November 20, 2008 — Results of a randomized trial show no beneficial effect of Ginkgo biloba in the prevention of Alzheimer's disease or dementia in subjects with normal cognition or in those with mild cognitive impairment.
The findings from the Ginkgo Evaluation of Memory (GEM) trial are published in the November 19 issue of the Journal of the American Medical Association.
The results of this trial are published hard on the heels of a negative trial with other supplements, vitamin E and vitamin C, in the prevention of cardiovascular disease and stroke in the Physicians' Health Study II. Results of that study were published in the November 12 issue of the Journal of the American Medical Association and were reported at the American Heart Association Scientific Sessions 2008. A second analysis looking at cancer was reported this week at the American Association on Cancer Research prevention conference and, similarly, showed no benefit of either agent in the prevention of cancer.
These outcomes underline the importance of randomized controlled clinical trials to assess the safety and efficacy of these agents, said GEM study coauthor Steven T. DeKosky, MD, from the University of Pittsburgh in Pittsburgh, Pennsylvania, and now is at the University of Virginia School of Medicine in Charlottesville.
"One of the major outcomes of this study is we proved you can actually do the study," he told Medscape Neurology & Neurosurgery. GEM is among the first trials that recruited a new cohort to look at a cognitive outcome using a supplement to actually finish and report findings. "It's disappointing," he says of their results, "but it's the way the science has to be done. The design would have been identical if it were a medication from a major pharmaceutical company, and not an over-the-counter alternative medication."
Preservation of Memory
In their study, the authors note that G biloba is prescribed in some areas of the world for the preservation of memory, although no medications are approved for the primary prevention of dementia. In the United States, worldwide sales of G biloba exceed $249 million annually.
The purported effect of G biloba is by the action of multiple antioxidants, although a recent in vitro study also suggested that has an antiamyloid aggregation effect, they note. Studies of G biloba in the setting of dementia have had mixed results, although a Cochrane Collaboration Review in 2007 found the evidence of a benefit, "not convincing," the study authors write.
The current study was a randomized, placebo-controlled clinical trial carried out at 5 academic medical centers in the United States to see whether treatment with G biloba in a dose of 120 mg 2 times/day could prevent incident dementia or Alzheimer's disease vs placebo. A total of 2587 subjects older than 75 years with normal cognition at baseline, and 482 subjects with mild cognitive impairment were included. Patients were assessed every 6 months for dementia.
After a median follow-up of 6.1 years, 523 subjects were diagnosed with dementia, 246 (16.1%) in the group taking placebo, and 277 (17.9%) in those taking G biloba. Of the total dementia cases, 92% were classified as possible or probable Alzheimer's disease or Alzheimer's disease with evidence of cerebrovascular disease.
The rate of total dementia did not differ between groups, with 3.3 vs 2.9 cases per 100 person-years with G biloba vs placebo. The rates of Alzheimer-type dementia were also similar, at 3.0 vs 2.6 cases per 100 person-years with G biloba vs placebo.
Table 1. GEM: Risk for Dementia and Alzheimer's Disease With Ginkgo Biloba vs Placebo*
Endpoint Hazard Ratio 95% CI P value
All-cause dementia 1.12 0.94 - 1.33 .21
Alzheimer's disease 1.16 0.97 - 1.39 .11
*GEM indicates Ginkgo Evaluation of Memory.
Similarly, there was no effect of treatment on the rate of progression to dementia in those with mild cognitive impairment.
Table 2. GEM: Risk for Dementia With Ginkgo Biloba vs Placebo in Patients With Mild Cognitive Impairment*
Endpoint Hazard Ratio 95% CI P value
All-cause dementia 1.13 0.85 - 1.50 .39
*GEM indicates Ginkgo Evaluation of Memory.
Adverse events were similar between groups, and there was no statistically significant difference in the rates of serious adverse events or mortality. Of note, there was no difference in the rates of major bleeding between groups or in the bleeding incidence in those taking aspirin.
Because of previous concerns about possible bleeding risk with G biloba, the protocol called for discontinuation of the study drug with the institution of warfarin therapy that resulted in the dropout of 214 subjects: 112 in the G biloba and 102 in the placebo group.
There were twice as many hemorrhagic strokes in the G biloba group vs placebo (16 vs
, but the number of cases was small and was not significant in this analysis, they note. The study authors suggest this effect should be explored in future studies.
An exploratory analysis did show a statistically significant interaction with treatment for those with a history of cardiovascular disease at baseline, with a hazard ratio (HR) of 1.56 (P = .006) with treatment vs placebo. This higher rate, they write, "is puzzling and should be viewed with caution," given the lack of evidence from basic science of a mechanism.
"What we take away from this is that it's safe, which is useful if there are other uses found for it," Dr. DeKosky said. For example, G biloba is also being investigated in the treatment of tinnitus, he noted.
They are also interested to see the results from the GuidAge trial being conducted in France, which is similar in size and scope and is using the same dose of the same standardized preparation but is not expected to report for another year. "I don't have high expectations of course that it will have something different than what we found, but it's another study looking at prevention," he said.
"Untenable" to Recommend Without Evidence
In an editorial accompanying the publication, Lon S. Schneider, MD, from the University of Southern California, Los Angeles, points out that the GEM trial is the largest and longest trial that "comprises the substantial bulk the non–industry-funded, placebo-controlled clinical database for G biloba extract" and provides no evidence that it contributes to clinically meaningful dementia risk reduction.
There was no reduction either in cardiovascular serious adverse events or in total mortality rates — 2 secondary endpoints of the trial, Dr. Schneider notes. The relationship with cardiovascular disease, though, is "potentially more complex," he adds, in that subgroup analyses showed an increased risk for dementia in those with cardiovascular disease at baseline and a nonsignificant increase in hemorrhagic stroke with treatment, although vascular dementia was lower with G biloba.
Although these observations may be the result of chance, they suggest that, "at least in patients aged 75 years or older with cardiovascular disease, G biloba may have risks and the decision to use this agent should be carefully considered," he writes.
"Users of this extract should not expect it to be helpful," Dr. Schneider concludes. "Moreover, the potential adverse effects of G biloba extract illustrate why it is untenable to recommend a drug or nutraceutical in the absence of efficacy evidence simply because it could possibly help and initially appears harmless."
Dr. Schneider added that results for 2 other secondary outcomes — overall cognitive decline and functional disability — are not reported in this study, although he speculates that it is unlikely that they are positive in the setting of an overall negative trial. Nevertheless, the effects of treatment on actual cognitive test scores and daily function ratings "are important because individuals without cognitive impairment who use G biloba may expect it to noticeably improve their intellectual function over the short term but not necessarily to prevent Alzheimer disease or other dementia in the long term."
Dr. DeKosky noted that these 2 secondary endpoints will be published at a later date. The follow-up testing on these endpoints was less sensitive to small changes in cognitive function, he explains. "We are going to look at those data and see if we can find something in there that gives us a signal, but that actually turns out to be a bit more complicated an analysis, and so we knew we would not be able to put it into this study in which there were some singular outcome and safety issues that we knew everyone would want to know about," he said.
The trial was supported by the National Center for Complementary and Alternative Medicine; the Office of Dietary Supplements and National Institute on Aging; National Heart, Lung, and Blood Institute; University of Pittsburgh Alzheimer's Disease Research Center; Roena Kulynych Center for Memory and Cognition Research; Wake Forest University School of Medicine; and the National Institute of Neurological Disorders and Stroke. Schwab Pharmaceuticals, Karlsruhe, Germany, provided the G biloba tablets and placebo in identical packaging. Dr. DeKosky has received grants or research support from Elan, Myriad, Neurochem, and GlaxoSmithKline and has served on the advisory boards of, or consulting for, AstraZeneca, Abbott, Baxter, Daichi, Eisai, Forest, Genentech, GlaxoSmithKline, Lilly, Medivation, Merck, NeuroPharma, Neuroptix, Pfizer, Myriad, and Servier. The other study authors have disclosed no relevant relationships.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
1. Describe the effect of Ginkgo biloba on all-cause dementia in elderly patients with and without mild cognitive impairment.
2. Describe the effect of Ginkgo biloba on Alzheimer's disease.
Dementia is a chronic illness affecting more than 5 million people in the United States and is a leading cause of age-related disability. The herbal product G biloba has been proposed as an agent that may protect against cognitive decline by its multiple antioxidative actions and antiamyloid effect. However, randomized clinical trials of G biloba are needed to assess its role in the primary prevention of dementia.
This is a randomized, double-blind, placebo-controlled trial to examine the effect of G biloba supplementation on dementia, Alzheimer's disease, and cognitive decline in elderly adults.
* Included were volunteers aged 75 years or older from 5 academic centers in 4 US communities with normal cognitive function or mild cognitive impairment.
* Excluded were those with a diagnosis of dementia or psychiatric disease; those taking cholinesterase inhibitors or other agents for cognitive problems or dementia; those with Parkinson's disease and other degenerative neurologic disease; and those with abnormal thyroid function, cardiovascular disease, or bleeding disorders.
* 1545 participants were randomly assigned to receive 120 mg twice daily of G biloba standardized extract (a high-potency dose) and 1524 to placebo.
* Among those randomly assigned, 2587 had normal cognition and 482 had mild cognitive impairment.
* Treatment adherence was tracked by counting pills in blister packs.
* Primary outcome was a diagnosis of dementia or Alzheimer's disease with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria.
* Secondary outcomes were overall cognitive decline and function, cardiovascular disease, and total mortality rate.
* The baseline battery of tests included memory, construction, language, attention/psychomotor speed, executive functions, and premorbid intellectual functioning.
* Participants were recruited for 2 years and were followed up for a median of 6.1 years.
* During follow-up, participants were tested every 6 months. If dementia was diagnosed, they were assigned to one of the following categories: Alzheimer's disease; Alzheimer's and vascular dementia; vascular dementia only; and dementia, other cause.
* Mean age at baseline was 79 years, 46% were women, 95% were white, one quarter had any history of cardiovascular disease, and 10% had a history of myocardial infarction.
* During the intervention period, dementia developed in 523 participants: 246 (16.1%) in the placebo group and 277 (17.9%) in the G biloba group.
* 92% were classified as having Alzheimer's disease.
* 6.3% were lost to follow-up.
* Adherence was 60.3% and did not differ between assigned groups.
* The cumulative rate of all-cause dementia was not statistically significantly different in the 2 groups: 3.3 vs 2.9 per 100 person-years (HR, 1.12 for G biloba vs placebo).
* The rate of Alzheimer's disease did not differ significantly between the 2 groups.
* There was no effect of modification by age, sex, or mild cognitive impairment.
* For a small subgroup with baseline cardiovascular disease, the HR for dementia in the G biloba group was 1.56 (P = .006), and there was no difference for those without baseline cardiovascular disease.
* There was no indication of interaction between apolipoprotein E status and treatment.
* Rates of adverse events were similar between the treatment and placebo groups.
* There were no differences in rate of coronary artery disease.
* The authors concluded that 240 mg of G biloba daily for 6 years was not effective in reducing the incidence of dementia in elderly patients with normal or mildly impaired cognition.
Pearls for Practice
* Use of 240-mg G biloba daily in elderly patients is not associated with reduced risk for all-cause dementia in those with normal or mildly impaired cognition.
* Use of 240-mg G biloba daily in elderly patients is not associated with reduced risk for Alzheimer's disease.
According to the study by DeKosky and colleagues, which of the following best describes the effect of 240 mg of G biloba daily in elderly patients?
G biloba reduces the rate of dementia in those with mild cognitive impairment
G biloba has no effect on dementia in those with normal cognition
G biloba reduces dementia rate in women only
G biloba slows dementia rate in those with dementia
According to the study by DeKosky and colleagues, G biloba may have an effect on rate of Alzheimer's disease in which of the following groups of elderly patients?
Those with baseline cardiovascular disease
Those with mild cognitive impairment
Those with a positive family history of Alzheimer's disease
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is News Editor for Medscape Neurology & Neurosurgery. She has been writing principally for physician audiences for nearly 20 years. Most recently, she was news editor of thekidney.org and also wrote for theheart.org; both of these Web sites have been acquired by WebMD. Prior to that, she spent 10 years covering neurology topics for a Canadian newspaper for physicians. She can be contacted at sjeffrey [at] medscape.net.
Disclosure: Susan Jeffrey has disclosed no relevant financial relationships.
Désirée Lie, MD, MSEd
Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California
Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.