By Brenda L. Mooney
SAN FRANCISCO – New research on cholinesterase inhibitors is reducing the already limited options VA clinicians have to treat VA patients with dementia.
More than a half-million veterans have Alzheimer’s disease (AD) and dementia, with most – but not all – being treated at the VA. Those numbers are expected to grow, not just because of the older patient population but also because so many younger veterans have conditions, such as traumatic brain injury, that are increasingly being linked to higher risk for AD.
The latest VA research suggested that medications used to treat dementia could be leading to weight loss which, in turn, is linked to increased mortality among veterans.
That study, published recently in the Journal of the American Geriatrics Society, found that cholinesterase inhibitors could be contributors to clinically significant weight loss in many older patients with dementia. Study authors from the San Francisco VAMC and the University of California San Francisco recommended that healthcare providers take that into account when prescribing and dispensing the drugs.1
“This is very relevant to patient care, because unintentional weight loss in older adults is associated with many adverse outcomes, including increased rates of institutionalization and mortality, a decline in functional status, and poorer quality of life,” said lead author Meera Sheffrin, MD, a geriatrics fellow.
Background information in the article noted that Alzheimer’s disease and other dementias affect one in six people over age 80. Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine are marginally beneficial for most patients, according to the report, but might have serious side effects, such as gastrointestinal symptoms.
Past research using data from randomized controlled trials has suggested that weight loss may be an under-recognized side effect of cholinesterase inhibitors, although evidence has been limiting and conflicting.
To look at that link, researchers used national VA data from 2007-2010 to evaluate patients age 65 or older diagnosed with dementia who received a new prescription for a cholinesterase inhibitor or other new chronic medication. Denoted as the primary outcome was a 10-pound weight loss over a 12-month period; study authors hypothesized that a degree of loss of that magnitude would be noticed by clinicians and possibly prompt further action in considering the causes and potential treatments.
Medical records of the 1,188 patients started on cholinesterase inhibitors were matched to 2,189 patients started on other medications. After a year, 78% were still on the cholinesterase inhibitors, compared to 66% for other medications. At the same time, about 29.3% of patients on the inhibitors experienced significant weight loss, compared to 22.8% of non-users.
Sheffrin said in a University of California San Francisco press release that the results demonstrate that patients started on the medications had a higher risk of clinically significant weight loss over a 12-month period compared to matched controls, adding that one out of every 21 of those patients experienced at least a 10-pound weight loss.
The investigators called for further research, especially since the sample included mainly older male veterans, so the generalizability of the findings to women is uncertain.
“Clinicians should take into account the risk of weight loss when weighing the risks and benefits of prescribing cholinesterase inhibitors in patients with dementia,” the authors wrote. “In addition, clinicians should monitor for weight loss if these medications are prescribed and consider discontinuing cholinesterase inhibitors if significant weight loss occurs.”
Effectiveness of Cholinesterase Inhibitors
The risk of weight loss isn’t the only reason VA clinicians should be cautious in prescribing cholinesterase inhibitors for Alzheimer’s disease (AD). There also is the issue of whether the benefits outweigh the risks.
Another recent study found that ethnically diverse AD patients show little or no benefit from one year of donepezil treatment. “These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients,” according to the authors of that study, which was published this past spring in the American Journal of Geriatric Psychiatry.2
That study involved 10 California sites, including VA Mental Illness Research and Education Centers in San Francisco and Palo Alto, CA.
Participants met criteria for probably or possible AD and were followed for a year in the prospective, observational study. Individual physicians determined the treatment regimens of the patients, who self-identified their ethnicity – using their usual criteria, including when deciding to prescribe donepezil.
Results indicated that the 64 ethnically diverse AD patients who received donepezil treatment and completed the study had an average one-year decline of 2.30 points on the 30-point Mini-Mental State Exam, compared with a 1.70-point decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the same time period.
The difference was not statistically significant, according to study authors, led by researchers from Sierra Pacific Mental Illness, Research, Education and Clinical Center and the VA Palo Alto Health Care System and the Department of Psychiatry and Behavioral Sciences at Stanford University.
The lack of benefits associated with donepezil treatment remained when a variety of analyses were applied, according to the study.
“We had initially hypothesized that there would be some benefit from donepezil treatment,” study authors wrote. “The lack of benefit was an unexpected finding and suggests decreased effectiveness of donepezil in minority populations.”
The researchers noted that their previous study in California, which involved only white non-Latino patients, was otherwise methodologically identical and showed a modest positive response to donepezil treatment.3
The problem is that VA practitioners don’t have a lot of options to treat patients with dementia, said Mary Sano, PhD, professor of medicine at the Mount Sinai Health System and director of research at the James J. Peters Veteran’s Administration Medical Center in Bronx, NY, explaining last year, “Since the cholinesterase inhibitors [galantamine, donepezil, rivastigmine], we have had very little to offer patients with mild-to-moderate dementia.”
That’s why VA research finding that a daily dose of 2,000 IUs of vitamin E slowed functional decline in patients with mild to moderate Alzheimer’s disease without significantly increasing mortality rates in the treatment group was met with so much excitement.
The `Veteran’s Administration Cooperative Randomized Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD)` study, led by Maurice W. Dysken, MD of the Minneapolis VA Health Care System, involved 613 patients at 14 centers. Results were published in early 2014 in the Journal of the American Medical Association.4
“This trial showed that vitamin E delays progression of functional decline by 19% per year, which translates into 6.2 months benefit over placebo,” Sano, who was a co-author, in a Mount Sinai press release at the time.
1. Sheffrin M, Miao Y, Boscardin WJ, Steinman MA. Weight Loss Associated withCholinesterase Inhibitors in Individuals with Dementia in a National HealthcareSystem. J Am Geriatr Soc. 2015 Aug;63(8):1512-8. doi: 10.1111/jgs.13511. Epub2015 Aug 3. PubMed PMID: 26234945. 2. Tinklenberg JR, Kraemer HC, Yaffe K, O’Hara R, Ringman JM, Ashford JW,Yesavage JA, Taylor JL; California Alzheimer’s Disease Centers. Donepeziltreatment in ethnically diverse patients with Alzheimer disease. Am J GeriatrPsychiatry. 2015 Apr;23(4):384-90. doi: 10.1016/j.jagp.2014.09.007. Epub 2014 Sep28. PubMed PMID: 25747405. 3. Tinklenberg JR, Kraemer HC, Yaffe K, Ross L, Sheikh J, Ashford JW, YesavageJA, Taylor JL. Donepezil treatment and Alzheimer disease: can the results ofrandomized clinical trials be applied to Alzheimer disease patients in clinicalpractice? Am J Geriatr Psychiatry. 2007 Nov;15(11):953-60. PubMed PMID: 17974866. 4. Dysken MW, Sano M, Asthana S, Vertrees JE, et al.Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan 1;311(1):33-44. doi:10.1001/jama.2013.282834. PubMed PMID: 24381967.