Systematic Review/Meta-analysis of Ginkgo Use in Cognitive Impairment and Dementia

EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) is a standardized ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract. It contains 22-27% flavonol glycosides, 5-7% terpene lactones, and < 5 ppm ginkgolic acids. Studies indicate that EGb 761 may be especially beneficial to patients with dementia plus neuropsychiatric symptoms (NPS). Hence, the objective of this systematic review and meta-analysis was to evaluate the effects of EGb 761 in patients with cognitive impairment or dementia and patients with NPS.

The following databases were searched from inception through March 2014: MEDLINE, EMBASE, PsycINFO, CINAHL, Cochrane Database of Systematic Reviews, and the Cochrane Controlled Trials Register. In addition, the following were searched: conference proceedings, abstracts, thesis dissertations, poster presentations, and materials from professional society meetings. The following search terms were used to identify relevant controlled trials on dementia, Alzheimer’s disease (AD), and cognitive impairment: Ginkgo* or Gingko* or EGB761 or “EGB 761” or EGB-761.

Included studies met the following criteria: (1) randomized, double-blind, parallel-group, placebo-controlled study with EGb 761; (2) patients with diagnosis of AD, vascular dementia (VaD), or mixed dementia according to the International Classification of Diseases (ICD), the Diagnostic and Statistical Manual of Mental Disorders (DSM), the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), or the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN); age-associated memory impairment according to the diagnostic criteria proposed by Crook et al.1; or mild cognitive impairment (MCI) according to international consensus criteria proposed by Winblad et al.2; (3) treatment duration of 22-26 weeks; (4) >10 patients/group; and (5) at least one measure of cognition, function, behavior, or global assessment of change. Excluded studies had “fatal flaws” in the study design or data analysis, according to the authors; also excluded were trials whose data were not readily available. A meta-analysis was conducted with the whole population, and subgroup analyses were conducted for the NPS population and AD population.

A total of 126 studies were identified, and nine studies met all inclusion/exclusion criteria. A total of 2561 patients were included in these studies, which were conducted in the United States (n = 2 studies), Ukraine (n = 2 studies), Russia or Russian-speaking countries (n = 2 studies), Germany (n = 1 study), Italy (n = 1 study), and the Netherlands (n = 1 study). The studies included patients with AD (n = 8 studies), VaD or mixed dementia (n = 6 studies), age-associated memory impairment (n = 1 study), MCI (n = 1 study), and NPS (n = 5 studies). [Note: This information comes from an error made in a previous study. Actually, only four studies enrolled patients with clinically significant NPS; all four studies used the Neuropsychiatric Inventory (NPI). One study rigorously excluded all patients with clinically significant NPS. In this study, even the mild, not clinically significant NPS were found to be effect modifiers. The other studies neither required nor strictly excluded clinically significant NPS.]

Cognition was evaluated in nine studies. The studies used different measures to assess cognition. To enable a meta-analysis, the Syndrom-Kurztest (SKT) scores were transformed to the Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-cog). Significantly better cognition scores were associated with EGb 761 240 mg/day (P < 0.00001, six studies), 160 mg/day (P < 0.00001, two studies), and all doses pooled (P < 0.00001, eight studies), compared with placebo. A subgroup analysis of NPS studies showed that EGb 761 240 mg/day was significantly better than placebo (P < 0.00001, four studies). A subgroup analysis of AD studies showed comparable results to the whole group analysis.

Functional outcome (i.e., activities of daily living [ADL]) was evaluated in seven studies. Significantly better ADL scores were associated with EGb 761 240 mg/day (P < 0.00001, six studies) and all doses pooled (P < 0.00001, seven studies), compared with placebo. A subgroup analysis of NPS studies showed that EGb 761 240 mg/day was significantly better than placebo on ADL (P < 0.00001, three studies). A subgroup analysis of AD studies showed comparable results to the whole group analysis.

Global assessment of change was measured with the Clinical Global Impression (CGI) and Clinical Global Impression of Change (CGIC) scales in eight studies; however, data could be extracted from only five studies. Significantly better CGI/CGIC scores were associated with EGb 761 240 mg/day (P < 0.00001, four studies) and all doses pooled (P < 0.00001, five studies) compared with placebo, but not with EGb 761 120 mg/day compared with placebo. A subgroup analysis of NPS studies showed that EGb 761 240 mg/day was significantly better than placebo on CGI/CGIC (P < 0.00001, three studies). A subgroup analysis of AD studies showed comparable results to the whole group analysis.

Behavioral outcome measured with NPI was included only in the four studies in the NPS subgroup. EGb 761 240 mg/day was significantly better than placebo on NPI (P < 0.00001, four studies).

Heterogeneity was high for all measures, which was attributed to two studies with large treatment effects favoring EGb 761. When these studies were excluded from the meta-analyses, the high heterogeneity was reduced and the significant treatment effects were still evident for all outcome measures.

The overall frequency of adverse events was similar between groups for the whole group analysis and subgroup analyses. EGb 761 treatment was associated with significantly lower incidence of dizziness (P = 0.0003, three studies), tinnitus (P = 0.0008, three studies), headache (P = 0.009, five studies), and angina pectoris (P = 0.01, two studies).

The authors conclude that the “[m]eta-analyses of these placebo-controlled trials of 22-26 weeks duration show the overall benefits of EGb761 for stabilizing or slowing decline in cognition, function, behavior and clinical global change of patients with dementia and cognitive impairment.” The data show that 240 mg/day EGb 761 is effective for patients with NPS and AD. The data are consistent with other meta-analyses; however, this study has a more comprehensive subgroup analysis. The benefits and safety of EGb 761 support its use in this population. This study was funded by grants from the National Natural Science Foundation of China and Shandong Provincial Natural Science Foundation, China.

References

1Crook TH, Larrabee GJ, Youngjohn JR. Diagnosis and assessment of age-associated memory impairment. Clin Neuropharmacol. 1990;13(Suppl 3): S81-S91.

2Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment – beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256(3):240-246. 

Tan M-S, Yu J-T, Tan C-C, et al. Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis. 2015;43(2):589-603.

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