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Statins Associated with Poorer than Expected Neuropsychological Test Performance in Hypercholesterolemic Adults

Statins Associated with Poorer than Expected Neuropsychological Test Performance in Hypercholesterolemic Adults

Critique date: Tue, 05/03/2005 - 12:53pm
Institution: 
Mount Sinai School of Medicine
   
Article Citation
Citation: 
Muldoon MF, Ryan CM, Sereika SM, Flory JD and Manuck SB . Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med. 2004;117(11):823-9.
   
Clinical Bottom Lines
  1. Treatment of middle aged hypercholesterolemic individuals (mean age 54 years) with simvastatin for 6 months demonstrated diminished learning effects on certain neuropsychological tests.
  2. This study partially replicated the results of a previous trial with lovastatin, finding simvastatin impairment on 2 of 4 lovastatin-affected tests and confirming the lack of statin effect on 6 others.
  3. Functional or clinical effects of these mild testing decrements have not been demonstrated.
  4. It is unknown whether these cognitive performance effects will translate into risks that outweigh the benefits of statin treatment in hypercholesterolemic older adults.
   
Methods
Type of Study: 
Therapy / Prevention
Study Design: 
Randomized, controlled clinical trial
Follow-up Period: 
Between group (placebo vs. simvastatin) and within group (baseline vs. 6 months) comparisons.
Patient Population: 

308 primarily white, healthy participants with mild to moderate hypercholesterolemia (defined as a low-density lipoprotein (LDL) cholesterol level 160 - 220 mg/dl). Mean age ~53.5 years; mean total cholesterol level of ~260 mg/dl; mean education 15 years. Group demography and neuropsychological test performance were similar at baseline with the exception of the Recurrent Words test (placebo vs. treatment groups: 79.6% vs. 84%, P=0.04).

Inclusions

Mild to moderate hypercholesterolemia

Significant Exclusions: 

Secondary lipid disorders, severe hypertriglyceridemia, coronary artery disease, stroke, diabetes, untreated hypertension, cancer, major neuropsychiatric conditions including dementia, concurrent use of lipid-lowering treatment, psychotropic medication, glucocorticoid, opiate analgesic, sexually active premenopausal women not using birth control.

Intervention/Exposure: 

Randomized, double blind, placebo-controlled trial

Daily treatment with placebo, 10mg simvastatin or 40mg simvastatin for 6 months.

Outcome Measures: 

Primary Outcome

Neuropsychological test performance using tests previously seen to be lovastatin-sensitive, insensitive, and new tests

Secondary Outcomes

Quality of life, primary outcome differences between 10 and 40mg of simvastatin

Participant Follow-up: 
92% (283/308). Number of withdrawals did not differ by treatment condition. Pill count compliance was 95%.
   
Conclusion
Results: 
  • Test performance was differentially affected by simvastatin
    • Statin sensitive tests [Digit Vigilance, Recurrent Words, Elithorn Mazes & Grooved Pegboard]
      • Mean Group difference Change Z score: 0.18; 95% CI; 0.07-0.29; P=0.002
      • Only the Recurrent Words and Elithorn Maze results were statistically significant
    • Statin insensitive tests1 (6 tests)
      • Mean Group difference Change Z score: 0.02; 95% CI: -0.07 to 0.10; P=0.72
    • New tests [Mirror Tracer, 4-Word Short-Term Memory tests]).
      • Mean Group difference Change Z score: 0.17; 95% CI, 0.05-0.29; P=0.007.
      • Only the 4 word Memory task was statistically significant

 

Performance on Individual Cognitive Tests at Baseline and After 6 Months of Treatment

 

Placebo Group

Simvastatin Group

Test

Baseline

Post-treatment

Baseline

Post-treatment

 

MEAN ( 95% CONFIDENCE INTERVAL)

Digit Vigilance (errors)*

6.2 (4.7-7.6)

5.7 (4.4-7.0)

6.9 (6.0-7.9)

6.2 (5.1-7.3)

Recurrent Words (%correct)*

80 (76-83)

83 (80-86)

84 (82-86)

85 (83-86)

Elithorn Mazes (seconds)*

172 (160-184)

144 (133-155)

162 (154-170)

160 (152-168)

Grooved Pegboard) (seconds)*

144 (139-149

144 (138-150)

147 (142-152)

145 (145-154)

Mirror Tracing (errors)

48 (40-56)

40 (32-48)

43 (38-48)

41 (35-46)

4 Word Memory  (no.correct)

18.9 (17.4-20.4)

20.8 (19.1-22.4)

19.4 (18.3-20.4)

20.0 (18.9-21.1)

-Tests showing Statistically Significant treatment effects with simvastatin are bolded and underlined above

*Performance affected by lovastatin

 

  • 40mg simvastatin did not produce a greater effect on cognitive performance than 10mg (P>0.15)
  • QOL did not differ between groups
Concerns Regarding Methodology, Applicability to Older Adults, etc.: 

Comments

  • This study's applicability to an older population is difficult to predict. Moreover, since new learning diminishes with normal aging, the cognitive effects of simvastatin in the elderly could be muted rather than similar or more pronounced. Further research is necessary to review the relationship between cognition and statins in the elderly.
  • The actual clinical or functional impact of the particular small differences in performance on the authors' neuropsychological tests is not clear and would be essential to evaluating the risk-benefit ratio of statin therapy for individuals.

Reference

1Muldoon MF, Barger SD, Ryan CM et al. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000; 108:538-546.

Funding Source and Role: 
National Institutes of Health Public Health Service Grant. No stated role.
Created By: 
Lesley Wiesenfeld, MD, FRCPC, Mt. Sinai Hospital, Dept. of Psychiatry, Faculty of Medicine, University of Toronto, CANADA
This is a review of the validity of a single study; the ‘bottom lines’ do not reflect comparison with the rest of the literature on this subject.