GINKGO BILOBA LEAVES AND EXTRACTS ARE WIDELY used over-the-counter preparations marketed in the United States as food supplements or nutraceuticals, and as such, explicit health claims are not listed in their labeling. In other countries and in the popular press, G biloba is advocated for the treatment of a broad and seemingly ever-increasing range of medical conditions. The extract used in the Ginkgo Evaluation of Memory (GEM) study reported in this issue of JAMA by DeKosky and colleagues and in many other clinical and preclinical studies is Ginkgo extract EGb 761 (Schwabe Pharmaceuticals, Karlsruhe, Germany). The extract is standardized to contain 2 major constituents: 22% to 27% flavonoids and 5% to 7% terpene lactones (ginkgolides and bilobalide). Unique to G biloba trees, the terpene lactones consist of several ginkgolides and bilobalide. The flavonoids and ginkgolides have protean biological activity in preclinical research. The flavonoids are active as antioxidants and appear neuroprotective. Ginkgolide B is a potent antagonist of the platelet activating factor receptor. Ginkgolides A and J variously inhibit hippocampal neuron dysfunction and neuronal cell death caused by amyloid beta protein-42 (A 42). Ginkgolides A and J decrease A 42-induced pathological behaviors, enhance neurogenesis in animal models of Alzheimer disease, and inhibit A aggregation, providing considerable rationale for G biloba extracts as potential treatments for Alzheimer disease. Some of the components of G biloba extract are as active in preclinical models of neurodegeneration and Alzheimer disease as new drug candidates being developed by pharmaceutical companies and some research universities. The GEM trial involved 3069 participants who were not cognitively impaired or had mild cognitive impairment and were randomized to receive EGb 761 (120 mg twice daily) or identically appearing and tasting placebo and were followed up for the onset of dementia. The main results were that use of EGb 761 over the median follow-up period of 6.1 years did not delay the onset of dementia due to any cause including Alzheimer disease specifically. The hazard ratios for all-cause dementia (1.12 [95% confidence interval {CI}, 0.94-1.33]) and for Alzheimer disease (1.16 [95% CI, 0.971.39]) numerically favored placebo and the lower limits of the 95% CIs were not compatible with any potentially meaningful level of dementia risk reduction. The investigators also found no favorable effects of EGb 761 for reducing cardiovascular serious adverse events or total mortality, 2 of 4 secondary outcomes. The relationship of ginkgo extract use and cardiovascular disease is potentially more complex, however, in that the 25% of participants with cardiovascular disease prior to randomized treatment showed increased risk for developing dementia with EGb 761 treatment (hazard ratio, 1.56 [95% CI, 1.14-2.15], P=.006). Moreover, the infrequently occurring serious adverse events of hemorrhagic stroke favored placebo—8 events with placebo vs 16 events with EGb 761—although the difference was not statistically significant. Furthermore, this difference appeared inconsistent with the similarly infrequent incidence of vascular dementia (by definition dementia subsequent to stroke) that favored EGb 761, 17 placebo cases vs 7 with EGb 761 (hazard ratio,0.41 [95% CI, 0.17-0.98], P=.05). These 2 latter observations may be the result of chance, often seen in post hoc analyses of very few events. The former observation, however, suggests 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. Although DeKosky and colleagues do not report results of their 2 other secondary outcomes—overall cognitive decline and functional disability—it is unlikely that a trial with no difference in dementia outcomes would yield significant benefits in the cognitive and functional impairments that define the dementia outcomes. Nevertheless, the effects of EGb 761 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 over the long term.
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Jan 5, 2014
Rachel F Long + 1
Open Access