Researchers, herbal experts interpret results of the five-year GuidAge clinical trial
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)
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, NSAIDs, [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 percent ginkgo flavone glycosides
and 6 percent 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 physician. 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 percent 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 percent 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, was
also 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 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 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 extract 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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