Issue:
97
Page: 32-37
Ginkgo and Alzheimer’s Disease Prevention:
Researchers, herbal experts interpret results of the five-year GuidAge clinical trial
by Tyler Smith
HerbalGram.
2013; American Botanical Council
Reviewed:
Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardized Ginkgo
biloba extract for the prevention of Alzheimer’s disease (GuidAge): a
randomized placebo-controlled trial. The
Lancet Neurology. 2012;11(10):851-859.
Alzheimer’s disease (AD) is the
sixth leading cause of death in the United States and is the most common form
of dementia in older adults.1 The National Institute on Aging
estimates that as many as 5.1 million Americans currently have AD,
and experts predict the prevalence of the disease will quadruple by 2050.2,3
In September 2012, a group of French scientists published the final results of
a long-term, placebo-controlled clinical trial assessing the effects of a
standardized ginkgo (Ginkgo biloba,
Ginkgoaceae) extract for the prevention of Alzheimer’s disease in older,
healthy adults.
The GuidAge study, as it is known,
was one of the largest and longest trials on Ginkgo biloba and AD prevention to date, and is the first of
its kind to be performed outside the United States. Researchers found that the
standardized Ginkgo biloba extract
did not reduce the participants’ risk of developing Alzheimer’s disease, and
some major media outlets erroneously reported that there is no benefit to
taking the supplement, failing to take into account several shortcomings of the
study.3
“After the results of GuidAge were
published, some comments pointed out that this study provides further proof
that ginkgo is ineffective in treatment of dementia. Those people are probably
confusing prevention and treatment,” said Wolfgang Weber, PhD, a
pharmacist with Dr. Willmar Schwabe GmbH & Co. in Karlsruhe, Germany, which
developed the EGb 761® ginkgo extract used in the trial (email,
October 19, 2012). Notably, EGb 761 is marketed in many countries around the
world for the treatment of
dementia symptoms.
“The GuidAge trial was
an Alzheimer’s dementia prevention trial;
EGb 761 is approved for treatment of
dementia. This is definitely not comparable,” said Dr. Weber. “Today there
is no compound which has an effect in prevention of AD, though there are many
trials available in which different compounds (acetylcholinesterase inhibitors [AChE-I, e.g., donepezil], vitamins,
statins, [nonsteroidal anti-inflammatory drugs, etc.]) were tested for that
purpose. All of them failed.”
Ginkgo biloba and Alzheimer’s Disease
Alzheimer’s disease is a progressive
brain disease that affects behavior and personality in addition to cognitive
processes such as thinking, judgment, and memory. The exact cause of the
disease is not known, but it is thought to involve buildup in the brain of
certain protein fragments known as beta-almyloid (βA), which can form clumps or
plaques that disrupt normal brain function and cause cell death.4
Among the primary active ingredients
in ginkgo are specific flavone glycosides (e.g.,
rutin, quercetin, kaempferol) and unique terpene lactones (ginkgolides,
bilobalides), which contribute to the neuroprotective and antioxidant
properties of the extract. In animal models, the extract or components of it
have been shown to increase neurogenesis and enhance neuroplasticity.5,6 Furthermore,
it can inhibit βA aggregation7 and βA-induced pathological
behavior.8 EGb 761, which has been used in numerous clinical
trials including the 2008 US-based Ginkgo for the Evaluation of Memory (GEM)
study, is standardized to 24% ginkgo flavone glycosides and 6% terpene
lactones.9
In a guest comment published in the
same issue of The Lancet Neurology as
the recent GuidAge trial results, Lon S. Schneider, MD, director of the
University of Southern California’s (USC) Alzheimer’s Disease Research and
Clinical Center, wrote that EGb 761 “had a typical preclinical pharmacological
profile for a modern Alzheimer’s disease drug.”10
Despite the promising
pharmacological profile of ginkgo extract, the findings of the GuidAge trial
were not as robust as expected. Researchers initially enrolled 2,854 healthy
individuals who had reported memory problems to their primary care physicians.
According to the study’s authors, “Subjective memory complaints in elderly
individuals, especially if spontaneously expressed to a doctor, are associated
with an increased risk of dementia, and have been linked to brain atrophy and
amyloid-β deposition … and could thus be a target population for interventions
aimed at prevention of Alzheimer’s disease.” After five years, 61 of the
1,406 individuals taking 240 mg ginkgo extract daily and 73 of the 1,414
participants taking a placebo equal in taste and appearance had been diagnosed
with probable Alzheimer’s disease — a statistically insignificant difference.3
Potential Issues with the GuidAge
Trial
In Schwabe’s “Facts and
Interpretations” sheet for the GuidAge trial sent to the American Botanical
Council, the company’s scientific team noted that choosing an appropriate
study population for such large-scale prevention trials is problematic in
itself. “Finding representative probands [i.e.,
study subjects with relevant genetic backgrounds] for an Alzheimer’s
prevention study is extremely challenging. Even with today’s technical
possibilities in analyzing genetic information, it is practically impossible to
predict the probability of Alzheimer’s disease developing in a healthy
individual within a defined period of time. This is also true for people
already complaining about memory impairment.”
Jerry Cott, PhD
— a pharmacologist and toxicologist at the US Food and Drug
Administration’s Center for Drug Evaluation and Research, chair of the Center’s
Dietary Supplement Subcommittee, and an ABC advisory board
member — speaking on behalf of himself, acknowledged the importance
of positive preclinical data for Ginkgo
biloba extracts, but said he was not surprised by the results of the
trial.
“The reason why this is important is
that the preclinical data would suggest that there might be a preventative
effect with ginkgo,” said Dr. Cott (oral communication, November 5, 2012).
“This is very different from the data on cholinesterase inhibitors, which are
for treating symptoms. You’re boosting the effect of what little acetylcholine
is left, but you wouldn’t expect that to have a neuroprotective effect. While
it’s disappointing, it’s not surprising that a preventative effect was not
found in this study. No preventative effect has ever been shown for [an Alzheimer’s] treatment, including the
best-selling pharmaceuticals.”
Importantly, the expected rate of AD
development in the GuidAge trial — a number that must be reached to
ensure ideal statistical significance — was not met. Although
researchers expected the cumulative incidence rate of AD to be 13.8%, only 4.8%
of trial participants were diagnosed with AD by the end of the study. According
to the trial authors, the “main limitation of [the] study was that the number
of dementia events was much lower than expected, leading to a lack of
statistical power to detect effects.”
However, of 13 planned subgroup
analyses, three groups showed a significant reduction in progression
to AD: participants who stayed in the trial for at least four years, men, and
those who consumed alcohol.3
According to Schwabe’s “Facts and
Interpretations” document, participants in the group that took the supplement
for at least four years had a 47% reduced incidence rate of AD compared to
placebo. “During the first four years of treatment, the difference between EGb
761 and placebo was not significant. However, after four years, the incidence
of AD for the placebo group (3.01) almost doubled compared to the rates
observed in the EGb 761 group (1.51),” wrote the Schwabe scientists. “Even
though the authors recommended treating these results with caution, this is a
clear trend towards a possible preventative effect of EGb 761.”
USC’s Dr. Schneider, in his guest
comment, offered a different explanation for the particular subgroups’ positive
analysis. “The hypothesis that an individual has to take Ginkgo biloba for 4 years before it
can protect against Alzheimer’s disease is essentially a proposition for a
filtering or survival effect according to which — assuming participants are
able to comply or survive with four years of Ginkgo biloba use and avoid discontinuing it, becoming lost to
follow-up, becoming ill, becoming demented, or dying (30% of the trial
participants had any of these events) — continued use into a fifth year will
decrease risk for dementia,” he wrote.10
Keith Laws, PhD, a professor of
cognitive neuropsychology at the University of Hertfordshire in the United
Kingdom and author of a September 2012 meta-analysis of randomized,
controlled clinical trials examining the effects of ginkgo on cognitive
enhancement in healthy individuals, failed to detect any significant benefits
in measures of memory, executive function, or attention. The 28 studies
included in the analysis —which ranged in duration from five days to four
months — included only individuals without dementia.11
According to Dr. Cott, making any
strong conclusions from meta-analyses can be problematic. “A meta-analysis can
show anything you want to show. Junk in, junk out,” he said. “The bias of the
investigator can really be present in a meta-analysis.”
Dr. Laws, though, said he was
impressed by the quality of the studies included in his meta-analysis. “Any
meta-analysis is limited by the studies that are published, i.e., the number and quality of
studies,” he said (email, October 19, 2012). “We found really high-quality
studies — all were randomized, controlled trials with double
blinding.”
The GuidAge study, according to Dr.
Laws, also was well-crafted. “The Vellas et al. study seems very sound — it … quite clearly found Ginkgo biloba made no difference to
rates of transition to Alzheimer’s,” he said (email, October 19, 2012). “I am
of the opinion that those who market Ginkgo
biloba as a substance that sustains, enhances, or maintains memory
need to provide evidence of that claim; our data suggest it is a claim with
little or no foundation, and I would prefer to see such claims removed from
packaging when they are unwarranted and unsupported.”
However, the meta-analysis differed
from the GuidAge clinical trial in that it examined studies specifically for
cognitive enhancement, not AD prevention. The 28 trials included in the
meta-analysis featured different doses of various ginkgo extracts such as Li
1370 (Lichtwer Pharma AG; Berlin, Germany) and Blackmores (Warriewood,
Australia), in addition to EGb 761. Although the marketing materials and/or
labels of many ginkgo formulations claim to have cognitive enhancing properties
(e.g., for improving mental
sharpness, memory, and concentration12) in healthy populations, EGb
761 is marketed in numerous countries as a licensed or registered medicinal
agent specifically for the treatment of dementia. The target group of EGb 761,
according to Schwabe’s website, “includes patients with demential syndrome in
primary degenerative dementia, vascular dementia, and mixed forms of both,” not
healthy individuals hoping to prevent Alzheimer’s disease.13
Dr. Laws acknowledged that ginkgo
extract might have an impact in people already suffering from dementia. “Ginkgo biloba may have a quite
different role in Alzheimer’s. Meta-analyses (e.g. Weinmann et al.
2010)14 do indicate that Ginkgo
biloba may have some beneficial effects on the cognition of those who
already have Alzheimer’s disease,” he explained. “So [it] may not prevent
transition to Alzheimer’s disease, but does appear to benefit patient cognitive
abilities once people have actually developed the disease. The issue
then becomes … for how long and to what degree, and these questions
require further investigation.”
Future Research and Ginkgo Safety
Kelly Harrison, PhD, an instructor
in the Department of Psychology at Virginia Tech University, noted a number of
such dementia treatment studies. “Wang et
al. (2010)15 performed a meta-analysis on the use of ginkgo
in the treatment of dementia in which subjects took the preparation for six
months and found a significant difference in favor of ginkgo,” she said (email,
October 26, 2012). “Once again, this was a study looking for improvement in
those already diagnosed with dementia, not ‘healthy populations.’ Similar
results were found by Yang et al.
(2011).16 I would suggest that the modest improvements found in
some clinical trials are as frequent in the literature as are those that find
no significant change. Such is the nature of scientific inquiry.”
According to Dr. Bruno Vellas, the
lead author of the GuidAge trial, more research needs to be conducted before
the effects of Ginkgo biloba on
AD prevention can be stated with any certainty. “We think that the ginkgo
hypothesis is still open and more studies have to be done,” he said (email,
October 22, 2012).
Dr. Harrison noted that researchers
should account for conventional pharmaceutical medications taken by
participants, many of whom are elderly, through blood draws and analyses to
help determine the blood levels of ginkgo’s primary active ingredients. “One in
three of the elderly uses five or more prescription medications regularly, and
about half use over-the-counter medications and dietary supplements,” she said.
“Thus each person could actually be receiving an individualized dosage based on
the number of drugs they are taking that interfere with ginkgo’s
conversion. This may account for a lot of the variability in the herb’s
performance and certainly deserves consideration before writing the drug off as
a wash.”
Bill Gurley, PhD, a professor of
pharmaceutical sciences at the University of Arkansas for Medical Science’s
College of Pharmacy, agreed that adding blood work to such long-term clinical
trials would be beneficial. “Having blood data to confirm compliance would
certainly have been helpful, but the samples have to be taken at the
appropriate times,” he said (email, November 5, 2012). “Too many clinical
studies fail to measure phytochemical levels to confirm compliance at best and
efficacy at least.”
Dr. Weber, too, sees room for
improvement in future clinical trials. “In my opinion the failure of EGb 761 to
show an effect in prevention trials for dementia might not so much be a problem
of EGb 761 but rather a problem of dementia prevention trials,” he said.
“Compliance is very difficult to achieve over a period of four or five years.”
Dr. Vellas, in the GuidAge paper’s
conclusion, suggested that future trials “should use new methods, such as less
burdensome cognitive assessments or home visits to reduce the number of
non-completers, and should include new biomarker and imaging surrogate outcomes
when these have been developed and validated.”3
Although various pharmaceutical
drugs have been developed in recent years to combat AD, unpleasant side effects
and limited effectiveness have prompted the investigation of alternatives such
as ginkgo extract. And, despite differing interpretations of the GuidAge trial,
the safety of EGb 761 has not been questioned. Researchers found no significant
differences between ginkgo extract and placebo in terms of reported adverse
events.3
“Our products are tested extensively
and EGb 761 is in fact [one of the] best researched herbal extracts worldwide,”
said Dr. Weber. “From numerous clinical and preclinical trials and also by the
sheer number of users we know for sure that it is a very safe product.”
Dr. Cott says that despite the
conventional medications or supplements one is taking, safety and tolerability
should be a primary concern. “One should always do this risk/benefit analysis when considering a
medication,” he said. “In a situation where one weighs the potential benefits
against the known side effects and/or harms, ginkgo is a strong contender.”
—Tyler Smith
References
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Association website. Available at: www.alz.org/alzheimers_disease_what_is_alzheimers.asp.
Accessed October 26, 2012.
2. About Alzheimer’s disease: Alzheimer’s
basics. National Institute on Aging website. Available at: www.nia.nih.gov/alzheimers/topics/alzheimers-basics.
Accessed October 26, 2012.
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Long-term use of standardized Ginkgo biloba extract for the prevention of
Alzheimer’s disease (GuidAge): a randomized placebo-controlled trial. The Lancet Neurology. 2012;11(10):851-859.
Available at: www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70206-5/abstract.
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