Atorvastatin for Preventing Dementia

(PREVENTABLE Trial)

Recruiting at 96 trial locations

Overseen By Catherine McNeal

Age: 65+

Sex: Any

Trial Phase: Phase 4

Sponsor: Duke University

Must not be taking: Statins

Disqualifiers: Cardiovascular disease, Dementia, ADL dependence, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to 5 years (estimated median of 3.8 years)

20000 Participants Needed

Trial Summary

What is the purpose of this trial?

PREVENTABLE is a multi-center, randomized, parallel group, placebo-controlled superiority study. Participants will be randomized 1:1 to atorvastatin 40 mg or placebo. This large study conducted in community-dwelling older adults without cardiovascular disease (CVD) or dementia will demonstrate the benefit of statins for reducing the primary composite of death, dementia, and persistent disability and secondary composites including mild cognitive impairment (MCI) and cardiovascular events.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those who have used statins in the past year or for more than 5 years previously. It's best to discuss your current medications with the trial team.

What evidence supports the effectiveness of the drug atorvastatin in preventing or treating dementia?

Research suggests that atorvastatin, a statin drug, may help improve memory and thinking skills in people with mild-to-moderate Alzheimer's disease. Studies showed that patients taking atorvastatin had better cognitive performance compared to those taking a placebo, especially when treatment started early. ^{1 2 3 4 5}

Is atorvastatin safe for humans?

Atorvastatin is generally safe and well tolerated in humans, with a good safety profile across various dosages. It may cause a slight increase in liver enzymes at higher doses, but this does not lead to serious health issues. It has a low risk of muscle problems and does not affect the brain, kidneys, or require dose changes for people with kidney issues. ^{1 6 7 8 9}

How does the drug atorvastatin differ from other treatments for preventing dementia?

Atorvastatin, commonly used to lower cholesterol, is unique in its potential to prevent dementia by possibly slowing the progression of Alzheimer's disease, especially when started early. Unlike traditional dementia treatments, it targets cholesterol levels, which may be linked to dementia risk. ^{1 2 10 11 12}

Eligibility Criteria

This trial is for community-dwelling adults aged 75 or older who primarily speak English or Spanish. It's not for veterans, those with recent statin use, severe visual impairments, intolerance to statins, evident cardiovascular disease like past heart attacks or strokes, recent heart failure hospitalization, dependence on help for daily activities (except incontinence), inability to talk on the phone, active liver disease, certain medication users (colchicine/verapamil/diltiazem), or diagnosed dementia.

Inclusion Criteria

I live in my own home or with family.

My primary language is either English or Spanish.

I am 75 years old or older.

Exclusion Criteria

I have been diagnosed with or show clear signs of dementia.

I am unable to speak.

Veteran

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person or virtual)

Treatment

Participants are randomized to receive either atorvastatin 40 mg or placebo daily

Up to 5 years (estimated median of 3.8 years)

Annual assessments (phone or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Annual follow-up calls and potential in-person assessments

Treatment Details

Interventions

• Atorvastatin
• Placebo

Trial Overview The PREVENTABLE study tests if Atorvastatin 40 mg can prevent death, dementia and disability compared to a placebo in older adults without CVD or dementia. Participants are randomly assigned either the drug or a placebo tablet equally and monitored for cognitive health and cardiovascular events.

Participant Groups

Group I: atorvastatin 40mg Experimental Treatment 1 Intervention

40mg atorvastatin po qd from consent to study end

Group II: Placebo Placebo Group 1 Intervention

matching placebo po qd from consent to study end

Atorvastatin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Wake Forest University Health Sciences

Collaborator

Trials

1,432

Recruited

2,506,000+

Findings from Research

The LEADe study, involving 641 participants with mild to moderate Alzheimer's disease, is investigating the effects of atorvastatin (80 mg daily) on cognitive decline while patients are also receiving donepezil, a common Alzheimer's treatment.

This study aims to determine if atorvastatin can improve cognitive function and brain volume in Alzheimer's patients, potentially highlighting a protective role of statins against Alzheimer's disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics. Jones, RW., Kivipelto, M., Feldman, H., et al.[2018]

A 1-year double-blind, placebo-controlled trial with 80 mg of atorvastatin daily showed significant cognitive and memory improvements in patients with mild-to-moderate Alzheimer's disease after 6 months, with a continued positive trend at 1 year.

The benefits of atorvastatin were more pronounced in patients who had higher baseline cognitive function, suggesting that earlier treatment may enhance its effectiveness in slowing the progression of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin therapy in Alzheimer's disease. Sparks, DL., Sabbagh, M., Connor, D., et al.[2015]

In a study of 2305 Canadians aged 65 and older, the use of lipid-lowering agents (LLAs), including statins, was linked to a significantly reduced risk of developing Alzheimer disease in individuals younger than 80 years, with an odds ratio of 0.26 after adjusting for various health factors.

The study found that LLA use was more common in younger individuals (ages 65-79) and was not associated with healthier lifestyle indicators, suggesting that the protective effect against dementia may be genuine rather than due to healthier lifestyle choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Rockwood, K., Kirkland, S., Hogan, DB., et al.[2021]

Statins may have a small benefit in delaying the progression of Alzheimer's dementia, but the evidence is of very low confidence and conflicts with previous shorter studies.

There was no significant difference in adverse events between statin users and non-users in the studies reviewed, indicating that the safety of statins in dementia patients remains uncertain due to insufficient data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits and Harms of Statins in People with Dementia: A Systematic Review and Meta-Analysis. Davis, KAS., Bishara, D., Perera, G., et al.[2021]

A systematic review of three studies involving 748 participants with Alzheimer's disease found that statins did not show any significant benefit in improving cognitive function, as measured by the Alzheimer's Disease Assessment Scale and the Mini-Mental State Examination.

There was no evidence that statins negatively affected cognitive function, but overall, the findings indicate that there is insufficient evidence to recommend statins as a treatment for dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cochrane review on 'Statins for the treatment of dementia'. McGuinness, B., O'Hare, J., Craig, D., et al.[2013]

Atorvastatin is generally well tolerated across various dosages, with only a slight increase in liver enzyme elevations at the highest dose (80 mg/day), but no significant risk of serious adverse events.

Unlike some other statins, atorvastatin has a low incidence of muscular toxicity and does not require dosage adjustments for patients with renal dysfunction, making it a safe option for older adults (65 years and older) as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin: a safety and tolerability profile. Arca, M.[2021]

Atorvastatin is a highly effective statin that significantly lowers LDL and total cholesterol levels, and it is the first statin proven to reduce triglycerides in patients with high triglyceride levels.

In addition to its cholesterol-lowering effects, atorvastatin has beneficial non-lipid effects, such as improving blood vessel function and reducing inflammation, although clinical trial evidence is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atorvastatin. Wierzbicki, AS.[2019]

Atorvastatin did not show any significant clinical benefits in improving cognitive function or overall condition in patients with mild to moderate Alzheimer's disease, based on a review of two randomized controlled trials involving 710 participants.

The treatment group experienced higher rates of adverse effects, including abnormal liver function and withdrawal from treatment, indicating potential safety concerns associated with atorvastatin use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of atorvastatin for the treatment of Alzheimer's disease. Sun, Y., Wang, G., Pan, Z., et al.[2020]

Both simvastatin and atorvastatin significantly reduced cholesterol synthesis in the central nervous system of rats, indicating their potential local action in the brain without affecting plasma cholesterol levels.

This study provides evidence supporting the role of statins in modulating cholesterol synthesis in the brain, which may have implications for their protective effects against dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cholesterol synthesis in central nervous system of rat is affected by simvastatin as well as by atorvastatin. Cibickova, L., Hyspler, R., Ticha, A., et al.[2018]

In a cohort study of 2798 adults aged 65 and older, statin use was not associated with a reduced risk of developing all-cause dementia or specific types of dementia, including Alzheimer's disease.

However, secondary analyses suggested that current statin users had a lower risk of all-cause dementia (HR 0.69) and Alzheimer's disease (HR 0.56) compared to those who never used lipid-lowering agents, indicating potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin use and the risk of incident dementia: the Cardiovascular Health Study. Rea, TD., Breitner, JC., Psaty, BM., et al.[2022]

Statin use is associated with a significantly lower risk of developing dementia, with statin users having a two- to threefold reduced risk compared to non-users, independent of serum cholesterol levels, based on a study of 1604 participants followed for about 25 years.

Higher total cholesterol levels at the first visit were linked to a reduced risk of mild cognitive impairment (MCI), while a decline in total cholesterol was associated with increased dementia risk in men, suggesting complex relationships between cholesterol levels and cognitive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. Beydoun, MA., Beason-Held, LL., Kitner-Triolo, MH., et al.[2022]

A systematic review of two large trials involving 26,340 participants found that statins, while effective in lowering cholesterol, do not prevent Alzheimer's disease or other forms of dementia in older adults at risk for vascular disease.

Despite initial observational studies suggesting a potential benefit, randomized controlled trials showed no significant difference in cognitive decline or dementia incidence between statin and placebo groups, indicating that statins do not have a protective effect on cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statins for the prevention of dementia. McGuinness, B., Craig, D., Bullock, R., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics. [2018]

2. Denmark pubmed.ncbi.nlm.nih.gov

Statin therapy in Alzheimer's disease. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Benefits and Harms of Statins in People with Dementia: A Systematic Review and Meta-Analysis. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Cochrane review on 'Statins for the treatment of dementia'. [2013]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Atorvastatin: a safety and tolerability profile. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Atorvastatin. [2019]

8. India pubmed.ncbi.nlm.nih.gov

Systematic review of atorvastatin for the treatment of Alzheimer's disease. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Cholesterol synthesis in central nervous system of rat is affected by simvastatin as well as by atorvastatin. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Statin use and the risk of incident dementia: the Cardiovascular Health Study. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Statins for the prevention of dementia. [2021]