Alzheimer disease (AD) is a neurodegenerative disease and the most common cause of dementia. Its characteristic symptoms include difficulties with memory, language, problem solving, and other cognitive skills that affect a person's ability to perform everyday activities. It is related to age, family history, and apolipoproteins E (APOE)-e4 gene.1 A total of 5.7 million Americans of all ages were estimated to be living with Alzheimer dementia in 2018. One in 10 people (10%) 65 years and older has Alzheimer dementia.2 Alzheimer disease not only seriously affects the quality of life of patients but also brings a heavy burden to the family and society.
No current medications can cure AD or stop the progression of AD. Some symptomatic treatments, such as memantine, donepezil, galantamine, and rivastigmine, may be beneficial in lessening memory loss and confusion. In the 1960s, scientists from Germany and France extracted ginkgo flavonoids and ginkgolide from the leaves of Ginkgo biloba (GB), which have protective effects against cardiovascular and cerebrovascular diseases and antiaging effects and might be effective in the treatment of AD.
Several systematic reviews have been performed on the use of Ginkgo biloba in treating cognitive impairment and dementia.3–7 However, most of them enrolled patients with mixed cognitive impairment (including mild cognitive impairment and other memory loss) or dementia (including AD, vascular dementia, or mixed dementia), or they compared Ginkgo biloba and other drugs.
This meta-analysis assessed the efficacy and safety of Ginkgo biloba by extracting data from selected randomized controlled trials (RCTs) published in both English and Chinese language journals.
According to the PICOS acronym, the following selection criteria were used:
- (1) Participants (P): Participants diagnosed with any one of the following criteria as AD were included, regardless of severity and disease course: (a) the Diagnostic and Statistical Manual of Mental Disorder III or IV or (b) the National Institute of Neurological and Communicative Disorder and Stroke-Alzheimer Disease and Related Disorder Association.
- (2) Intervention (I) and Comparison (C): Ginkgo biloba versus placebo or other single drug + Ginkgo biloba versus other single drugs.
- (3) Outcomes (O): At least one of the following items is included: (a) efficacy and (b) the adverse events of the drug.
- (4) Study design (S): Randomized placebo-controlled, trials. Languages include Chinese and English.
Repeated publication; lack of access to the full text; case reports, reviews, and systematic evaluation; inability to extract data; animal experiments; and subjects with severe organ failure.
Major English (PubMed, Embase, Cochrane Library databases, and the Cochrane Controlled Trials Register) and Chinese databases (WanFang Database, Chinese Biomedical Database, Chinese Scientific Journals Database, and China Network Knowledge Infrastructure) were searched from their inception until July 3, 2019. At the same time, the relevant literature is searched manually to supplement them.
The English search terms included “ginkgo biloba*,” “Ginkgo biloba extract*,” “GBE 761,” “Alzheimer disease*,” “senile dementia,” “randomized controlled trial,*” and “randomized.” The Chinese search terms included “a_er_ci_hai_mo_bing,” “lao_nian_chi_dai,” “a_er_ci_ hai_mo_shi_bing,” and “lao_nian_xing_chi_dai,” Ginkgo biloba (“yin_xing_ye_zhi_ji,” “yin_xing_ye”), and randomized (“sui_ji_dui_zhao,” “sui_ji”). The search details are listed in the supplement (available online as supplemental digital content at http://links.lww.com/CNP/A13).
Assessment of Study Quality
Two evaluators used the modified Jadad scale to evaluate the quality of the literature (1–3 points for low quality and 4–7 points for high quality).8 Low-quality articles were screened out, and high-quality articles were included. The Cochrane Risk of Bias Tool was used to assess the risk of bias of included RCTs.9 We assessed 6 biases accordingly, namely, selection bias (random sequence generation and allocation concealment), performance bias and detection bias (blinding), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and other bias. We categorized each item into low, unclear, or high risk of bias.
Data Synthesis and Statistical Analyses
According to the recommendations of the Cochrane Collaboration Review, Review Manager Version 5.3 (http://www.cochrane.org) and STATA Version 14.0 (http://www.stata.com/) were used to perform meta-analyses. For dichotomous data, risk ratio (RR) ±95% confidence interval (CI) was calculated. For ordered data, odds ratio (OR) value of ±95% CI was calculated. Study heterogeneity was measured using I2, with I2 values greater than 50% indicating heterogeneity. Funnel diagrams and Egger tests could not be used to test for publication bias because of the small number of studies that were included.
As shown in Figure 1, a total of 756 related literatures were searched, 19 articles were obtained after screening, and 12 low-quality documents (≤3 points, the main reasons for low score include: random sequence generation not clear, allocation concealment not described, or blind method not used. For details, see the Supplementary Table, http://links.lww.com/CNP/A13) were removed by using the modified Jadad score. Seven RCTs articles were included in the meta-analysis.11–17
Seven studies were included, all in English. The selected studies met the inclusion criteria and were double-blind RCTs. A total of 939 patients were included in 7 articles, including 352 male patients and 687 female patients. In the 7 studies, the duration of drug treatment ranged from 3 months to 26 weeks. All the drugs used were standard Ginkgo biloba extract EGb 761. The dosage of drugs included 120, 160, and 240 mg/d. One of the studies compared the efficacy of Ginkgo biloba preparations alone, donepezil alone, and the combination of the 2 drugs. We included data from the combination group and donepezil alone for analysis. Other studies compared the efficacy of Ginkgo biloba preparation and placebo. Details of the included literature are shown in Table 1.
Risk of Bias Assessment
Seven studies described in detail the method of random allocation with the use of the computer generated random sample set, and all of them were double-blind experiments. Four experiments described the allocation hiding method. All studies reported the number of withdrawal patients and the reasons for withdrawal, including adverse drug reactions, loss of follow-up, and the use of drugs prohibited under the agreement. Overall, all the included studies were of high quality (Figs. 2, 3).
We evaluated the efficacy of the drug based on the cognitive function, activities of daily living (ADLs), and global clinical assessment mentioned in the article.
Cognitive Function and ADLs
Three studies used the Alzheimer Disease Assessment Scale-cognitive section18 and one study used Syndrom Kurz Test (SKT)19 to assess cognitive function. The effectiveness was judged by the change of scores before and after treatment (Alzheimer Disease Assessment Scale-cognitive section or SKT score decreased by at least 4 points). Two studies were based on the Geriatric Evaluation by Relative's Rating Instrument,20 the Gottfries–Bråne–Steen (GBS)21 Scale subscore of ADLs, and GBS Scale to determine the improvement of ADLs.
Four studies (7 data sets) were included. The heterogeneity test showed that I2 = 52.4 > 50%, and P = 0.050 < 0.1 of Q test, suggesting that existed heterogeneity between the selected literature (Fig. 4). The L‘Abbé is inspected, as shown in Figure 5. Sensitivity analysis was performed on data from 4 studies (Fig. 6). In view of the different types of scales, the scales were divided into 2 groups and meta-analysis was conducted on each one (group 1 used cognitive function averaging and group 2 used daily living ability assessment). The results were as follows (Fig. 7):
For group 1, I2 = 12.4 < 50%, P = 0.331 > 0.1, indicates no heterogeneity (RR = 1.983, 95% CI = 1.521–2.585, Z = 5.05, P < 0.001). For group 2, I2 = 0 < 50%, P = 0.624 > 0.1, indicates no heterogeneity (RR = 1.089, 95% CI = 0.828–1.432, Z = 0.61, P = 0.542).
This finding indicates that Ginkgo biloba preparation had a certain effect (during a period of 3 months to 26 weeks in the trials), unlike placebo in cognitive function. However, the effect on daily functioning is uncertain.
Global Clinical Assessment
Three studies used the Clinical Global Impression Change (CGIC)22 score to determine global clinical assessment. The degree of change was divided into improvement, no change, and deterioration. The CGIC is not included in this analysis because a study classifies CGIC as improved or unchanged and deteriorated, and no specific improvement or unchanged population can be achieved. The included data were meta-analyzed (Fig. 8). After heterogeneity test, I2 = 31.1% < 50%, P = 0.234 > 0.1, in Q test (OR = 3.119, 95% CI = 2.206–4.410, Z = 6.44, P < 0.001), indicates that the efficacy of Ginkgo biloba preparation is better than that of placebo.
One study reported that no adverse reactions were observed during treatment. Four studies reported the types of adverse reactions; 3 studies reported in detail the number of adverse reactions and the number of events, and one study reported the types and quantities of adverse reactions of different doses of Ginkgo biloba preparations. Common adverse reactions include dizziness, headache, upper respiratory tract infections, and agitation, and most adverse events were considered of mild intensity. No serious adverse reactions related to Ginkgo biloba preparations were reported in all trials.
A meta-analysis of the number of patients with adverse reactions showed that I2 = 0 < 50%, P = 0.776 > 0.1, RR = 0.916, 95% CI = 0.840–0.998, Z = 2.00, P = 0.046, which indicated that Ginkgo biloba preparation had better safety (Fig. 9).
Summary of Evidence
In this article, the efficacy of Ginkgo biloba preparation in the treatment of AD was systematically and comprehensively reviewed and meta-analyzed. The results of 5 studies directly showed that Ginkgo biloba preparations had a certain effect (during a period of 3 months to 26 weeks in the trials) on AD and whether it had effects was independent of drug dosage. However, a study did not find a clear difference between the Ginkgo biloba preparation group and the placebo group. This result may be related to the slow deterioration of the disease in the control group. After subgroup analysis of AD patients with psychiatric symptoms, the efficacy of Ginkgo biloba preparation was concluded to be better than that of placebo, and the difference was statistically significant. Another study compared the treatment differences between Ginkgo biloba preparation combined with the donepezil group and the donepezil-alone group and found no significant difference. However, the study compared the Ginkgo biloba preparation group with the donepezil-alone group and found no significant difference. Therefore, the authors believe that Ginkgo biloba preparation has the same effect as donepezil in the treatment of AD, and it has a certain effect in the treatment of AD.
Previously, a systematic review evaluated the efficacy of Ginkgo biloba preparations in the treatment of AD considering 6 studies. The results showed that 240 mg of Ginkgo biloba preparations could improve patients' daily living ability and may be beneficial in slowing down the deterioration of cognitive function and mental symptoms.5
In this review, the effects of Ginkgo biloba preparation on cognitive function and clinical changes of AD patients were analyzed. Through an analysis of the included data, Ginkgo biloba preparation is concluded to have a certain efficacy in improving the above symptoms, as well as good security. However, when we analyzed the ability of daily life, no difference was found between Ginkgo biloba preparation and placebo, which may be related to the limited data we included.
Some studies have shown that ginkgolides contained in Ginkgo biloba preparations have antioxidant and anti-apoptotic biological activities as well as significant promoting and protecting effects on the development of brain neurons.23–25 Ginkgo flavonoids can improve the level of acetylcholine and monoamine transmitters in brain tissue, increase the activity of superoxide dismutase in brain tissue, scavenge free radicals, resist lipid peroxidation, reduce apoptosis in brain tissue, and protect brain function.26
Our systematic review has some limitations. (1) Some differences exist in AD diagnostic criteria, dosage, course of treatment of Ginkgo biloba preparations, and selection of dementia scale, which may lead to bias, thus affecting outcome indicators. (2) Subgroup analysis of all studies was not conducted according to dosage because of limited data. (3) No further analysis was performed for all studies. The efficacy on other symptoms (such as psychiatric symptoms) of patients was analyzed. (4) There was a lack of discussion about the size effect of Ginkgo biloba formulations, because only studies with placebo were included, such as cholinesterase inhibitors and memantine and other nonpharmacological interventions such as cognitive rehab and enhanced physical activity. This deserves further discussion in future analysis. (5) No publication bias test was conducted because of the small number of studies, which may have an impact on the reliability of data. Moreover, only 7 studies that meeting the standards are included. No long-term study is involved. Therefore, this meta-analysis only proves that the ginkgo leaf preparation can alleviate the AD symptoms in the short term. The results do not suggest that the preparation can modify the disease. The modifying effect of the preparation needs to be further discusses in the studies at larger scale and with a longer duration.
Therefore, the overall conclusions tend to be weak. In the future, additional large samples and multicenter RCTs with high-quality meta-analysis should be included.
The evaluation of this system shows that Ginkgo biloba preparation can improve the cognitive function and overall improvement of AD patients and that it has good safety, indicating that Ginkgo biloba preparation is a safe and effective drug for AD. However, because of the limited number of samples, the evidence supporting this conclusion may not be strong.
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