The Efficacy of Ginseng (Panax) on Human Prediabetes and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Results from different clinical trials on the effects of ginseng on prediabetes and type 2 diabetes (T2DM) are still inconsistent. To fill this knowledge gap, we investigated the overall effects of ginseng supplementation on improving cardiometabolic biomarkers among these patients. A systematic literature search was conducted on PubMed/MEDLINE, Scopus, Web of Science, and Cochrane library. A random-effect model was applied to estimate the weighted mean difference and 95% CI for each outcome. Overall, 20 eligible RCTs were included. Meta-analyses revealed that ginseng supplementation significantly reduced serum concentration of FPG, TC, IL-6, and HOMA-IR values. It also increased HR and TNF-α levels. Ginseng supplementation changed HOMA-IR and HDL-C significantly based on dose and changed HOMA-IR and LDL-C significantly based on study duration in a non-linear fashion. Furthermore, meta-regression analyses indicated a linear relationship between ginseng dose and absolute changes in HDL-C. Moreover, subgroup analyses showed that ginseng supplementation changed TC and LDL-C when the supplementation dose was ≥2 g/day. Our findings suggest that ginseng supplementation may be an effective strategy for improving cardiometabolic profiles in individuals with prediabetes and T2DM.


Study Selection and Eligibility Criteria
All recorded articles from electronic or manual searches were imported into Endnote software for further review. Titles and abstracts of all articles found in the initial search were reviewed independently by two researchers (S.S. and K.N.). Discussion with a third reviewer (O.A.) resolved disagreement regarding full-text eligibility. To determine article eligibility, we employed the population, intervention, comparison, outcome, and study design (PICOS) framework (Table 1). Studies were excluded from this investigation if they: (1) co-administered ginseng as a part of a mixed intervention; (2) lacked a suitable control; (3) had no viable end-point data in ginseng or control groups; (4) were carried out on children, pregnant women, or animals; and (5) were performed less than 4 weeks in duration. In addition, conference abstracts, gray literature, unpublished studies, and protocols were not included.

Parameter Inclusion Criteria
Population Individuals older than 18 years and with physician's diagnosis of impaired glucose tolerance or prediabetes or T2DM Intervention Administration of ginseng in different chemical forms including capsule, tablet, and powder Comparator Comparison with placebo, usual care, or any pharmacological or non-pharmacological intervention(s)

Data Extraction
The following information was extracted from each eligible clinical trial by two independent researchers: study author; year of publication; study location; study design; the number of participants; participants' ethnicity, age, comorbidities, and body mass index; the type, dose, duration, and frequency of the intervention; and the study results (mean or median with standard deviations, standard errors, 95% CIs, or interquartile ranges) at study baseline, post-intervention, and/or changes between baseline and post-intervention. If the data for each parameter was reported in different units, we converted them to the most commonly used units.

Quality Assessment
The likelihood of bias in the included RCTs was explored through the Cochrane Risk of Bias Tool for clinical trials [38]. Two independent authors assessed each publication's quality based on the following seven domains: (1) random sequence generation; (2) allocation concealment; (3) selective outcome reporting; (4) blinding of participants and personnel; (5) detection bias (blinding of evaluators); (6) incomplete outcome data; and (7) other probable sources of biases. Based on the Cochrane handbook recommendation, every article was assigned a label of bias (low risk (L), high risk (H), or unclear (U) risk of bias) (Supplementary Table S2).
The quality of the evidence for each result was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach [39]. Two independent reviewers (S.S. and K.N.) graded each outcome based on the risk of bias, inconsistency (heterogeneity), indirectness, and imprecision, as specified in the GRADE guideline [39]. Each outcome was rated high, moderate, low, or very low.

Data Synthesis and Meta-Analysis
We used the mean difference in the changes in the outcome variables (BW, BMI, WC,  FPG, OGTT, HbA1c, fasting insulin, HOMA-IR, TG, TC, LDL-C, HDL-C, SBP, DBP, HR,  CRP, IL-6, TNF-α, ALT, AST, and GGT), comparing ginseng to the control groups, to obtain the overall effect sizes. When mean changes were not reported, we computed them by considering changes in each outcome variable during the trial. We also converted standard errors (SEs), 95% confidence intervals (CIs), and interquartile ranges (IQRs) to SDs using the relevant formulas [40]. We applied a random-effects model that considers betweenstudy variations to obtain the overall effect sizes. Heterogeneity was determined using the I 2 statistic and the Cochrane's Q test. The Q-test's I 2 value > 50% or p < 0.05 was characterized as significant between-study heterogeneity [41,42]. Subgroup analyses were performed to find probable sources of heterogeneity, according to the predefined criteria, including ginseng dosage (≥2/<2 g/day), length of follow-up (>8/≤ 8 weeks), baseline levels of outcome variables (abnormal/normal levels) and participants' baseline BMI level (normal/overweight or obese). Fractional polynomial modeling was executed to determine the potential non-linear effects of ginseng dosage (g/day) on each index. Due to the lack of information on ginseng dosage in some of the included studies, we decided to perform a non-linear dose-response analysis of ginseng administration. Sensitivity analysis was used to determine the extent to which inferences might depend on a particular study. The formal test of Begg assessed the possibility of publication bias. The meta-analysis was performed using the Stata version 11.2 (StataCorp). The p-value < 0.05 was considered statistically significant. Figure 1 illustrates the literature search and screening process performed for this systematic review. Initial database searches for all RCTs of ginseng supplementation yielded 1978 records, of which 540 were duplicates. Eligibility based on title and abstract was assessed for the remaining 1438 articles. Of those, 1236 RCTs were not relevant to the subject, leaving 202 records eligible for full-text review. Furthermore, after excluding 6 studies examining the impact of ginseng in combination with other ingredients due to the impossibility of determining the independent effect of ginseng [43][44][45][46][47][48], 3 eligible studies which reported in a language other than English [49][50][51], 1 study with multiple-crossover, acute dose escalation design [52], and 172 records which did not provide sufficient data and/or did not fulfill the inclusion criteria, 20 RCTs with 24 effect sizes met the inclusion criteria for qualitative synthesis.
The remaining two studies did not report the type of ginseng [29,58]. The dosage of ginseng varied from 0.1-8 g/day, and the duration of intervention differed from 4 to 24 weeks across included RCTs.  Abbreviations: BMI-body mass index; IG-intervention group; CG-control group; R-randomized; PC-placebo controlled; DB-double blind; T2DM-type 2 diabetes mellitus; M-male; F-female; NR-not reported; HTN-hypertention.

Inflammatory Markers and Adipocytokines
Ginseng administration significantly reduced serum IL-6 levels (WMD: −1.  Figure S1) [30]. Subgroup analysis was not conducted for CRP, IL-6, TNF-α, adiponectin, or leptin, as there were not enough studies reported on these parameters (Table 3).  Figure S1) [30]. However, subgroup analyses were not performed for ALT, AST, or GGT due to the limited number of studies that reported liver function tests.

Non-Linear Dose-Response between Dose and Duration of Ginseng Supplementation on Cardiometabolic Indicators
Dose-response analysis showed that ginseng supplementation significantly altered HOMA-IR based on dose (r = −0.26, p-nonlinearity = 0.02) and study duration (r = 7.18, p-nonlinearity = 0.04) in a non-linear fashion. Furthermore, the dose of ginseng affected HDL-C (r = −0.31, p-nonlinearity = 0.009) and duration of intervention affected LDL-C (r = −16.61, p-nonlinearity = 0.04) in a non-linear fashion. No significant associations were observed for other outcomes in non-linear dose-responses (Table 4), (Supplementary Figures S3 and S4).

Meta-Regression Analysis
Meta-regression using the random-effects model was undertaken to investigate the potential association between a change in cardiometabolic indicators and the dose of ginseng (g/day) and the duration of the trial. Meta-regression analysis indicated a linear relationship between dose absolute changes in HDL-C (p = 0.02) but not for other studied outcomes (Table 4), (Supplementary Figures S5 and S6).

Discussion
This meta-analysis evaluated the effects of ginseng supplementation on cardiovascular biomarkers, including anthropometric indices, glycemic and lipid profiles, blood pressure (BP), inflammatory biomarkers, adipocytokines, and liver function indicators among subjects with prediabetes and T2DM. According to the findings of this study, ginseng consumption was associated with a reduction in FPG, HOMA-IR, TC, and IL-6, and escalations in HR and TNF-α, without any significant alterations in anthropometric measurements (BW, BMI, and WC), glycemic responses (OGTT, HbA1c, and fasting insulin), lipid profile (TG, LDL-C, and HDL-C), BP (SBP and DBP), inflammatory markers and adipocytokines (CRP, adiponectin, and leptin), and liver enzymes (ALT, AST, and GGT) when compared with a control group.
A comprehensive review of human trials and in vitro and in vivo studies suggests that ginseng modulates insulin secretion, glucose uptake, and glucose metabolism through inhibition of β-cell apoptosis and raising the production of glucagon-like peptide-1 (GLP-1) to exert anti-diabetic effects [11]. However, in 2011, a systematic review and meta-analysis of four RCTs showed that ginseng intake did not change blood glucose-related indices in patients with T2DM [13]. Furthermore, data from two meta-analyses on the general population suggested conflicting reports regarding ginseng supplementation effects on FPG levels. One study reported significantly reduced levels of FPG following ginseng intake [6], and the other indicated no effect [34]; both confirmed that there was no significant effect of ginseng consumption on fasting plasma insulin and HbA1c. Similar to our results, a recent experimental study revealed that Panax quinquefolius decreased FPG levels and improved insulin resistance (IR) in T2DM [62]. In addition, Gui et al. [63], based on a meta-analysis of eight RCTs, reported that FPG and HOMA-IR were improved by ginseng consumption with no change in OGTT, HbA1c, and fasting insulin in patients with T2DM. Likewise, we extended these findings by pooling the results of 24 effect sizes (n = 1295 participants) and showed that ginseng supplementation significantly improved FPG stronger when the consumption lasted for 8 weeks or more and significantly reduced HOMA-IR values regardless of the length of follow-up. Moreover, as seen in our subgroup analyses, ginseng supplementation had a beneficial effect on the concentration of FPG for either patient with a baseline level of FPG ≥ 126 mg/dL or when the supplementation dosage of ginseng was less than two g/day. Therefore, it seems that the effect of ginseng intake on FPG depends on baseline levels of FPG, dose, and duration of intervention. In dose-response analyses, lower duration and dose of ginseng consumption had a greater lower effect on HOMA-IR values. It is noteworthy that the discrepancies between meta-analyses could be due to different numbers of included studies and various studied populations.
Insulin resistance is the driving factor that leads to the development of T2DM [64]. Long-term IR in adipocytes leads to elevated free fatty acids (FFAs) and an accelerated TG formation, which contributes to dyslipidemia in patients with T2DM [65,66]. A series of pharmacological investigations suggested hypolipidemic effects of ginseng administration, mainly through activating AMP-activated protein kinase (AMPK) among individuals with prediabetes and T2DM [5,22,62,67]. In this study, we have shown that consumption of ginseng reduced TC levels stronger among those with baseline TC < 200 mg/dL and intake of ≥ 2 g/day. Additionally, we found that patients with prediabetes and T2DM had a significantly lower level of LDL-C after consuming ≥2 g/day of ginseng. The subgroup analysis in the current study also suggests that ginseng supplementation reduces serum levels of TG in individuals with baseline TG values < 150 mg/dL. The underlying mechanisms of the lipid-lowering effects of ginseng are still unclear. However, we assumed a possible reason for the relationship between ginseng intake and levels of lipid profile components in our meta-analysis. The steroidal structure of triterpene saponins may alter gene transcription, protein synthesis, and cholesterol production in the liver through inhibition of β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase [68,69], which was also reported as the possible anti-diabetic mechanism of some citrus flavonoids [70]. The meta-regression and dose-response analyses also revealed that the longer the study duration, the greater the effect of ginseng supplementation on lowering LDL-C. The higher the dose, the greater the effect of ginseng supplementation on lowering HDL-C. We found a disparity in findings obtained from previous meta-analyses investigating the efficacy of ginseng administration on lipid profile parameters. One suggested no lipid-lowering effects of ginseng consumption from three previous meta-analyses conducted on healthy and unhealthy individuals [36], while others indicated significant exerted effects of ginseng intake [32,34]. Additionally, a previous meta-analysis that investigated ginseng supplementation in patients with T2DM demonstrated a significant effect of ginseng supplementation on serum TC, TG, and LDL-C levels [63]. The disagreements may be due to different types of ginseng supplements, different target populations, and a limited number of studies included in previous reviews.
Another aspect of the pathogenesis of T2DM is low-grade chronic inflammation. The inflammatory process contributes to IR and, consequently, to T2DM-associated cardiovascular complications [71]. Elevated levels of TNFα have been shown to directly affect insulin receptor signaling and decrease insulin sensitivity [71,72]. Several molecular pathways could be influenced by ginsenosides, manifesting anti-inflammatory effects. The most notable anti-inflammatory mechanisms are inhibition of toll-like receptor four signaling pathway, inhibition of NF-κB signaling pathway, activation of AMPK, and increased nuclear factor erythroid-2-related factor 2 (Nrf2) expression and translocation [73]. A growing body of evidence proposed that ginseng treatment significantly inhibits the expression of inflammatory factors and exerts a protective effect in patients with prediabetes and T2DM [74][75][76]. However, the recent meta-analyses in the general population did not show significant overall effects of ginseng consumption on CRP levels [33,35]. The second study also demonstrated significant reductions in IL-6 and TNF-α following ginseng supplementation [33]. Notably, the current study is the first systematic review and meta-analysis investigating the effectiveness of ginseng supplementation on inflammatory biomarkers in subjects with prediabetes and T2DM. Our meta-analysis was in line with the previous ones concerning CRP and IL-6 changes. However, we observed significantly elevated levels of TNF-α after ginseng consumption. The results of this study should be interpreted cautiously, and more research should be conducted on the effects of ginseng supplementation on inflammatory markers. Future long-term dose-escalation studies are necessary since the TC, HOMA-IR, and IL-6 findings were not robust due to their sensitivity.
Obesity is believed to be a promoter of T2DM [77]. Increased BMI is associated with higher leptin levels, one of the major adipokines released by adipocytes [72]. It has already been known that ginsenosides inhibit adipogenesis and lipid accumulation in adipocytes [78]. The current study is the first report investigating the effects of ginseng administration on anthropometric indices and adipocytokines among subjects with prediabetes and T2DM. Our meta-analysis showed that ginseng consumption did not affect anthropometric measurements (BW, BMI, and WC) and adipocytokines (adiponectin and leptin) in individuals with prediabetes and T2DM. The findings are consistent with previous studies [19,34], suggesting that ginseng intake did not significantly differ in anthropometric measurements between the intervention and placebo groups in the general population. The findings from the present study were concluded in a relatively small sample size (n = 648 participants). Therefore, if well-designed clinical studies establishing appropriate inclusion criteria and larger sample sizes are documented, significant results are not far from expectation on these markers.
We have also demonstrated that consumption of ginseng significantly accelerated the HR. However, its effects on SBP and DBP among individuals with prediabetes and T2DM were insignificant. Also noteworthy is that the present study represents the first meta-analysis to investigate the effects of ginseng on BP and HR in people with prediabetes and type 2 diabetes. In preclinical evidence, ginseng supplementation decreased the BP through the activation of endothelial nitric oxide synthase and the release of nitric oxide and sped up the HR [79,80]. A systematic review and meta-analysis study in subjects with hypertension revealed significantly reduced BP levels following ginseng intake. However, the total sample size was insufficient to draw conclusions [81]. Similarly, another review record on healthy and unhealthy individuals showed the same results [34]. However, non-significant levels of SBP and DBP were observed after ginseng supplementation in the general population with a larger sample size than the previous ones in a meta-analysis setting [82]. Likewise, the findings do align with those of our meta-analysis. Although we can consider the HR acceleration as a side effect of ginseng consumption, the limited number of included studies necessitates more direct investigations.
Based on our findings, ginseng supplementation did not change measures of hepatic function in patients with prediabetes and T2DM. Nevertheless, some evidence has suggested that ginseng has favorable impacts on hepatocellular function through its antiinflammatory, anti-oxidative, and anti-apoptotic properties [83]. In addition, a recent clinical trial study on individuals with hepatic dysfunction reported that ginseng supplementation significantly changes liver function enzymes level [84]. Our study confirmed the earlier meta-analysis study, which found that ginseng did not appear to have hepatoprotective effects in the general population [31]. Finally, it is noteworthy that we could not perform a subgroup analysis for any outcome based on the different forms of ginseng supplementation (extract vs. powder) since most of the included studies intervened extract form of ginseng. A study of 4-week supplementation of fermented red ginseng showed that only glucose values following oral glucose tolerance test were lowered, without any significant changes in FPG following ginseng supplementation [27]. In contrast, in another study with the administration of ginseng extract, FPG concentrations decreased [5]. As the extract form of any supplement has higher bioavalibity than the powder form, we can hypothesize that studies with extraction form have more promising findings.

Strengths and Limitations
In this paper, we included multiple endpoints to provide a comprehensive overview of the effects of ginseng on cardiometabolic parameters in individuals with prediabetes and T2DM. Both parallel and crossover randomized trials written in the English language were included. Additionally, we conducted dose-response and meta-regression analyses to assess the association between pooled effect size, dosage, and duration of ginseng supplementation. Subgroup analyses were also conducted to further explore each listed outcome's results. Finally, we graded the overall certainty of evidence across the studies according to the GRADE guidelines. Despite the above strengths, the present study is not without limitations. First, the sample sizes of the included studies were also relatively small, with only one study including more than 100 participants. Second, relatively half of the studies were conducted in Asia, limiting generalizability. Third, some factors, such as duration of diabetes and smoking status, may influence the cardiovascular risk and should also be considered confounders, but were not included in the analysis due to poor reporting of these variables. Fourth, statistical heterogeneity is apparent in our analysis. This may be attributed to the poor methodological quality and/or differences in treatment regimens (doses/durations) or the ginseng type used.

Conclusions
This meta-analysis suggests that ginseng can improve cardiometabolic outcomes in individuals with prediabetes and type 2 diabetes. These results may provide important information to health agencies in formulating future guidelines for the use of ginseng in managing diabetes and the associated risk factors and preventing the progression of prediabetes. However, large-scale, well-designed RCTs should be performed to further verify these findings in the future.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/nu14122401/s1, Figure S1: Forrest plots presenting mean difference (MD) and 95% confidence intervals for the impact of ginseng supplementation; Figure S2: Funnel plots demonstrating publication bias in the trials reporting the effect of ginseng supplementation; Figure S3: Dose-response relations between ginseng dosage (mg/day) and mean difference in each outcomes; Figure S4: Dose-response relations between duration of ginseng (week) and mean difference in each outcomes; Figure S5: Random-effects meta-regression plots of the association between dose of ginseng (mg/day) and weighted mean difference of each outcome; Figure S6: Random-effects meta-regression plots of the association between duration of ginseng (week) and weighted mean difference of each outcome; Table S1: Search terms used across the various databases; Table S2: Risk of bias assessment; Table S3: Publication bias assessment.