**6. Risk of Bias of Studies Included**

Figure 2a,b show the risk of bias graph and risk of bias summary, respectively, of the studies in this review. There was low risk of bias in relation to incomplete outcome data (attrition bias), selective reporting (reporting bias), blinding of participants and personnel, and other bias in all the studies. Nine of the 16 studies demonstrated unclear risk of bias with respect to random sequence generation, while 11 studies demonstrated unclear risk of bias in relation to allocation concealment. In terms of blinding of outcome assessments, there were 3 studies with unclear risk of bias.

**Figure 2.** Graphs showing (**a**) risk of bias (**b**) risk of bias summary [18,31,32,36–48].

#### **7. Effects of Interventions**

Three distinct areas were identified based on the results of the systematic review and NWM, namely: Gut microbiome; Glycaemic control; and Body Mass Index (BMI).

Gut Microbiome.

The effects of prebiotics and oral antidiabetic agents on gut microbiome were varied (Table 3). For example, Birkeland et al. [37] found significant increase in faecal levels of *Bifidobacteria* following daily supplement of inulin-type fructans, while Gonai et al. [39] observed significant restoration of *Bifidobacteriaceae* in patients with T2D after the consumption of galacto-oligosaccharide. In addition, Zhao et al. [48] found high fibre diet promoted the growth of short chain fatty acid producing microbes in patients with diabetes. However, the effect of prebiotic treatment on *Bifidobacterium*, *Lactobacillus* and *Roseburia* was not significant in Pedersen et al. [32] study.

**Table 3.** Effects of prebiotics and Oral antidiabetic agents on gut microbiome.



**Table 3.** *Cont.*

Abbreviations: N/A (Not Applicable).

While Gu et al. [40] and Su et al. [45] found acarbose can increase the relative abundances of *Bifidobacterium* species, Wu et al. [18] noted *Bifidobacterium adolescentis* increased after metformin treatment.

#### **8. Bifidobacterium**

The Network meta-analysis for *Bifidobacterium* included 5 studies, 239 participants and 3 treatments. The result showed prebiotic treatment increased the relative abundance of *Bifidobacterium* although this was not significantly different compared with placebo with a SMD of 0.43 [95% CI, −0.69, 1.55; *p* = 0.45] (Figure 3a). In contrast, metformin treatment reduced the relative abundance of Bifidobacterium with a SMD of −1.81 [95% CI, −4.16, 0.54; *p* = 0.13] compared to placebo, but again this was not significant. Pairwise meta-analysis conducted to estimate effect sizes based on head-to-head comparisons of treatments and/or control conditions (Figure 3b) found no significant difference (*p* > 0.05) between prebiotic treatment and control on the relative abundance of *Bifidobacterium*. The effect of metformin was significant (*p* < 0.05).

**Figure 3.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on *Bifidobacterium* [31,32,37,41,42].

#### **9. Lactobaccilus**

The Network meta-analysis for *Lactobaccilus* included 3 studies, involving 159 participants. The effect of metformin treament on the relative abundance of *Lactobaccilus* showed a significant increase with SMD of 1.43 [95% CI, 0.23, 2.64; *p* = 0.02] compared to placebo (Figure 4a). However, the effect of prebiotic compared to placebo was not significantly different with a SMD of −0.14 [95% CI, −0.81, 0.53; *p* = 0.68]. The meta-analysis (Figure 4b) also showed metformin significantly (*p* < 0.05) increased *Lactobaccilus* compared with control while differences between prebiotics and control did not differ significantly (*p* > 0.05).

**Figure 4.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on *Lactobaccilus* [37,41,42].

#### **10. Akkermansia**

The Network meta-analysis for Akkermansia included 2 studies, 111 participants and 3 treatments. Both metformin and prebiotic treatments increased the relative abundance of *Akkermansia*, although the effects did not differ significantly (*p* > 0.05) compared to placebo (Figure 5a). The SMD was 0.10 [95% CI, −0.32, 0.52; *p* = 0.64] for prebiotic and 0.49 [95% CI, −0.33, 1.30; *p* = 0.24] for metformin treatments, respectively, compared with placebo. The results of the meta-analayis did not show any significant difference (*p* > 0.05) between the prebiotic and control, and metformin and control (Figure 5b).

**Figure 5.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on *Akkermansia* [41,42].

#### **11. Glycaemic Control**

In the study by Arias-Córdova et al. [36], it was found that the native banana starch (NBS) with a content of 70.5% resistant starch and 10% digestible starch caused a reduction in fasting blood glucose from baseline compared with digestible maize starch with 100% digestible starch content. There was improvement in insulin sensitivity and significant improvement in glycaemic control including significant reduction in parameters such as HbA1c, postprandial blood glucose and fasting blood glucose levels in patients with type 2 diabetes who consumed prebiotic diets compared with control in some studies [31,38,41,43,44,48].

However, following the consumption of prebiotic diets, there was no improvement in glucose control in other studies [32,39].

With respect to the oral antidiabetic agents, Wu et al. [18] found metformin significantly reduced HbA1c and fasting blood glucose levels compared with calorie restricted diet. Furthermore, Tong et al. [46] reported metformin improved Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) compared with control, while Su et al. [45] observed acarbose treatment improved glycemic control in patients with type 2 diabetes. Both dapagliflozin and gliclazide reduced HbA1c and fasting blood glucose levels in the study by van Bommel et al. [47]. Similarly, the acarbose and glipizide groups improved glycemic control, with no significant differences between the two groups [40].

However, Shin et al. [42] reported that *Scutellaria baicalensis* with metformin treatment or placebo did not change the glucose and HbA1c levels.

Glycated Haemoglobin (HbA1c).

The Network meta-analysis for HbA1c included 12 studies, 7 treatments and 1012 participants (number of observations). Compared with control, glipizide, herbal formula and metformin treatments reduced HbA1c although the difference was not significant (*p* > 0.05). In contrast, prebiotic treatment significantly reduced HbA1c compared to control with a SMD of −0.43 [95% CI, −0.77, −0.08; *p* = 0.02] (Figure 6a). The results of the meta-analysis demonstrated prebiotics significantly (*p* < 0.05) reduced HbA1c compared to control, whereas the differences between the other treatments and control were not significant (*p* > 0.05) (Figure 6b).


**Figure 6.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on glycated haemoglobin (HbA1c) [31,32,38–46,48].

Fasting Blood Glucose.

There were 9 studies, 731 participants or number of observations and 5 treatments involved in the Network meta-analysis of fasting blood glucose (Figure 7a). While prebiotic treatment reduced fasting blood glucose level with SMD of −0.10 [95% CI, −0.41, 0.21; *p* = 0.52], acarbose and glipizide increased fasting blood glucose with SMD of 0.15 [95% CI, −0.26, 0.57; *p* = 0.48] and 0.25 [95% CI, −0.33, 0.83; *p* = 0.41], respectively. However, differences between the various treatments (acarbose, glipizide and prebiotic) and the control were not significant (*p* > 0.05). The meta-analysis revealed that the various treatments did not differ significantly (*p* > 0.05) from control (Figure 7b).



**Figure 7.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on Fasting Blood Glucose [32,36,38–41,43,45,46,48].

Postprandial Blood Glucose.

Two studies, 189 number of observations and 3 treatments were included in the Network meta-analysis of postprandial blood glucose (Figure 8a). While the difference between acarbose and control were not significant (*p* > 0.05), glipizide increased postprandial blood glucose significantly with SMD of 1.03 [95% CI, 0.44, 1.62; *p* = 0.001]. The result of the metaanalysis revealed that acarbose significantly (*p* < 0.05) reduced postprandial blood glucose compared to gliplizide, while the effect of acarbose compared to control, and metformin compared to herbal formula were not significantly different (*p* > 0.05) (Figure 8b).

**Figure 8.** Network Meta-analysis (**a**) and Meta-analysis (**b**) of the effect of treatments versus control on Postprandial Blood Glucose [40,45,46].
