What is the evidence of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, commonly referred to as statins, causing cognitive dysfunction?

From the Guidelines

The current evidence does not support a significant association between statin use and cognitive dysfunction, and therefore, fear of cognitive decline should not be a barrier to statin use in individuals with diabetes and a high risk for cardiovascular disease. The most recent and highest quality study, published in 2023 1, found that published data do not reveal an adverse effect of statins on cognition. This is consistent with previous studies, including a systematic review of the U.S. Food and Drug Administration’s (FDA’s) postmarketing surveillance databases, randomized controlled trials, and cohort, case-control, and cross-sectional studies evaluating cognition in patients receiving statins 1.

Some key points to consider include:

• Large randomized controlled trials and meta-analyses have generally not confirmed concerns about statin use and cognitive problems like memory loss, confusion, and brain fog.
• The FDA added a warning about potential cognitive side effects to statin labels in 2012 based on post-marketing reports, but subsequent research has been reassuring.
• Medications like atorvastatin (Lipitor), rosuvastatin (Crestor), and simvastatin (Zocor) have been studied extensively, with most large trials showing no significant difference in cognitive outcomes between statin users and non-users.
• Some research suggests statins may actually have neuroprotective effects and potentially reduce dementia risk in certain populations.
• If patients experience cognitive symptoms while taking statins, they should discuss these with their healthcare provider rather than discontinuing medication independently.
• Alternative explanations for cognitive symptoms should be considered, including normal aging, other medications, or underlying health conditions.
• The cognitive benefits of statins in preventing stroke and vascular dementia through cardiovascular protection may outweigh potential risks, especially in high-risk patients.

From the FDA Drug Label

There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks) 2 Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks) 3

Cognitive Dysfunction and Statins: The FDA drug labels for atorvastatin and simvastatin report rare cases of cognitive impairment associated with statin use.

• Key Findings:
  • Cognitive impairment is generally nonserious and reversible upon statin discontinuation.
  • Symptom onset and resolution times vary.
• Main Points:
  • Cognitive impairment has been reported with statin use, although rarely.
  • Statin discontinuation typically leads to symptom resolution.

From the Research

Evidence of Statin-Induced Cognitive Dysfunction

• Studies have investigated the potential cognitive effects of statins, with mixed results 4, 5, 6, 7, 8.
• A 2020 study found that 17.8% of patients on moderate- or high-intensity statin therapy experienced cognitive impairment, with a higher frequency of impairment in the high-intensity group 4.
• In contrast, a 2016 review concluded that there is no good evidence that statins cause cognitive impairment to a significant degree, with reported cases being rare and a causal relationship not established 5.
• A 2017 pilot study found that combined statin-exercise therapy may improve cognitive function in patients with coronary artery disease and mild cognitive decline, suggesting a potential beneficial effect of statins on cognition 6.
• Case reports have also described simvastatin-induced cognitive dysfunction, with two patients experiencing reversible cognitive deficits after starting simvastatin 7.
• A 2021 review discussed the potential protective effects of statins on cognition, suggesting that statin use may reduce the risk of cerebrovascular disease and subsequent cognitive decline in certain patient groups 8.

Mechanisms and Correlations

• The relationship between cholesterol levels and cognitive function is complex, with statins showing both protective and potentially harmful effects on cognition 4, 7.
• A weakly negative correlation was found between the duration of statin therapy and cognitive function score in one study 4.
• Exercise may be a beneficial aspect of combined statin-exercise therapy in improving cognitive function, with changes in body mass index (BMI) negatively correlated with changes in cognitive function scores 6.

Patient-Specific Factors

• Patient age, level of education, and comorbid conditions may influence the risk of cognitive impairment associated with statin therapy 4, 6.
• The type and intensity of statin therapy may also impact cognitive function, with high-intensity statin therapy associated with a higher frequency of cognitive impairment in one study 4.