myopathy” with a relative risk of 1.7 (95% CI 1.0-2.9) overall (n=98); and 2.3 (95% CI 1.1-4.9) after the first year (n=42).186 a (The relative risk was 1.2 in the first year, 95% CI 0.6-2.7; n=56.) - Type 2 diabetes mellitus is strongly linked to impaired mitochondrial function, with an estimated 22% (95% CI 6%-38%) of type 2 diabetes mellitus associated with mitochondrial DNA defects.377
Obesity378	In a study of statin AEs in the transplant setting, “the incidence of confirmed statin-related complications was higher among patients with BMI>29kg/m2 than among those with lower BMI (p=0.055).”378
High Triglycerides94, 333	- Triglyceride concentrations were commonly high in patients with myopathy (n=972) or rhabdomyolysis (n=81), with a mean triglyceride value in the combined sample of 341mg/dL.94, 333 - High triglycerides arise in settings of impaired fatty acid beta oxidation and may signal existing metabolic/ mitochondrial derangement. - In mice, high triglycerides increased resting respiration and predispose animals to mitochondrial permeability transition.379
History of CK Elevation34	- OR 2.04; 95% CI 1.55-2.68, p<0.0001 for development of statin muscle AEs in the setting of history of high CK.34 - Elevated CK may signal existing metabolic derangement.
Thyroid Disorders, Hypothyroidism, Including Unnoticed or Asymptomatic Hypothyroidism36, 94, 163, 180, 222, 353, 380-382	- Thyroid hormone is critically involved in regulation of oxidative phosphorylation (mitochondrial function), and thyroid pathology, even if treated, may signal metabolic vulnerability because of the importance of triiodothyronine (thyroid replacement focuses on thyroxine).383-389 - Thyroid problems alone are a risk factor for rhabdomyolysis.222 - Statins have rarely aggravated hypothyroidism – produced loss of stable control on thyroid medication, with control restored on statin discontinuation.390, 391 One case involved amiodarone-induced hypothyroidism.391 Since both statins and amiodarone produce AEs through mitochondrial toxicity,282 we suggest thyroid dyscontrol on statins may occur in cases of hypothyroidism linked to mitochondrial or energetic impairment.392
Personal History or Family History of Hereditary Muscle Problems36, 393	Possible mechanisms include: - May signal pre-existing mitochondrial or metabolic vulnerability. - May provide for a lower threshold at which damage to muscle is clinically evident.
Prior Muscle Problems on Statins or Other Cholesterol Drugs34, 36, 180	- OR was reported to be 10.1, 95% CI 8.2-12.5 for statin muscle AEs (p<0.0001).34, 35 - Not merely an index of vulnerability, but of expressed problems.
Hyperkalemia163, 394	- Risk may arise in part with hyperkalemia serving as a marker of mitochondrial derangements that produce lactic acidosis, which can cause elevated potassium.395 - Statins might therefore be expected to sometimes cause potassium elevation, and indeed have been reported to do so.394, 396
Genetic Mutations Associated with Mitochondrial Dysfunction155, 397	- Just as adequate coenzyme Q10 ‘bypasses’ and renders clinically silent a range of respiratory chain defects, so statin-induced reductions in coenzyme Q10 may ‘unmask’ previously clinically silent mitochondrial pathology, such as that demonstrated in a plurality of cases of statin-induced mitochondrial myopathy.155 - The term ‘unmask’ may be misunderstood to imply that a clinical condition was always present. There is no basis to presume clinical expression would necessarily have occurred in the absence of pharmacological reduction of coenzyme Q10: in the pre-drug state, the subjects may have had adequate physiological compensatory mechanisms in place. - Mutations in the COQ2 gene are associated with primary coenzyme Q10 deficiency and severe inherited myopathy. Mild common variants were associated with vulnerability to myopathy on statin monotherapy (113 myopathy subjects, 158 matched statin tolerators).397
Other Genetic Variants	- The C-allele of the rs4149056 single-nucleotide polymorphism (SNP), located within SLCO1B1 on chromosome 12,b was associated with increased risk, with OR 4.5 (95% CI 2.6-7.7) per copy of the C-allele, and 16.9 (95% CI 4.7-61.1) for CC homozygotes relative to TT homozygotes.a More than 60% of the ‘myopathy’ cases in that trial (SEARCH trial) could reportedly be attributed to the C variant.186 The C-allele has a prevalence of approximately 15% in those of European descent. - Genetic polymorphism of CYP2D6 have been linked to susceptibility to atorvastatin AEs;398 and to simvastatin AEs in some studies331, 398, 399 but not others.400 - In a case-control discovery study the CYP2D6*4 isoform was linked to atorvastatin muscle AEs (OR 2.5, p=0.001, frequency ~50% in cases vs 28% in controls) and simvastatin muscle AEs (OR 1.7, 49% of cases, p=0.067).398 Sources disagree about the role for CYP2D6 in simvastatin metabolism331, 398, 399. The excess in AEs with one genetic group was not accompanied by greater absolute lipid reduction.399 - CYP2D6 variants are involved in toxin (e.g. pesticide) detoxification and both inactivation and bioactivation401, 402. We conjecture that some CYP2D6 variants may heighten vulnerability to oxidative stressors. While adequate coenzyme Q10 levels may functionally ‘bypass’ resulting mitochondrial defects,23, 25, 403 dose- dependent reductions in coenzyme Q10 by more potent statins,20, 21 like atorvastatin and simvastatin, may ‘unmask’ mitochondrial dysfunction and lead to muscle symptoms. - One study reported an association of ABCB1 gene polymorphisms and AEs on simvastatin.404 - Genetic variants in serotonin receptor genes have been presumptively linked to statin myalgia, an effect hypothesized to be mediated by influences on pain pathways.405

ALT = alanine aminotransferase; BMI = body mass index; CK = creatine kinase; CYP = cytochrome P450; LDL-C = low-density lipoprotein cholesterol; OR = odds ratio; SEARCH = Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; ULN = upper limit of normal.

^aThe SEARCH trial randomly allocated 12,064 subjects with prior myocardial infarction to 20 or 80mg of simvastatin. Relative risks for developing “definite/incipient myopathy” based on baseline characteristics were calclulated from the 6031 subjects assigned to 80mg of simvastatin. ORs for genetic characteristics in genome-wide association studies were based on 85 cases of “definite or incipient myopathy” that arose on 80mg of simvastatin within that trial, compared to 90 age, sex, glomerular filtration rate, and amiodarone-use ‘matched’ simvastatin controls who did not develop “definite or incipient myopathy. ” “Definitemyopathy” was defined as muscle symptoms with CK elevations exceeding 10 × ULN (meeting definitions of rhabdomyolysis that do not require renal involvement). “Incipient myopathy” was defined as CK exceeding 3 × ULN and more than 5 × baseline, coupled with an ALT elevation exceeding 1.7 × baseline without an isolated ALT elevation at any other visit, irrespective of muscle symptoms. 50% of cases were ‘definite.’ (Note that ALT elevation reflects liver function and is not a characteristic of myopathy. However, joint muscle and liver dysfunction may signal widespread cellular consequences of statins.)

^bComment: SLCO1B1 encodes OATP1B1, an organic anion-transporting polypeptide that regulates hepatic uptake of statins. The C-allele retards hepatic uptake of statins, and in most reports increases statin serum concentrations, while slightly attenuating the LDL-C reduction by simvastatin.¹⁸⁶ Of note, the study found that the G variant of rs 2306283 showed lower risk of myopathy – and was associated with lower statin concentrations.¹⁸⁶