Introduction

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases, with a prevalence estimated to exceed 536.6 million patients and expected to reach 783.2 million patients by 2045 (Sun et al. 2022). The increasing prevalence of T2DM is attributed to an aging population, unhealthy lifestyle behaviors, and the increased prevalence rate of T2DM risk factors, particularly obesity (Chan et al. 2020). Diabetes is a multifactorial disease caused by the interaction of genetic and environmental factors. It is associated with high morbidity and mortality worldwide (Vassalle and Gaggini 2022). T2DM is characterized by chronic hyperglycemia due to insulin resistance, β-cell dysfunction, or both (Giacco and Brownlee 2010). Under hyperglycemic conditions, increased glucose uptake leads to elevated oxidative stress markers. Consequently, this rise in oxidative stress markers can trigger the activation of inflammatory markers like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The interplay between inflammatory and oxidative stress pathways may contribute to T2DM dysfunction and complications (Vassalle and Gaggini 2022). It has been suggested that reducing oxidative stress and inflammation may be a target for developing novel antidiabetic medications (Vassalle and Gaggini 2022).

Current medications for T2DM are often costly and associated with various side effects, including severe hypoglycemia (Vassalle and Gaggini 2022). As an alternative, herbal medicines offer a promising avenue for developing new treatments due to their widespread availability, affordability, and relatively safe profile (Thomford et al. 2018; Soltani et al. 2022). An excellent example is metformin, the first-line drug for T2DM, which originated from Galega officinalis, a herbal medicine utilized in Europe to manage diabetes (Bailey 2017). Current evidence suggests that various hypoglycaemic herbal medicines can significantly reduce inflammation and oxidative stress biomarkers in diabetes (Atkin et al. 2016; Ebrahimpour koujan et al. 2015; Ghafouri et al. 2020). Hence, plants offer a valuable resource for developing novel antidiabetic drugs due to their antioxidant and anti-inflammatory effects. Since there are inconsistent results regarding the use of herbal medicines with anti-inflammatory and antioxidant properties on T2DM (Adab et al. 2019; Alnajjar et al. 2020; Azimi et al. 2014; Basu et al. 2013), the current systematic review and meta-analysis were conducted to critically assess all the trials that simultaneously evaluated the antioxidative and anti-inflammatory activities of hypoglycaemic herbal medicinal on T2DM.

Methods

This systematic review and meta-analysis study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Page et al. 2021). It was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the ID: CRD42021226147. In addition, the ethics committee of the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences has authorized this study (IR.TUMS.EMRI.REC.1397.046).

Search strategy

A comprehensive and systematic search was conducted through PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases. The following keywords were used: (“herbal medicine”, “diabetes”, “inflammation”, “antioxidant”, the name of each oxidative or inflammatory biomarker, antioxidative enzyme, and their equivalents) to retrieve all clinical trials published in English from their inception to April 2022. In addition, the reference lists of all relevant articles were screened to find any eligible studies that might have been missed. The search strategy is available in Table S1.

Study selection and eligibility criteria

All clinical trials conducted in English that met the following criteria were included in this study: (1) evaluated the effect of extract or powder of hypoglycaemic herbal medicine simultaneously on oxidative and inflammatory biomarkers; (2) conducted on patients with prediabetes, T2DM, or metabolic syndrome; (3) compared the effectiveness of herbal medicines to no treatment, placebo, or conventional pharmacological treatments. Clinical trials on type 1 diabetes mellitus, preclinical studies, review articles, letters, thesis, and unpublished data were excluded. At least two independent researchers evaluated all studies according to inclusion/exclusion criteria during the screening phase. After removing duplicates, the publications’ titles, abstracts, and full text were evaluated to see whether they met the inclusion criteria. Any discrepancies at each screening step were discussed and resolved in consultation with the corresponding author.

Quality assessment of included studies

Methodological quality assessment of each included study was independently performed by at least two researchers using the modified Jadad checklist (Oremus et al. 2001). Clinical trials with a score < 3 were rated as poor quality. In addition, the risk of bias for each study was assessed using the Cochrane Risk of Bias tool (Higgins et al. 2011), where the domains were judged as “low-risk, high-risk, or unclear”.

Data extraction

From the included studies, the following data were extracted: (1) Study characteristics, such as author name, year of publication, study design, and duration of intervention; (2) Patient characteristics, such as age, gender, number of patients in each group, and underlying disease; (3) Specific information regarding the interventions, such as herbal medicine name, intervention modality, dosage, and duration of treatment, as well as type of intervention for the control group, including placebo, standard pharmacological treatments, or no treatment; and (4) Primary outcomes (measurements of antioxidative and anti-inflammatory biomarkers) and secondary outcomes (total antioxidant capacity and antioxidant enzymes activity).

Statistical analysis

All data were extracted from the included studies using mean difference (MD) and standard deviation (SD) for both the intervention and control groups. When the standard error (SE) or confidence interval (CI) was reported, it was transformed into SD. Using standard statistical formulas, the SD of change was calculated based on the baseline and final SDs (Higgins et al. 2019). Clinical and methodological heterogeneity was statistically evaluated using the chi-square and I2 tests, and P < 0.1 was considered statistically significant (Ioannidis 2008). To determine the pooled effect of the herbal medicine, random- or fixed-effect methods were employed to conduct the meta-analysis based on the level of heterogeneity between studies.

Furthermore, a random-effect meta-regression analysis was performed to evaluate the impact of influencing factors (Higgins et al. 2011). Forest plots were used to show the findings of the meta-analysis schematically. STATA software, version 14.0 (StataCorp, College Station, TX, USA), was used for all analyses.

Results

General results

Out of 6209 studies, 47 clinical trials were eligible for inclusion in the meta-analysis (Fig. 1). A total of 2636 participants, including men and women aged between 20 and 79 years, were included in these studies. Forty-four studies were conducted on patients with T2DM, two on metabolic syndrome patients, and one on patients with prediabetes. The design of most studies was a double-blind, randomized controlled trial (DBRCT) in which the use of a sole plant was compared to a placebo. Some of the herbal medicines used include turmeric, bilberry, M. officinalis, garlic, cardamom, cinnamon, ginger, saffron, pomegranate, Camellia sinensis, Cichorium intybus, Crataegus laevigata, silymarin, Rheum ribes, Nigella sativa, Anethum graveolens, grape, or blueberry. Details of the included studies and characteristics of the participants are shown in Table 1. The quality score of most studies was ≥ 3. The quality assessment results based on the modified Jadad checklist and the Cochrane risk of bias assessment are presented in Tables 1 and 2, respectively.

Fig. 1
figure 1

Flow diagram of the study selection processes

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Table 1 Characteristics of controlled trials included to the study
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Table 2 Cochrane risk of bias item for each included trial
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Meta-analyses of the main outcomes

Total change in oxidative stress biomarkers, including malondialdehyde (MDA), nitric oxide (NO), and F2-isoprostane, was assessed in 30 studies (68 data), which pooled data showed a significant reduction with a standardized mean difference (SMD) of − 0.36 and 95% CI − 0.64 to − 0.09 (P < 0.001) in a random-effect meta-analysis (I2: 91.9%), Fig. 2.

Fig. 2
figure 2

Forest plot of oxidative stress’ biomarkers in the random-effect meta-analysis

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Total change in inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF-α, IL-6, and CRP, was measured in 45 studies (98 data) and showed a significant reduction (P < 0.001) with an SMD = − 0.47 and 95% CI − 0.63 to − 0.31 in the random-effect meta-analysis (I2: 85.4%), Fig. 3.

Fig. 3
figure 3

Forest plot of total inflammatory biomarkers in the random-effect meta-analysis

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Meta-analyses of the secondary outcomes

Total antioxidant capacity (TAC) was measured in 27 studies (28 data). It was significantly (P = 0.002) improved with an SMD = 0.46 and 95% CI 0.16–0.75 in a random-effect meta-analysis (I2: 86.9%), Fig. S1.

The activity of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPX), was assessed in 14 studies (37 data). The pooled results showed a significant (P < 0.001) increase in total activity (SMD = 1.80, 95% CI 1.26–2.33), in the random-effect meta-analysis (I2: 94.9%), Fig. S2.

Subgroup analyses

In subgroup analyses, a significant change was observed in oxidative stress biomarkers, including MDA and NO (SMDs = − 0.96 and 1.01, 95% CIs − 1.30 to − 0.63 and 0.63 to 1.40, respectively). However, the change was not significant (P ≥ 0.05) for F2-isoprostane (SMD = − 0.67 95% CI − 1.42 to 0.09). Regarding the inflammatory biomarkers, subgroup analyses showed significant changes for hs-CRP and TNF-α (SMDs = − 0.64 and − 0.71, 95% CIs − 0.84 to − 0.44, and − 1.18 to − 0.24, respectively). On the other hand, the change for IL-6 and CRP were not significant (P ≥ 0.05) (SMDs = − 0.14 and 0.25, 95% CIs − 0.28 to 0.005 and − 0.01 to 0.52, respectively).

Except for CAT (SMD = 0.24, 95% CI − 0.19 to 0.67), the subgroup analysis antioxidant enzyme revealed a significant increase in SOD (SMD = 2.29, 95% CI 0.97–3.62) and a significant decrease in GSH (SMD = 1.44, 95% CI 0.79–2.10) and GPX (SMD = 3.29, 95% CI 0.79–5.79).

Additional subgroup analyses were performed to assess the effect of the herbal medicines on primary and secondary outcomes compared to placebo/non-placebo treatment in the control group and also based on the duration of intervention; ≤ 8 weeks vs. > 8 weeks. The details of the analyses are shown in Table S2.

Meta-regression test

A meta-regression analysis was performed to determine the sources of the heterogeneity. The results of this analysis demonstrated that the type of treatment in the control groups (placebo/non-placebo) and the duration of the intervention (≤ 8 weeks vs. > 8 weeks) were not the sources of heterogeneity observed in the results of primary and secondary outcomes. However, biomarkers of oxidative stress were significantly affected by the duration of the intervention (coefficient = 1.31 for > 8 weeks, P = 0.027).

Discussion

The present meta-analysis demonstrated a simultaneous and significant reduction in oxidative stress and inflammatory biomarkers, along with a noteworthy increase in TAC and antioxidant enzyme activity.

Recognizing the escalating global prevalence of T2DM and the limited accessibility of conventional antidiabetic medications, the World Health Organization (WHO 2013) advocates for the utilization of accessible and indigenous natural products. Consequently, the use of herbal medicines is on the rise in both developed and developing countries (WHO 2013), underscoring the need for a scientific evaluation of their efficacy and safety (WHO 2013). It is essential to note that meta-analysis studies rank as the highest level of evidence-based medicine, contributing valuable scientific insights (Howick et al. 2022). Our meta-analysis revealed that when a placebo was administered to the control group, the effect size was more significant, suggesting that a standard trial design yields a more reliable effect. A standard trial design eliminates the effect of chance on the trial outcomes through randomization, blinding, and placebo (Ahmad et al. 2021).

Curcuma longa L. root (turmeric), the rhizome of Zingiber officinale Roscoe (ginger), stigmas of Crocus sativus L. (saffron), Vaccinium spp. fruits (bilberry), fruit extract of Punica granatum L. (pomegranate extract), Nigella sativa L. oil extract, and Elettaria cardamomum (L.) Maton (cardamom) were the extensively studied herbal medications in this study. Remarkably, these medicinal plants are commonly used as spices or food additives in daily culinary practices, suggesting their safety even over prolonged periods. Utilizing herbal medicines as spices or food additives could pave the way for functional foods, offering a promising approach to harnessing food as a medicine without the risk of adverse effects or non-adherence, which often presents a significant barrier to conventional pharmacological therapies (Nieto 2020).

Plant-derived supplementations contain numerous bioactive compounds responsible for their pharmacological effects. Therefore, it is valuable to identify these bioactive compounds and investigate their pharmacological effects alone or in combination to determine synergistic, additive, or antagonistic effects (Soltani et al. 2022). On the contrary, each active compound within herbal medicine may exhibit its beneficial effects by acting through distinct pathways. This implies that herbal medicines containing multiple active compounds can simultaneously exert therapeutic effects through multiple pathways. This may make the combination of the active compounds of a herb more effective than using a single ingredient (Yuan et al. 2017). Therefore, it is necessary to apply modern pharmacological science in studying the beneficial effects of polyherbal medicine.

Terpenoids, carotenoids, and phenolic compounds such as phenolic acid, flavonoids, and stilbenoids were the primary active compounds detected in these hypoglycaemic plant-derived medicines. These bioactive compounds could exert their pharmacological effects through attenuation of oxidative stress, inhibition of inflammation, protection of pancreatic beta cells, activation of insulin signaling, stimulation of insulin secretion, and beneficial effects on glucose metabolism (Smitha Grace et al. 2019; Sun et al. 2020; Zhang and Tsao 2016).

A randomized controlled trial (Maithili Karpaga Selvi et al. 2015) investigated the efficacy of turmeric, with curcumin as its main bioactive compound, as an adjuvant to conventional therapy in T2DM patients. This study showed that consuming four 500-mg capsules daily along with metformin had more beneficial effects than taking metformin alone. It effectively reduced oxidative stress and inflammatory biomarkers and increased TAC without any significant effect on antioxidant enzymes, possibly due to its short duration (4 weeks). Turmeric exerts protective anti-inflammatory effects by inhibiting the synthesis of proinflammatory cytokines and mediators such as cyclooxygenase-2, prostaglandins, and leukotrienes (Maithili Karpaga Selvi et al. 2015). The antioxidant effects of curcumin are mediated by scavenging free radicals, inhibiting the production of lipid peroxides, increasing TAC, the expression of antioxidant enzymes, and enhancing Sirtuin 3 (SIRT3) activity (Bankowski et al. 2022). However, several meta-analysis studies have separately reported curcumin's anti-inflammatory and antioxidant effects (Bengmark 2006; Derosa et al. 2016; Gorbi et al. 2021). In another study (Shidfar et al. 2015), in a DBRCT, the effect of daily intake of 3 g of ginger, in which phenolic and terpenoid compounds are its main bioactive compounds, on glycemic control, oxidative stress, and inflammatory biomarkers in a 12-week trial had been investigated. Their results showed a significant reduction in MDA and CRP and a significant increase in TAC. The potential mechanism of the antioxidative effect of ginger is induced via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The underlying mechanisms of its anti-inflammatory effects are the inhibition of phosphatidyl inositol-3-kinase (PI3K)/ protein kinase B (Akt) and the nuclear factor kappa light chain-enhancer of activated B cells (NF-κB) signaling pathways (Mao et al. 2019). Some of its antioxidative and anti-inflammatory effects include reducing free radicals, lipid peroxidation, and nitrosative stress levels, accelerating gene expression, increasing the level and activity of antioxidant enzymes, and reducing proinflammatory cytokines. In a recently published meta-analysis, the beneficial effects of ginger supplementation on hs-CRP, IL-6, and TNF-α levels in T2DM have been shown. These results align with our findings (Mohammad et al. 2021).

Based on our knowledge, the current meta-analysis is the first study that assessed the simultaneous antioxidative and anti-inflammatory effects of plant-derived anti-diabetic medicines on T2DM. The main strength of this review is that most of the included studies are randomized, double-blind, controlled trials with low levels of bias. However, we had several limitations. There was high heterogeneity across studies due to differences in plant species, dosage, duration of interventions, and methods of measuring oxidative stress and inflammatory biomarkers. Moreover, there were differences between the sources of each herb, the part of the plant used, their geographical area, and their preparation method (bulk, powder, or extract), which have been found to cause heterogeneity between the studies (Ahmad et al. 2021).

Conclusions

Some hypoglycaemic plant-based treatments have a positive effect on T2DM patients by concurrently reducing the serum level of oxidative stress and inflammatory indicators and boosting antioxidant enzyme activity. Further research is warranted to explore the antioxidative and anti-inflammatory effects of hypoglycaemic plant-derived medicines, which would enhance our understanding of their active ingredients and shed light on their therapeutic and adverse effects. To achieve this, well-designed trials with substantial sample sizes should be conducted, employing gold-standard methods for measuring and reporting outcomes, allowing for a comprehensive assessment of their impact through comparative data analysis.