Long-Term Use of Ibuprofen Lowers Alzheimer's Disease Risk

Long-Term Use of Ibuprofen Lowers Alzheimer's Disease Risk  CME/CE

News Author: Caroline Cassels
CME Author: Penny Murata, MD
Disclosures

Release Date: May 8, 2008; Valid for credit through May 8, 2009

Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians; Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians; Nurses - 0.25 nursing contact hours (0.25 contact hours are in the area of pharmacology)

To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Describe the association between the incidence of Alzheimer's disease and the use of nonsteroidal anti-inflammatory drugs.
2. Describe the association between the incidence of Alzheimer's disease and the use of specific nonsteroidal anti-inflammatory drugs and those that suppress formation of amyloid beta-1-42.

Authors and Disclosures

Caroline Cassels
Disclosure: Caroline Cassels has disclosed no relevant financial relationships.

Penny Murata, MD
Disclosure: Penny Murata, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

 

May 8, 2008 — Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, lowers the risk for Alzheimer's disease.

A new study by investigators at Boston University School of Medicine found that individuals who specifically used ibuprofen for more than 5 years had a 40% reduced risk for Alzheimer's disease. In addition, there appeared to be a dose-response effect so that the longer ibuprofen was used, the greater the risk reduction.

Individuals who used other types of NSAIDs for more than 5 years were 25% less likely to have the disease vs nonusers.

Although other NSAIDs such as indomethacin were associated with lower risk, agents such as celecoxib did not appear to have an effect on the risk for dementia.

"These results suggest that the effect may be due to specific NSAIDs rather than all NSAIDs as a class," study author Steven Vlad, MD, said in a statement from the American Academy of Neurology.

"Some of these medications taken long-term decrease the risk of Alzheimer's disease, but it's very dependent on the exact drugs used. It doesn't appear that all NSAIDs decrease the risk at the same rate. One reason ibuprofen may have come out so far ahead is that it is by far the most commonly used," he added.

The study is published in the May 6 issue of Neurology.

Suppressors More Likely to Have a Protective Effect?

The aim of the study was to examine the effects of long-term use of specific NSAIDs on the risk for incident Alzheimer's disease. The investigators also looked at whether NSAIDs that suppress levels of amyloid beta-1-42 (Aβ 1-42), a major component of senile plaques in Alzheimer's disease amyloid, would be more likely to have a protective effect against the disease.

Study subjects included US veterans 50 years and older who received medical care and prescriptions through the US National Veterans Affairs Health Care system.

Researchers identified 49,349 subjects in whom incident Alzheimer's disease developed from 1998 to 2005 and compared their use of NSAIDs with that of 196,850 matched control subjects from the same population.

Exposure to NSAIDs was categorized into 7 periods of duration of use: no use, up to 1 year, more than 1 year but up to 2 years, more than 2 years but up to 3 years, more than 3 years but up to 4 years, more than 4 years but up to 5 years, and more than 5 years.

The investigators then tested the link between the development of the disease and the use of any NSAID, any NSAID excluding nonacetylated salicylates, each NSAID class, each individual NSAID, and Aβ 1-42–suppressing NSAIDs (which in this study included ibuprofen, indomethacin, sulindac, and diclofenac).

Among the study subjects, 42.2% of case patients and 40.2% of control subjects received at least 1 prescription for a NSAID during the study period. Arylpropionic acids, which include the agents ibuprofen and naproxen, were the most frequently prescribed class.

No Clinical Implications

Approximately 15% of case patients and control subjects used NSAIDs for longer than 1 year, with almost half of these using either ibuprofen or naproxen. A total of 400 case patients and 1952 control subjects used NSAIDs for longer than 5 years.

Compared with individuals who did not use NSAIDs, the adjusted odds of Alzheimer's disease decreased from 0.98 for those with 1 year of use or less to 0.76 in those with more than 5 years of use. Among ibuprofen users, it decreased from 1.03 to 0.56.

The researchers found no protective effect for cyclooxygenase-2 inhibitors or nonacetylated NSAIDs.

Unfortunately, say the researchers, because of the small numbers of patients taking other Aβ 1-42–suppressing NSAIDs such as sulindac and flurbiprofen, it was not possible to determine whether they had a similar protective effect as ibuprofen.

For the same reason, the study also could not confirm that other non–Aβ 1-42 suppressors had no effect.

Because this research is observational, no clinical recommendations can be extrapolated from these results. However, the researchers note, the study has implications for future trials of NSAIDs in Alzheimer's disease, particularly with ibuprofen.

The study was supported by the National Institutes of Health. The study authors have disclosed no relevant financial relationships.

Neurology. 2008;70:1672-1677.

Clinical Context

NSAIDs might postpone the onset of Alzheimer's disease, as reported by de Craen and colleagues in the January 2005 issue of the American Journal of Epidemiology. However, results from the Alzheimer's Disease Anti-Inflammatory Prevention Trial, published in the May 22, 2007, issue of Neurology, showed that naproxen or celecoxib did not decrease the risk for Alzheimer's disease after 3 years of follow-up.

Different NSAIDs might differ in their effect on Alzheimer's disease. For example, Morihara and colleagues noted in the June 2005 issue of Neuropsychopharmacology that the NSAID ibuprofen reduces serum levels of Aβ 1-42, which is present in senile plaques in Alzheimer's disease amyloid.

Study Highlights

• Veterans at least 50 years old who had at least 1 outpatient visit through the US Veterans Affairs Health Care system during the 7-year study period were eligible.
• Exclusion criteria were a diagnostic code consistent with Alzheimer's disease or any dementia or use of a drug for dementia within 6 months of the initial visit.
• 49,349 case patients had a new diagnostic code indicating Alzheimer's disease during the study period, with date of onset based on the earliest code, any dementia code, or dementia drug prescription.
• 196,850 control subjects were matched by age within 5 years, sex, treatment facility, visit in same year of first outpatient visit, and inpatient or outpatient visit in the same year of onset of the disease.
• Mean age of onset was 74.1 years.
• Most subjects were men (97.4%), white (64.8% - 65.8%), and in need of financial assistance (57.6% - 59.4%).
• Study controlled for race, low-dose aspirin use up to 325 mg daily, level of disability, financial parameters, and comorbid diseases.
• Case patients vs control subjects had more than a 2% difference in comorbidity prevalence for low-dose aspirin (48.7% vs 39.3%), gastrointestinal tract bleeding (12.0% vs 9.6%), acute renal failure (6.5% vs 3.9%), hearing loss (37.3% vs 34.3%), and osteoarthritis (48.0% vs 46.0%).
• NSAID classes were arylpropionic acids, indolic acids, heteroarylacetic acids, enolic acids, cyclooxygenase-2 inhibitors, nonacetylated salicylates, and high-dose aspirin.
• Aβ 1-42 suppressors included ibuprofen, sulindac, indomethacin, and diclofenac.
• Duration of use was categorized as no use, up to 1 year, more than 1 up to 2 years, more than 2 up to 3 years, more than 3 up to 4 years, more than 4 up to 5 years, and more than 5 years.
• At least 1 prescription for NSAID was used for 42.4% of case patients and 40.2% of control subjects.
• The most common NSAID class used was arylpropionic acids for both case patients (31.3%) and control subjects (29.1%).
• Most frequently prescribed specific NSAIDs were ibuprofen (20.9% case patients and 18.7% control subjects) and naproxen (15.2% case patients and 14.6% control subjects).
• The odds for Alzheimer's disease decreased as the duration of NSAID use increased from up to 1 year (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.95 - 1.00) to more than 5 years (OR, 0.76; 95% CI, 0.68 - 0.85).
• Exclusion of nonacetylated NSAIDs did not affect results
• The only NSAID class that showed a similar decrease in the OR for Alzheimer's disease was arylpropionic acid because its use increased from up to 1 year (OR, 1.00) to more than 5 years (OR, 0.63).
• The individual NSAID that showed the most protective effect was ibuprofen because its use increased from up to 1 year (OR, 1.03; 95% CI, 1.0 - 1.06) to more than 5 years (OR, 0.56; 95% CI, 0.42 -0.75).
• Limitations of the study were possible diagnostic coding errors and errors in recorded drug exposure.

Pearls for Practice

• NSAID use for more than 5 years decreases the odds of the development of Alzheimer's disease.
• Ibuprofen is the only specific NSAID that is protective against Alzheimer's disease.