Table VIII.

Statin Adverse Effects (AEs) Supported or Suggested by Case Series, Case Studies and Observational Designs^a,^b

Statin AE	Relevant reports	Triangulating evidence and effect modification
Peripheral Neuropathy (PN)^c	- High-quality case control study using Danish databases.⁴⁴² - Also, many case reports/case series.⁵⁶¹-⁵⁷⁵ - Includes reports of multiple mononeuropathy.⁵³⁸, ⁵⁷⁶ - Reversibility is not complete in all cases, inferable from some case reports; from rate in former relative to current statin users⁴⁴² and shown in Australian Adverse Drug Reaction Advisory Committee report.⁵⁶¹	- Hypo–lipoproteinemia is linked to PN.⁵⁷⁷-⁵⁸¹ - Cholesterol transports antioxidants essential to protection against PN.⁵³⁹-⁵⁴² - We also observe that statins impair mitochondrial function, and impaired mitochondrial function has been linked to PN.⁵⁴³, ⁵⁴⁴
Sexual Dysfunction^c	Numerous case reports, case series, including several from European and Australian AE databases.⁴⁴⁴, ⁵⁴⁵-⁵⁵⁵, ⁵⁸², ⁵⁸³	- Cholesterol is the biochemical precursor to testosterone. - Experimental and RCT evidence shows that statins reduce testosterone in men, though the average effect is modest.¹⁵, ³⁶⁹, ⁵⁵⁸ (Studies in small samples and /or with lower statin doses do not show a significant change in testosterone on average.) Clinical data showing testosterone reductions complement in vitro studies demonstrating statin effects on human testicular testosterone synthesis;⁵⁸⁴ and animal studies demonstrating statin effects on morphology and function of Leydig cells.⁵⁵⁹ - Mitochondrial dysfunction associated with gonadal dysfunction⁵⁶⁰ – of potential relevance given statin effects on mitochondrial function. - Oxidative stress associated with gonadal dysfunction⁵⁸⁵ – of potential relevance given adverse statin effects on oxidation in some.⁵¹, ⁵² - Testicular morphologic changes occurred in an animal study of high-dose statins, in which it was stated that testicular tissue (in dogs) was “the only organ for which a comparably low margin of safety was observed.”⁵⁸⁶ - Note that statins have also been reported to improve erectile function⁵⁸⁷ and the sexual benefits of sildenafil (Viagra™) in some subjects through endothelial function benefits,⁵⁸⁸-⁵⁹⁰ which may rely on the antioxidant effects of statins⁵⁹¹-⁵⁹³ that predominate over pro-oxidant effects in many.⁵¹
Male Endocrine, Other^c	- Gynecomastia: several reports of gynecomastia associated with statins.⁵⁹⁴-⁵⁹⁶ Statin use in organ transplant recipients was associated with increased risk of gynecomastia (statin use in 83.3% of those with gynecomastia, 39.6% of those without, p=0.041).⁵⁹⁷ - Oligospermia.⁵⁵⁶ - Questions have been raised about male infertility with statins.⁵⁵⁷ - Testicular pain: Case report.⁵⁹⁸	See above, “Sexual dysfunction.”
Thyroid Dysfunction	See discussion in Table IV under ‘Thyroid disorders.’
Renal^c	- Renal tubule toxicity.⁵⁹⁹ - Proteinuria: statins, particularly, high-dose statins, have led to proteinuria and hematuria.¹⁸⁰, ⁶⁰⁰ - Statins have led to renal failure and death from renal failure in the context of rhabdomyolysis.⁸², ⁹⁸-¹⁰⁰, ¹⁰²-¹⁰⁴, ¹¹⁰, ²⁰², ²¹⁹, ²⁴⁷, ³⁰⁸, ⁴¹⁹, ⁴³¹, ⁶⁰¹-⁶⁰⁵	- Statins have been reported, in an observational study, to be associated with less contrast nephropathy.⁶⁰⁶ This could reflect that statins signal higher lipids (and fat-soluble antioxidant transport) – i.e. indication bias, or could result from antioxidant effects of statins (antioxidants have been reported to reduce contrast nephropathy). - Statins have reduced proteinuria in some groups on average but may not do so in other groups (meta-analysis of RCTs – proteinuria was not reduced, e.g. in diabetes mellitus or hypertension).⁶⁰⁷, ⁶⁰⁸ Moreover, statins have been reported to increase proteinuria in some.¹⁸⁰ In one study, statin use (compared with placebo) was associated with lower creatinine,⁶⁰⁹ which was presumed to reflect better kidney function.⁶⁰⁹ However, because muscle mass correlates with creatinine, and statins can reduce muscle mass, it is unclear the extent to which the creatinine reduction was driven by benefit to the kidney versus harm to the muscle (subclinical muscle wasting).⁶⁰
Irritability/Aggression / Behavior Change^c	- Case series of severe irritability and/or aggression reproducibly arising on statins,⁴⁴³ also in pharmacovigilance database.⁴⁶⁷ - Observational study showing women on statins are more aggressive.⁶¹⁰	- Low cholesterol linked to conduct disorder, violent antisocial personality disorder, and violent crime prospectively; to violent death in numerous observational studies; and in animal studies to aggression.⁶¹¹-⁶²³ - Several meta-analyses of prestatin cholesterol-lowering RCTs (including those with the most appropriate inclusion/exclusion criteria⁶²⁴, ⁶²⁵) showed significant increases in violent death.⁶¹¹ Statin meta-analysis has not.⁶²⁶ - Elucidated potential mechanisms include low central serotonin⁴⁸⁶, ⁶¹¹ and altered omega-3 to omega-6 ratios.¹⁷ Here, we add the suggestion of impaired cell energetics and oxidative stress, which are associated with a number of other aggression- and irritability related exposures.¹²⁷, ⁶²⁷-⁶⁴¹ This offers the possibility that benefits may predominate in some persons through benefits to endothelial function/ flow and/or anti-inflammation, consistent with bidirectional effects suggested in an RCT.⁶⁴²
Pulmonary, Respiratory, Shortness of Breath (see also ‘Cardiac Function and Heart Failure’)^c	- Shortness of breath as a symptom in statin AEs (including reports of dyspnea as the presenting symptom of otherwise asymptomatic rhabdomyolysis,⁹⁵ associated with lactic acidosis⁴¹²). - Respiratory failure has accompanied statin rhabdomyolysis.⁹⁸ The following have also been reported in association with statins: - Chylothorax.⁶⁴³ - Dermatomyositis with lung involvement/pulmonary fibrosis.⁶⁵, ⁷⁴ - Eosinophilic pneumonia.⁶⁴⁴ - Interstitial lung disease.²⁸², ⁶⁴⁵-⁶⁴⁷ - Pulmonary fibrosis.⁷⁴, ⁶⁴⁸ - Pleural effusion (see also ‘Cardiac function and heart failure’).⁶⁴⁵, ⁶⁴⁹, ⁶⁵⁰ - Hypersensitivity pneumonitis.⁶⁵¹, ⁶⁵² - Autoimmune conditions affecting pulmonary function (see ‘Immune, autoimmune’). - Cough (see ‘Oral cavity’).	- Cardiopulmonary function and respiratory exchange ratio are affected by statins.¹⁵⁶, ¹⁵⁷ - Mitochondrial (cellular) respiration is affected by statins (see section 5). - Statins accelerate aging effect on (rat) diaphragm mitochondrial cellular respiration⁴²⁶ – affecting the major muscle of breathing. - Myopathy arises with statins (see section 1): effective respiration relies on skeletal muscles such as the diaphragm. -Statin pulmonary restrictive disease occurs, and resembles amiodarone pulmonary disease⁶⁴⁷ compatible with common mitochondrial origin.²⁸² - Statins lower cholesterol, which is the precursor to vitamin D, which is associated with protection against autoimmune diseases, including lupus. - See also ‘Cardiac function and heart failure.’
Cardiac Function and Heart Failure^c	- Heart failure, pulmonary edema, and cardiac muscle rhabdomyolysis have been reported in cases of statin rhabdomyolysis.⁹¹, ¹⁰⁹, ¹¹¹ - In an observational study, statins adversely affected cardiac diastolic function in a fashion that was partially reversed by coenzyme Q10.⁶⁵³	- The heart muscle, like other muscles, may be affected in myopathy. - Statins lower coenzyme Q10, while addition of coenzyme Q10 in RCTs has reduced hospitalizations for heart failure and pulmonary edema.⁶⁵⁴ - Statins reduce coenzyme Q10, and coenzyme Q10 reportedly improves diastolic function,⁶⁵⁵ which is strongly ATP dependent. Diastolic function has reportedly been reduced with statins, an effect reversed by coenzyme Q10⁶⁵³ (study prospective but not placebo-controlled). - Statins lead to average improvement in heart failure or left ventricular systolic function in some studies, including randomized trials.⁶⁵⁶, ⁶⁵⁷
Heart Rhythm Disturbance:^c Heart Block, Atrial Fibrillation	- Atrioventricular block with rhabdomyolysis reported.²³⁹ - Bradycardia including heart block in a range of US FDA reports (secured under the Freedom of Information Act dated 8-1-06). - Atrial fibrillation with statin use reported.⁶⁵⁸	- Statins lower coenzyme Q10, and coenzyme Q10 has reportedly reduced arrhythmia in a range of settings.⁶⁵⁹, ⁶⁶⁰ - Patients with atrial fibrillation show greater oxidative damage to atrial mitochondrial DNA than those without,⁶⁶¹ consistent with a role for statin oxidative/antioxidant effects. - Statins have reportedly produced heart block.²³⁹ They have also produced lactic acidosis²², ⁴¹¹, ⁴¹³ and hyperkalemia,²⁰⁹, ³⁹⁶ each of which have been linked to heart block.⁶⁶², ⁶⁶³ - Heart block may arise because of the energy dependence of cell signaling (with mitochondrial impairments impeding these) or due to alterations in tissue excitability (due to change in pH etc.). Heart block has been induced in other settings in which mitochondrial dysfunction induced high lactate.³⁹⁵ - Low cholesterol, associated with lower transport of fat- soluble antioxidants, has been linked observationally to higher atrial fibrillation rates.⁶⁶⁴ - Statins have pro-oxidant and antioxidant, proinflammatory and anti-inflammatory effects, with each dominating in different persons (more commonly, antioxidant and anti-inflammatory at modest doses in clinical-trial-equivalent middle-aged men). Atrial fibrillation has been linked to oxidant and inflammatory mechanisms, and its protection to the reverse.⁶⁶⁵-⁶⁶⁹ - Statins have reduced arrhythmia/atrial fibrillation in a clinical trial setting;⁶⁷⁰ individual effects may depart from average effects.
Hyperkalemia	See discussion under ‘Heart rhythm disturbance’ (immediately above).
Weight Gain^c	Observational study with high rate of weight gain in high-dose statin group.²⁷	- Statins lead to dose-dependent reductions in coenzyme Q10.²⁰, ²¹ - Coenzyme Q10 supplementation has reduced appetite in patients with hyperphagia,⁶⁷¹ and also improved insulin sensitivity.⁶⁷²
Neurodegenerative Disease: Parkinson Disease, also ALS or ALS-like Syndrome^c	Case reports⁶⁷³ and case series.¹⁴⁴, ¹⁴⁵	- Statins reduce coenzyme Q10.²⁰, ²¹ - Coenzyme Q10 protects against neurodegeneration in animal models; and retards progression of early Parkinson disease in humans.⁶⁷⁴-⁶⁷⁷ - Low LDL-C has been linked to increased risk of Parkinson disease.⁶⁷⁸ - Higher cholesterol has been linked to increased survival with ALS.⁶⁷⁹ - LDL-C transports (and statins reduce) key fat-soluble antioxidants;⁶⁸⁰ reduced antioxidant transport unfavorably affects redox state (and mitochondrial function), which has a role in neurodegeneration protection.⁶⁸¹-⁶⁸⁴ - Statins may be selectively toxic to muscle satellite cells, the stem cells for muscle that have (finite) regenerative potential.⁶⁸⁵ This may impair recovery of muscle in some statin users who experience normal or increased muscle injury on statins. (However, this is based on in vitro study.) - Observational studies link lower but not higher potency statins with dramatically lower rates of neurodegeneration⁶⁸⁶-⁶⁸⁸ and have implied there is causality, although this is incompatible with findings from RCTs, and is more consistent with confounding, e.g. by education and indication. Confounding by education was a likely factor in the similar apparent association of HRT to lower Alzheimer disease rates, which similarly suggested vastly lower rates of dementia in users;⁶⁸⁹ however, in fact, significantly increased rates of dementia arose with HRT when compared to placebo in RCTs, i.e. when treatment and placebo groups were chosen to be otherwise similar.⁶⁹⁰, ⁶⁹¹Confounding by indication³⁵⁶ is also a significant possibility given the protective association of higher LDL- C to lower Parkinson disease rates,⁶⁷⁸ and the use of LDL-C as a criterion for statin use.⁶⁹² (That is, statin use is a proxy for higher LDL-C prior to and often despite statin treatment – except with the most potent statins.) - Authors of recent studies continued not to control for lipids,⁶⁸⁸, ⁶⁹³ despite prior criticisms³⁵⁵, ³⁵⁶ noting potential for indication bias in similar studies.⁶⁸⁷ A later study attributed the lesser benefit of the more potent atorvastatin to selective benefits by simvastatin – the less potent statin in that study (vs alternative explanations such as atorvastatin more effectively overcoming benefit of high LDL-C). However, in the same authors' prior study, simvastatin was the more potent statin, and the one with which statin “benefit” was lost.⁶⁸⁷ The author holds a patent on simvastatin for Alzheimer disease. - Findings are potentially consistent with confounding by indication for Parkinson disease (given the association of higher LDL-C with Parkinson disease protection, and the association of statins as a proxy for higher prior, perhaps lifelong, and often current LDL-C); and confounding by education (higher education is linked to lower rates of incident dementia, and also higher use of preventive healthcare).³⁵⁵, ³⁵⁶ - It merits additional note that pro-oxidant conditions may spawn physiologic adaptations that ramp up antioxidant access, which may include elevation of lipid levels to boost antioxidant delivery. Association of higher lipid levels to conditions⁶⁷⁹ may reflect protective adaptations rather than causal predisposition. See in-depth discussion of proposed mechanism for statin- associated neurodegeneration.¹⁴⁵
Immune, Autoimmune^c	- Case series and reports of lupus-like syndrome, autoimmune hepatitis, dermatomyositis and other.⁶⁷, ⁷¹, ⁷², ⁷⁴, ⁴⁷⁵, ⁴⁹⁸, ⁵⁰², ⁵⁰³, ⁵⁰⁶, ⁶⁹⁴-⁷¹⁰ - See above (Table I) for case reports of Guillain Barre-like syndrome and myasthenia gravis on statins.	- Cholesterol is the precursor to vitamin D. High levels of vitamin D are associated with lower autoimmune disease risk, which we propose as a possible mechanism.⁷¹¹-⁷²³ - Enthusiasm for trials of statins has been expressed in autoimmune diseases, particularly those with inflammatory components.⁷²⁴
Pancreatitis^c	Case reports of statin-induced pancreatitis alone or associated with statin rhabdomyolysis or muscle pain;¹⁰⁵, ⁷²⁵-⁷³⁹ including recurrent cases.⁷²⁶, ⁷³⁷, ⁷⁴⁰, ⁷⁴¹	See also discussion in this table, in rows entitled ‘Gastrointestinal’ and ‘Immune, autoimmune.’ - A population-based case-control study using Danish databases reported the adjusted OR for acute pancreatitis “among ever, current, new and former users of statins” (respectively) were: 1.44 (95% CI 1.12-1.80), 1.26 (95% CI 0.96-1.64), 1.01 (95% CI 0.43-2.37), and 2.02 (95% CI 1.37-2.97).⁷⁴² The authors suggest this may imply protection by statins. However, this conclusion does not follow from this study design. Former users may disproportionately include those who experienced statin AEs (statin ‘noncompliance’ is linked to statin AEs⁴⁸⁴) and attendant mitochondrial injury (arising with and contributing to statin use). Occurrence of pancreatitis accompanying statin rhabdomyolysis suggest causal mediation by shared mitochondrial effects of statins, which may persist after treatment is discontinued; and mitochondrial pathology has repeatedly been linked to acute, chronic, and recurrent pancreatitits.⁷⁴³-⁷⁵⁰ However, it is also possible that statins may, analogously to the case for muscle and kidney function, both protect from pancreatitis and conduce to it in different subjects (based on predominance, e.g. of statin antioxidant vs pro-oxidant effects).
Liver Pathology^c	Case reports of statin hepatitis or hepatic dysfunction alone or associated with rhabdomyolysis: autoimmune hepatitis, cholestasis, cholestatic hepatitis, steatosis, viral- like hepatitis, microvesicular hepatitis, hepatic fibrosis, progression to cirrhosis.⁹⁶, ¹⁰⁷, ¹⁰⁸, ¹⁷², ⁴⁷⁴, ⁴⁷⁵, ⁴⁷⁷-⁴⁷⁹, ⁴⁸¹, ⁴⁹²-⁵⁰⁴, ⁵⁰⁶, ⁵⁰⁸, ⁵¹², ⁵¹³, ⁷⁵¹, ⁷⁵²	Includes documentation of hepatic failure necessitating liver transplant.⁷⁵³
MELAS, Lactic Acidosis, other Mitochondrial Syndromes^c	- Statin induced lactic acidosis as an AE.⁴¹³ - ‘Unmasking’ of mitochondrial myopathy as an AE, reduced fatty oxidation. - Statin induced MELAS alone or associated with rhabdomyolysis.¹¹², ⁴¹¹	See section 5 for discussion of mitochondrial effects of statins.
Dermatologic^c	- See also “Immune, autoimmune” (dermatomyositis, lupus and lupus-like reactions). - Actinic dermatitis (chronic).⁷⁵⁴, ⁷⁵⁵ - Acute generalized exanthematous pustulosis.⁷⁵⁶ - Alopecia.⁷⁵⁷-⁷⁵⁹ - Angioneurotic edema.⁷⁶⁰ - IgA bullous dermatosis.⁷⁰² - Cheilitis.⁷⁶¹ - Contact dermatitis.⁷⁶², ⁷⁶³ - Dermatographism.⁷⁶⁴ - Drug eruption.⁷⁶⁵ - Eczema.⁷⁶⁶, ⁷⁶⁷ - Eosinophilic fasciitis.⁷⁶⁸ - Ichthyosis.⁷⁶⁹, ⁷⁷⁰ - Lichen planus pemphagoides.⁷⁷¹ - Lichenoid drug eruption.⁷⁷²-⁷⁷⁵ - Photosensitivity/ Phototoxicity.⁷⁷⁶, ⁷⁷⁷ - Radiation recall.⁷⁷⁸ - Skin lesions.⁷⁷⁹ - Toxic epidermal necrolysis.⁷⁸⁰ - Urticaria (chronic).⁷⁸¹	- Range of potential mechanisms: hypersensitivity, autoimmune, nutritional. - Cholesterol is important in skin barrier function.⁷⁸²-⁷⁸⁵ - Icthyosis and disorders of cornification have been reported with several lipid-lowering agents.⁷⁶⁹ - Statins were reported to possibly improve skin response to sodium lauryl sulfate in one experiment.⁷⁸⁶ - Statins have been theorized as potential treatments for a range of skin disorders.⁷⁸⁷ - Regression of vitiligo with high-dose simvastatin was reported in one case.⁷⁸⁸
Oral Cavity	- Dry mouth.⁵³⁷ - Bitterness.⁵³⁷ - Oral paresthesias or itching.⁵³⁷ - Cough.⁵³⁷	Oral symptoms were appraised in a study in which 26 patients (50-70 years of age) with hyperlipidemia on statins in a general practice were referred over a month for oral evaluation.⁵³⁷ Of these, 23 reported dry mouth, 15 oral itch or paresthesia, 14 bitterness, and 12 cough. A trial of 2 weeks off statins led to marked abatement or resolution in each of these symptoms in 74%, 87%, 93%, and 92%, respectively.⁵³⁷
Vision^c	- Cataracts.⁷⁸⁹-⁷⁹¹ - External ophthalmoplegia.⁷⁹² - A case series of 256 pharmacovigilance reports of ptosis, diplopia, and ophthalmoplegia on statins included 62 positive dechallenge and 14 positive rechallenge reports.⁷⁹³ Reports include 23 instances of total ophthalmoplegia; 8 of ptosis alone and 18 of ptosis in concert with diplopia.	- Lens opacity seen in animal studies (high-dose).⁵⁸⁶ These led to concerns about cataracts with statins, but cataracts have not been increased on average in small studies of humans.⁷⁹⁴-⁷⁹⁶ Cataracts are thought to be induced by oxidative stress;⁷⁹⁴, ⁷⁹⁷, ⁷⁹⁸ so statins' bi-directional effects on oxidation with effect modification may be operative. Cataracts have been described in mitochondrial cytopathy.⁷⁹⁷ - In a British study, the unadjusted OR linking any recorded statin exposure to cataract was 1.41 (95% CI 1.21-1.65). It was 1.04 (95% CI 0.89-1.23, p=0.6) after “adjustment for consultation rate.”⁷⁹⁵ This is difficult to interpret: those seen more due to lipid therapy could have better access to cataract diagnosis leading to incorrect inferences in absence of adjustment; however, such adjustment could also extinguish a true association, through collinearity. - In a US study, incidence of nuclear cataract was lower in statin users relative to nonusers controlling for age (OR 0.55; 95% CI 0.36-0.84).⁷⁹⁹ Five-year incidence of cortical cataract showed the opposite trend (OR 1.28; 95% CI 0.79- 2.08) but was not significant.⁷⁹⁹ Confounding is a major concern in such correlational studies, and associations observed may be different in magnitude and direction from true relationships. - Statins lower coenzymye Q10 and alter omega-3 to omega-6 balance;¹⁷ combination of coenzyme Q10 with omega-3 (and one other substance) reportedly reversed early age-related macular degeneration in an RCT.⁸⁰⁰ - External ophthalmoplegia has been widely described in mitochondrial disease,⁸⁰¹-⁸⁰⁶ and has been linked to deficiencies of fat-soluble vitamins transported by cholesterol.⁸⁰⁷
Olfaction	Hyposmia.⁸⁰⁸	Lipids transport carotenoids,⁸⁰⁹ the precursor to retinol (vitamin A), which is important in smell and has been used in treatment of anosmia.⁸¹⁰-⁸¹²
Hematologic and Bone Marrow, Including Hemorrhagic^c	- See ‘Hemorrhagic Stroke’ Table VII. - Ocular hemorrhage reported as a statin AE.⁸¹³ - Hematuria (microscopic).¹¹⁰, ¹⁸⁰ - Bone marrow toxicity among multiple-organ toxicity arising on statins.⁹⁶, ¹⁷³ - Thrombocytopenia.⁸¹⁴ - Petechia, and thrombotic thrombocytopenic purpura.⁸¹⁵-⁸²² - Hemolytic anemia.⁸²³ - Nonhemolytic anemia.⁹⁶	- Statin use has been observationally linked to lower bleeding, possibly as a proxy for higher cholesterol (and vitamin K?) in studies not adjusted for lipids.⁸²⁴, ⁸²⁵ (In one, only long-term [not current] statin use was linked to this, and those patients started on statins in an earlier era had higher average lipids.⁸²⁵) - After percutaneous coronary intervention, acquired thrombocytopenia developed more frequently, assessed by multivariate analysis, in patients who had previous statin administration (OR 3.28; p=0.0002).⁸¹⁴ - Statins reportedly have antithrombotic effects, inhibit platelet aggregation, decrease platelet activity, have anticoagulant activity, affect blood viscosity, RBC deformability, and ‘improve’ von Willebrand factor activity.⁸²⁶-⁸²⁹ - Erosions and hemorrhage in the gastrointestinal tract and the brain in animal studies (high-dose).⁵⁸⁶ - Hemorrhage in gall bladder and brain, erosions in large intestines in animal study.⁸³⁰ - Mitochondrial mechanisms have been linked to ineffective erythropoiesis.⁸³¹ - Statins inhibit bone-marrow-derived dendritic cell maturation – in vitro.¹⁷⁴
Hypotension^c	Hypotension and angioedema have been described in a case of an atorvastatin hypersensitivity reaction entailing shock and collapse – with recurrence of angioedema on rechallenge.⁷⁶⁰	Statins (simvastatin and pravastatin), compared to placebo, led on average to modest but significant reductions in systolic and diastolic blood pressure in an RCT. The effect extended to persons with blood pressure below the sample median.⁸³²
Gastrointestinal ^c	- Ulcerative colitis.⁸³³, ⁸³⁴ - Severe gastric ulceration (with abdominal pain).⁸³⁵ - Ileus in association with statin rhabdomyolysis.⁴³¹ - Protein-losing enteropathy.⁸³⁶ - Gastrointestinal AEs were the most common AE class in an analysis of AEs from clinical trials;⁸³⁷ and were the second most common in a small study.²⁶ - Patients who are noncompliant on statins are more likely to have AEs – e.g. gastrointestinal and neurologic.⁴⁸⁴	- Statins affect omega-3 to omega-6 ratio;¹⁷ omega-3s provisionally associated with reduced gastrointestinal inflammation.⁸³⁸ - Additionally, cholesterol is the precursor to vitamin D, which has been linked to protection against inflammatory bowel disease.⁷¹², ⁸³⁹, ⁸⁴⁰ - Mitochondrial dysfunction can produce gastrointestinal symptomatology.⁴⁴⁸, ⁸⁴¹-⁸⁴⁴
Exercise Limitation^c and Fatigue/Lack of Energy	- See ‘Exercise limitations or exercise-induced muscle symptoms,’ Table I. - Fatigue without muscle pain on statins was reported and evaluated in three patients.⁸⁴⁵ All were found to have low serum coenzyme Q10. Coenzyme Q10 supplements conferred subjective benefit to energy and reduced fatigue with exertion.⁸⁴⁵	Combined statins and beta blockers affect perceived effort and cardiorespiratory function.⁵⁹
Psychiatric^c	- See also ‘Irritability/aggression/behavior change’ in this table and ‘Sleep’ in Table VII. - Reports of psychosis, depression, paranoia, anxiety, and personality change, to surveillance databases (including Scandinavian and New Zealand pharmacoviligance databases as well as our UCSD Statin Effects Study patient targeted statin AE surveillance database).⁴⁴⁴, ⁴⁴⁵, ⁴⁶⁷, ⁸⁴⁶ - One report described four cases of depression arising with initiation of pravastatin and reversing on discontinuation, including one case with “the likelihood of suicide.”⁴⁴⁶	Mitochondrial dysfunction can produce psychiatric symptoms.⁴⁵⁵, ⁴⁵⁶, ⁸⁴⁷-⁸⁵⁷
Headache^c	- Headache.⁸⁵⁸, ⁸⁵⁹ - Migraine (altitude associated).⁸⁶⁰ - A case of yawning headache was described in a patient with statin-induced myopathy and neuropathy, but was not ascribed to statins.⁸⁶¹	- Mitochondrial dysfunction is linked to migraines.⁸⁶²-⁸⁶⁷ - Migraine occurrence in migraineurs has been shown to be reduced with coenzyme Q10 in an RCT.⁸⁶⁸
Other	- Acid maltase deficiency.¹⁶¹ - Vasospasm after subarachnoid hemorrhage reported to be greater in statin users⁸⁶⁹ (possibly from statin withdrawal or indication bias, however). - Nasal obstruction and nasal polyps resolving with statin discontinuation; three cases reported.⁸⁷⁰ - Temperature dysregulation^c, including hyperthermia.⁸⁷¹-⁸⁷³

ALS = amyotrophic lateral sclerosis; CI = confidence interval; HRT = hormone-replacement therapy; LDL-C = low-density lipoprotein cholesterol; MELAS = Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; OR = odds ratio; RBC = red blood cells; RCT = randomized controlled trial; UCSD = University of California, San Diego.

List is not complete.

Comment: statins are contraindicated during pregnancy due to concerns about teratogenicity.⁸⁷⁴-⁸⁸⁰

Also reported to our UCSD Statin Effects Study group.