Are anti-hyperlipidemic (cholesterol-lowering) medications associated with mental status changes?

From the Guidelines

Anti-cholesterol medications, including statins, are not associated with a significant risk of mental changes or cognitive decline, and their use should not be deterred in individuals with diabetes at high risk for cardiovascular disease. The most recent evidence from a 2024 study published in Diabetes Care 1 suggests that several lines of evidence point against an association between lipid-lowering agents and cognitive dysfunction. This includes large randomized trials of statin versus placebo, where no differences were seen in cognitive tests between statin and placebo groups. Additionally, the study found that the addition of ezetimibe or PCSK9 inhibitors to statin therapy did not affect cognitive function, even at very low LDL cholesterol levels.

Some key points to consider include:

• A systematic review of the U.S. Food and Drug Administration's postmarketing surveillance databases, randomized controlled trials, and cohort, case-control, and cross-sectional studies found no adverse effect of statins on cognition 1.
• The FDA has acknowledged potential cognitive side effects of statins, but maintains that the cardiovascular benefits generally outweigh these risks for most patients.
• Other cholesterol medications like ezetimibe, PCSK9 inhibitors, and bile acid sequestrants have fewer reported cognitive side effects.
• If mental changes are experienced while taking cholesterol medication, patients should consult their healthcare provider promptly to discuss symptoms and explore alternatives or dosage adjustments.

It's worth noting that an earlier study published in 2022 in Diabetes Care 1 also reported that data do not support an adverse effect of statins on cognition, and that fear of cognitive decline should not be a barrier to statin use in individuals with diabetes and a high risk for cardiovascular disease. However, the 2024 study 1 provides more recent and comprehensive evidence on this topic.

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. Psychiatric Disorders: depression

Mental Changes Associated with Anti-Cholesterol Meds:

• The FDA drug label reports rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins, including atorvastatin.
• Additionally, depression is listed as a psychiatric disorder that has been reported in patients taking atorvastatin.
• These mental changes are considered rare and may be reversible upon statin discontinuation 2.

From the Research

Association between Anti-Cholesterol Meds and Mental Changes

• The available evidence suggests that there is no proven association between statin use and cognitive dysfunction or memory loss 3.
• In fact, some studies have indicated a possible beneficial effect of statins in the prevention of dementia 3.
• Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven, and most recent data suggest that the cardiovascular benefits of statins far outweigh non-cardiovascular harms, including potential mental changes 3, 4, 5.
• The studies reviewed did not find any significant association between statin use and mental changes, such as depression, anxiety, or other psychiatric disorders 4, 5.
• However, it is essential to note that individual responses to statins may vary, and some patients may experience adverse effects, including musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic stroke 5, 6, 7.

Mechanisms and Consequences of Statin Use

• Statins inhibit the critical step of cholesterol synthesis, which reduces cardiovascular risk and decreases mortality 4, 5.
• The mevalonate pathway, influenced by statins, also affects endothelial function, the inflammatory response, and coagulation, leading to pleiotropic effects independent of cholesterol lowering 4.
• Depletion of nonsteroid isoprenoids, resulting from statin use, may lead to adverse effects, such as myopathy, hepatotoxicity, peripheral neuropathy, and impaired myocardial contractility 4.

Safety and Efficacy of Statin Therapy

• The overall safety profile of statins appears to be generally comparable to other lipid-lowering treatments, with a low frequency of adverse effects 6, 7.
• Statin therapy has been shown to be effective in reducing LDL-C levels, achieving LDL-C targets, and improving cardiovascular outcomes in various patient populations, including those at high cardiovascular risk 3, 6, 7.