By Susan T. Marcolina, MD, FACP

Internist, Issaquah, WA

Dr. Marcolina reports no financial relationships relevant to this field of study.

SYNOPSIS: Despite earlier concerns by the FDA about adverse effects of statins on cognitive functioning, a meta-analysis of data from more than 28,000 patients enrolled in 18 randomized, placebo-controlled trials of statin therapy failed to show a causal relationship between treatment and adverse neurocognitive effects for patients with and without cognitive impairment.

SOURCE: Ott BR, et al. Do statins impair cognition? A systemic review and meta-analysis of randomized controlled trials. JGIM 2015;30:348-358.


Summary Point

  • A large systematic review and meta-analysis of cognitive outcome data collected from the major randomized, placebo-controlled trials of statin treatment failed to show any association between statin therapy and cognitive decline in either cognitively intact or impaired patients with Alzheimer’s disease.

A consumer advisory issued by the FDA in February 2012 regarding potential adverse effects of statins on cognitive functioning concerned both physicians and patients, given the widespread use of statins for primary and secondary prevention of atherosclerotic cardiovascular disease, and hyperlipidemia treatment.1 The postmarketing adverse reports, reported via the Adverse Event Reporting System, upon which the FDA based its warnings, generally described individuals older than 50 years age who experienced ill-defined memory loss, confusion, and foggy thinking with variable onset of symptoms ranging from 1 day to years after statin exposure. The statins involved were primarily the lipophilic statins simvastatin and atorvastatin (see Table 1). These symptoms resolved after discontinuation of the statins and in some instances recurred with resumption.

Table 1: Statin Properties


Statin


Solubility


CYP P450 Metabolism


Drug Interactions

Blood Brain Barrier Permeability

Lovastatin

Lipophilic

Metabolized by 3A4 isoform

3A4 inhibitors: macrolides, calcium channel blockers, azole antifungals, grapefruit juice

Low

Simvastatin

Lipophilic

Metabolized by 3A4 isoform

3A4 inhibitors: macrolides, calcium channel blockers, azole antifungals, grapefruit juice

High

Atorvastatin

Lipophilic

Metabolized by 3A4 isoform

3A4 inhibitors: macrolides, calcium channel blockers, azole antifungals, grapefruit juice

Low

Fluvastatin

Lipophilic

Metabolized by 2C9 isoform

2C9 inhibitors: omeprazole, ritonavir, azole antifungals

High

Pravastatin

Hydrophilic

Minimal

2C9 inhibitors: omeprazole, ritonavir, azole antifungals

Low

Rosuvastatin

Hydrophilic

Minimal

2C9 inhibitors: omeprazole, ritonavir, azole antifungals

Low

Adapted from: Schachter M. Chemical, pharmacokinetic, and pharmacodynamics properties of statins: An update. Fundam Clin Pharmacol 2005;19:117-125; and Chong, PH, et al. Clinically relevant differences between the statins: Implications for therapeutic selection. Am J Med 2001;111:390-400.

Ott and colleagues’ meta-analysis and systematic review is timely and comprehensive in scope in its purpose to synthesize current evidence linking statin use with adverse cognitive outcomes. Since the public health implications of the FDA advisory were enormous, the authors compiled information on statin therapy and neurocognitive testing outcomes from all of the major randomized, placebo-controlled trials (RCTs) of statin therapy from several sources including Cochrane Central trial registries, MEDLINE, and EMBASE. Outcomes were analyzed separately in studies of both cognitively normal participants and in cognitively impaired trial patients with a diagnosis of Alzheimer’s disease, and were designed to detect signals for adverse neurocognitive outcomes utilizing a summary statistic called the standardized mean difference (SMD).

SMDs are used in meta-analyses when the same outcome is being measured (neurocognitive outcomes in this case) using different psychometric scales. SMD values of ± 0.2 imply small differences, particularly when confidence intervals (CI) are narrow.2

For the 14 RCTs of cognitively normal patients included in the quantitative analysis, nine of the trials enrolled healthy patients without a specified medical diagnosis (age range 18 to 70 years), and five enrolled patients with cardiovascular risk factors (age range 40 to 83 years). Cognitive test outcomes among these participants at baseline included both global functioning and specific domains such as attention, executive function, memory, processing speed, and working memory.

For the four RCTs of cognitively impaired patients with Alzheimer’s disease (mean age > 68 years), cognitive test outcomes were assessed with either the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or the Mini-Mental Status Examination. The ADAS-Cog measures language and memory and can determine incremental improvements or declines in cognitive functioning, which are important metrics in this group of patients.

This meta-analysis of the cognitive test data collected from these trials failed to show significant adverse effects of statins across all the measured cognitive domains in cognitively intact trial participants (SMD 0.01; 95% CI, -0.01 to 0.03; P = 0.42) or Alzheimer’s disease trial participants (SMD -0.05; 95% CI -0.19 to 0.10, P = 0.38).

The authors also noted that adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects.


COMMENTARY

The time has now come to breathe a sigh of relief and reassure patients who require statin therapy that these medicines will not cause cognitive impairment.

This is an important message of reassurance because statins (HMG CoA reductase inhibitors) are the drugs of first choice for risk modification in patients at high risk for cardiovascular and cerebrovascular disease, the leading causes of death and disability (including cognitive disability) among adult patients. As a matter of fact, high levels of adherence and longer duration of statin therapy are associated with progressively increasing clinical benefits in terms of primary and secondary prevention of cardiovascular events.3 The statin-associated relative risk reductions of 20-30% for myocardial infarction, 20% for ischemic stroke, and 10-15% for all-cause mortality underscore the importance of these medications.4

The multiple mechanisms of action by which statins mitigate risk include:

  1. decreases in LDL cholesterol,
  2. modification of inflammatory response,
  3. antioxidant effects,
  4. antithrombic effects, and
  5. plaque stabilization effects such as reduction of smooth muscle proliferation and cholesterol accumulation.5,6 See Table 1 for the most commonly used statins and differences in characteristics.

In 2013, a meta-analysis of eight randomized, controlled, statin-treatment trials showed no evidence of altered cognitive function between statin-treated and control patients.7 A systematic review of three RCTs and 24 observational studies published in the same year showed that statin treatment was not associated with increased risk for incident dementia, Alzheimer’s disease, or mild cognitive impairment. During the course of the study, Richardson et al reviewed the FDA postmarketing surveillance databases and found that the reporting rates for cognitive adverse events were similar for statins, losartan, and clopidogrel, although no studies suggested memory losses from the latter two commonly prescribed medications.8

Another important factor to consider about the FDA advisory was that the Adverse Event Reporting System reports that formed the basis of the warning did not mention concomitant medications taken by patients at the time of the adverse cognitive events. Several types of medications may impair statin disposition and metabolism, especially for high-intensity therapy and for statins primarily metabolized by the P-450 cytochrome enzyme system (see Table 1). Simvastatin, in particular, as a cytochrome P-450 3A4 inhibitor, when taken in conjunction with macrolide antibiotics (3A4 inhibitors) or amiodarone (3A4 substrate and inhibitor), can result in both increased risk for QT prolongation and arrhythmias and statin-induced myopathy.

Although clinician and patient concerns about statins causing cognitive decline can largely be allayed as a result of this study, new onset of cognitive decline in a patient on statins for cardiovascular risk reduction deserves evaluation. It may be reasonable to discontinue certain other medications and screen for dementia, depression, as well as endocrine, infectious, inflammatory, vascular, and other degenerative illnesses, as root causes. It may be also reasonable to give a statin holiday. This presents an opportunity for a patient-centered discussion of options.


REFERENCES

  1. U.S. Food and Drug Administration. Consumer Health Information. FDA expands advice on statin risks. 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed June 1, 2015.
  2. Van DenNoortgate W, Onghena P. Estimating the mean effect size in meta-analysis: Bias, precision, and mean squared error of different weighting methods. Behav Res Methods Instrum Comput 2003;354:504-511.
  3. Simpson RJ Jr, Mendys P. The effects of adherence and persistence on clinical outcomes in patients treated with statins: A systematic review.
    J Clin Lipidol 2010;4:462-471.
  4. Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: A prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;19:403-414.
  5. Schachter M. Chemical, pharmacokinetic and pharmacodynamics properties of statins: An update. Fundam Clin Pharmacol 2005;19:117-125.
  6. Chong, PH, et al. Clinically relevant differences between the statins: Implications for therapeutic selection. Am J Med 2001;111:390-400.
  7. Swiger KJ, et al. Statins and cognition: A systemic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013:88:1213-1221.
  8. Richardson K, et al. Statins and cognitive function: A systematic review. Ann Int Med 2013;159:688-697.