Statins are a class of drugs that inhibit HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, widely used to lower cholesterol and reduce the risk of atherosclerotic cardiovascular disease (ASCVD). According to CDC estimates, over 25% of adults aged 40 and older in the United States use statins, making them one of the most prescribed medications.
Main indications: As an adjunct to diet and exercise to lower TC, LDL-C, and TG and increase HDL-C; primary and secondary prevention of ASCVD events; familial hypercholesterolemia.
Contraindications: Drug hypersensitivity, acute liver failure, decompensated cirrhosis.
This article provides an overview of both the side effects and potential therapeutic effects of statins in the field of neuro-ophthalmology.
QWhat kind of drug are statins, and why are they related to neuro-ophthalmology?
A
Statins are drugs that inhibit HMG-CoA reductase and limit cholesterol biosynthesis. Their relevance to neuro-ophthalmology arises from two aspects. One is side effects such as orbital myositis and myasthenia gravis. The other is the potential therapeutic effects on neuro-ophthalmic diseases such as multiple sclerosis and Parkinson’s disease, due to pleiotropic effects including anti-inflammatory and neuroprotective actions derived from mevalonate pathway inhibition.
2. Main Symptoms and Clinical Findings (Neuro-ophthalmic Side Effects)
First report: In 2006, unilateral ptosis was reported as an unrecognized side effect of statins1).
Number of cases: 256 cases of ptosis, diplopia, and ophthalmoplegia have been reported. Dechallenge was positive in 62 cases, and rechallenge was positive in 14 cases1).
Onset timing: 2 days to 1 month after starting statins. In large series, median 3.5 months (range 1 day to 84 months)1).
Patient background: median age 69 years, slightly more common in males1).
Statin-associated MG and myopathy
Myasthenia gravis (MG): Among 184,284 statin-related cases in the WHO adverse drug reaction database, 3,967 mentioned MG, and 169 were suspected statin-induced MG. Case reports include ocular MG with new-onset seropositive cases or relapse from long-term remission.
Immune-mediated necrotizing myopathy (IMNM) and rhabdomyolysis: Reported as neuromuscular side effects of statins.
MRI findings (orbital myositis): Enlargement and contrast enhancement of the affected extraocular muscles and levator palpebrae superioris muscle1).
Muscle biopsy findings (systemic statin-associated myopathy): Mitochondrial dysfunction, increased intramitochondrial lipid accumulation, cytochrome c oxidase-negative muscle fibers, and ragged red fibers1).
QHow often do statin-related ocular side effects occur?
A
SAMS is reported in 10–25% of patients on statin therapy. Although 256 cases of orbital myositis have been accumulated, the exact prevalence is unknown. Suspected statin-induced MG cases have been reported in 169 cases in the WHO adverse drug reaction database. Although the absolute frequency is low for each, given the large number of statin users, a certain number of patients experience these side effects.
3. Causes and risk factors (mechanisms and risk factors of statin side effects)
Decreased coenzyme Q10 (CoQ10) → reduced ATP production → combined with the high metabolic demand of extraocular muscles, induces myalgia and myopathy1)
Decreased sarcoplasmic reticulum cholesterol, impaired calcium metabolism in skeletal muscle, induction of muscle fiber apoptosis, and immune-mediated processes have also been proposed1)
Pathogenesis of myasthenia gravis:
The immunomodulatory effects of statins are involved. Animal studies have shown upregulation of Th2 cytokine secretion that stimulates anti-AChR responses.
Statin metabolic pathways and drug interaction risk:
MRI: Enlargement and contrast enhancement of affected extraocular muscles and levator palpebrae superioris muscle1)
Dechallenge/rechallenge test: If symptoms disappear after stopping statins (positive dechallenge) and recur upon re-administration (positive rechallenge), it suggests a causal relationship. Among 256 cases by Fraunfelder et al., 62 were dechallenge positive and 14 rechallenge positive1)
Histopathology: No muscle biopsy reports exist for statin-associated orbital myositis, but findings from systemic myopathy biopsies (e.g., mitochondrial dysfunction, ragged red fibers) can be referenced1)
Diagnosis of Myasthenia Gravis:
Follow standard MG diagnostic procedures including anti-AChR antibody test, ice pack test, and Tensilon test (edrophonium test).
Monitoring of insulin resistance:
Statin trial meta-analyses show a 9–12% increase in diabetes risk. Regular monitoring of HbA1c is recommended.
5. Standard treatment (management of side effects)
Discontinuation of statins is the first-line treatment. Complete resolution of symptoms has been reported 3 weeks after statin discontinuation alone1).
Literature on side effect management is limited, and no standardized protocol has been established1).
Management of statin-associated myasthenia gravis:
Consider discontinuing statins.
It is difficult to clarify differences in clinical presentation and prognosis among individual statins and doses1).
Management of SAMS in general:
Consider switching from lipophilic statins (e.g., atorvastatin, simvastatin) to hydrophilic statins (e.g., pravastatin, rosuvastatin).
Pravastatin, rosuvastatin, and pitavastatin, which are not metabolized via CYP3A4, have a lower risk of drug interactions.
Statins have a dihydroxyglutaric acid moiety structurally similar to HMG-CoA and competitively bind to HMG-CoA reductase 2). Inhibition of HMG-CoA reductase → restriction of cholesterol biosynthesis → decreased intracellular cholesterol in hepatocytes → increased LDL receptor expression → enhanced removal of circulating LDL, thereby lowering LDL-C.
Pleiotropic effects resulting from inhibition of isoprenoid intermediate biosynthesis in the mevalonate pathway are associated with neuro-ophthalmic diseases.
Inhibition of Rho protein isoprenylation → upregulation of eNOS expression → increased NO production → vasodilation2)
Decreased iNOS/nNOS activity → suppression of neurotoxic NO production2)
Haplotype 7 (H7; rs17244841, rs17238540, rs3846662) is associated with interindividual variability in statin treatment response and is strongly linked to a splicing product with exon 13 deletion. Patients carrying H7 have reduced statin affinity and a smaller total cholesterol reduction after 24 weeks of pravastatin treatment (22% reduction vs. non-H7 carriers) 2). The prevalence of H7 is 3% in Caucasians and 6% in African Americans 2).
7. Latest Research and Future Perspectives (Research Stage Reports)
Administration of simvastatin 80 mg/day for 6 months has been reported to significantly shorten VEP (visual evoked potential) latency, increase amplitude, and improve contrast sensitivity, color vision, and self-assessed visual function. In secondary progressive MS, a significant reduction in annual whole-brain atrophy rate compared to placebo was shown. However, other trials found no significant differences in brain atrophy rate or Gd-enhancing lesion count, and no consensus has been reached.
Pierzchlinska et al. (2021) reported a meta-analysis of 17 observational studies showing a reduced incidence of PD with statin use (OR=0.92; 95% CI: 0.86–0.99) 2). Atorvastatin showed the most beneficial effect, and lipophilic statins were associated with better MoCA scores. Progression of motor symptoms was slower in statin users, with the greatest effect on rigidity.
However, in a meta-analysis by Bykov et al., the protective effect disappeared after adjusting for cholesterol levels, suggesting that cholesterol lowering itself may be a confounding factor 2).
The HMGCR rs3846662 AA genotype has been reported to be associated with a protective effect against Alzheimer’s disease (AD) in women (OR=0.521; p=0.0028) and a 3.6-year delay in onset2).
Statins have been shown to reduce ESR and downregulate IL-16/IL-17, but do not affect vision-related outcomes. No significant difference in acute visual ischemic complications was observed between statin users and non-users.
A meta-analysis of 11 RCTs and 12 cohort studies showed that statins significantly reduce the risk of recurrence for all stroke subtypes. The role of statins in cardiovascular risk management after retinal artery occlusion is also being investigated.
Pre-onset and continuous statin use is associated with reduced incidence of radiological vasospasm, shorter hospital stay, and favorable functional outcomes. Meta-analyses have shown that statins reduce cerebral vasospasm, delayed cerebral ischemia, and delayed ischemic neurological deficits after aSAH.
Statin-induced reduction of inflammatory cytokines may contribute to minimizing inflammation-mediated tissue damage in wet age-related macular degeneration, dry eye, uveitis, and diabetic retinopathy. Meta-analyses have also shown an association with reduced risk of proliferative DR, non-proliferative DR, and diabetic macular edema. On the other hand, statins have been suggested to potentially increase the risk of glaucoma, requiring further research.
QCan statins be used to prevent Parkinson's disease or Alzheimer's disease?
A
An association with reduced risk of PD (OR=0.92) has been shown in meta-analyses of observational studies2), but cholesterol levels themselves may be a confounding factor, and causality has not been established. For AD, a protective effect has been suggested for specific HMGCR gene polymorphisms2), but statin administration for the purpose of preventing these diseases is not standard treatment at present.
Ang T, Tong JY, Patel S, et al. Drug-induced orbital inflammation: A systematic review. Surv Ophthalmol. 2024;69(4):622-631.
Pierzchlinska A, Drozdzik M, Bialecka M. A Possible Role for HMG-CoA Reductase Inhibitors and Its Association with HMGCR Genetic Variation in Parkinson’s Disease. Int J Mol Sci. 2021;22(22):12198.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
