In this secondary analysis of MARCH study, we observed how different sources of fiber influence treatment outcomes following certain oral antidiabetic drug regimens, suggesting that optimizing drug/dietary fiber combinations may provide greater success than drug targets considered in isolation.

In this clinical trial, high intakes of both total fiber and whole grain fiber were positively associated with improved β‐cell function, insulin sensitivity, and postprandial glycemic control in the acarbose group. Additionally, a high intake of legume fiber was associated with favorable glycemic control in both the acarbose and metformin groups, suggesting that whole grain and legume fibers exert protective effects in T2DM. Several meta-analyses have confirmed this protective role of dietary fibers in T2DM. One meta-analysis of 15 RCTs concluded that dietary fiber intake significantly improves FBG and HbA1c [18]. Another meta-analysis also concluded that the intake of whole grains improves glycemic markers such as FBG, Hb1Ac, and insulin sensitivity (HOMA-IR) [19]. Several mechanisms have been proposed to explain these effects, including both direct effects of fiber on gut physiology and indirect effects stemming from alterations in the gut microbiome.

Dietary fiber can be classified as soluble or insoluble based on its solubility in water. Insoluble fiber is the most abundant type of fiber in legumes and is highly dominant in whole grains. Dietary fibers, especially insoluble fibers, mix with intragastric fluids and form a sticky digesta that moves slowly through the gut. The slow passage of the sticky digesta through the gut reduces the absorption rate of nutrients such as glucose, thereby slowing PPG and insulin upsurge. Additionally, the slow passage results in the flattening of the glycemic curve following carbohydrate intake by prolonging the intestinal transit time [20].

In addition to the hypoglycemic effects, a high intake of legume fiber may play a beneficial role following metformin treatment due to positive associations with weight loss. Jovanovski et al. [21] performed a meta-analysis of 62 RCTs with durations ≥4 weeks and observed a similar reduction in body weight and BMI. Mechanistically, low energy intakes contribute to energy balance for weight maintenance. A high fiber intake could reduce the energy density of foods, slow down the rate of food consumption, and initiate satiety by stimulating the release of gut hormones. This cascade ultimately results in a reduction in the number of calories ingested, facilitating weight maintenance [22]. The feeling of satiation can be induced by both soluble and insoluble fibers. Notably, soluble fibers primarily prolong satiety. Soluble fibers include several types of polysaccharides, including hemicellulose, which is abundant in foods such as legumes [23]. European guidelines for the management of T1DM and T2DM have emphasized the benefits of soluble forms of dietary fiber from legumes [24]. This emphasis on dietary fiber sources may be more appropriate for Chinese patients with T2DM who are receiving acarbose or metformin treatment.

Dietary fiber has also been shown to indirectly improve metabolic health and weight loss by modulating the gut microbiome. Humans live in symbiosis with trillions of microbes, most of which are found in the gastrointestinal tract. Prone to fermentation by gut microbes, dietary fibers exert pleiotropic physiological effects on the composition and functionality of the gut microbiota. These effects include nurturing the growth of selected beneficial gut microbes, altering the production of hormones and cytokines, and promoting the fermentation of short-chain fatty acids (SCFAs) [25]. SCFAs play an important role in maintaining human hosts’ metabolic health [26]. Similar to our results, ref. [27] demonstrated that supplementation with fiber-rich pea, a kind of legume fiber, improves glycemia by inducing changes to the gut microbiota composition and altering the serum SCFA profile in glucose-intolerant rats. Additionally, Kovatcheva-Datchary et al. [28] reported that the gut microbiota becomes enriched in Prevotella copri following a meal of barley kernel-based bread, a kind of whole grain fiber. Both of these studies indicate legume fiber and whole grain fiber-mediated gut microbiota modulation plays a major role in improving glucose metabolism. Moreover, the gut microbiota plays crucial roles in the modulation of drug action. Mounting evidence suggests that the therapeutic and synergistic effects of oral glucose-lowering drugs, such as acarbose or metformin, are mediated, in part, through diverging or overlapping effects on gut microbial composition or functional capacity in individuals with T2DM [29, 30]. Furthermore, the gut microbiota can influence patients’ response to specific oral glucose-lowering drugs by altering the drug’s bioactivity, bioavailability, or toxicity. For example, acarbose could inhibit host glucoamylases to prevent fiber-rich food digestion in the gut, thus reducing PPG levels. Consequently, there is an increase in dietary fiber in the gut, which subsequently serves as food for the gut bacterial community. Other studies investigating metformin-microbiota interactions revealed that metformin can promote an increase in the abundance of mucin-degrading bacteria (e.g., Enterobacteriales and Akkermansia muciniphila). Additionally, metformin has been demonstrated to enhance the production of SCFAs [31]. These effects could work in tandem with dietary fibers, promoting the growth of a multitude of beneficial bacterial genera to yield more pronounced additive or synergetic effects on metabolic health. Pre-clinical animal models [29, 32, 33] or clinical trials [34] have indicated that the addition of dietary fiber to metformin or acarbose monotherapy improves glucose and lipid metabolism. As therapy becomes individualized, the interplay between nutrition, medication, and gut microbiota needs to be taken into consideration to maximize therapeutic benefits and prevent unwanted side effects. However, their interaction is complex, seemingly involving a wide range of undiscovered gut microbes, enzymes, and metabolites. In addition, as research findings accumulate, certain controversies have arisen, occasionally presenting conflicting outcomes [35]. For example, a recent study analyzing the microbiome revealed a positive association between butyrate production and insulin response in β-cells. Conversely, an increase in fecal propionate levels was found to be associated with the incidence of T2DM [36]. Since the current study did not perform gut microbiota sequencing, further investigations are needed to elucidate whether the synergistic benefits of acarbose or metformin and specific dietary fiber are associated with gut microbiota composition and microbiota-derived metabolites. This investigation could provide insight into the potential role of the gut microbiome as a target for improving the therapeutic efficacy of T2DM treatment options.

Notably, positive associations were observed between fruit fiber intake and DBP, TC, and LDL-C levels in the acarbose group. These associations indicated a higher risk of dyslipidemia and cardiovascular complications. Contrary to that, the beneficial health effects of fruit are well-documented. Potential mechanisms for lipid reduction associated with fruit consumption—such as the low energy density of fruit, the production of satiety factors, and the influence of micronutrients on metabolic pathways—exhibit indirect correlations with dyslipidemia-related diseases and fruit intake. However, given the presence of simple sugars in fruit (glucose, fructose, sucrose, etc.), which are well-known contributory factors to dyslipidemia-related diseases, it is reasonable to expect that their consumption should contribute to dyslipidemia rather than metabolic improvement [37]. The EPIC-InterAct study, a nested case-cohort study involving 26,088 adult participants, indicated statistically significant reductions in T2DM risk associated with total fiber, vegetable fiber, and cereal fiber intake but not fruit fiber intake [38]. In particular, children and adolescent might be more sugar-sensitive than adults. An investigation involving 15,000 American children indicated that weight gain in preadolescent and adolescent age groups could be attributed to the consumption of a fruit-rich diet, provided that the total caloric intake was not adjusted to meet their specific nutritional requirements [39]. However, another national cross-sectional study in China including 14,755 children and adolescents aged 5–19 years supports the beneficial health effects of regular, moderate fruit intake on improving lipid profiles in children and adolescents [40]. The contradictory characteristics of fruit in relation to lipid management have prompted us to investigate the specific contributions of various fruit types to lipid regulation. Additionally, the anti-dyslipidemia properties of known fruit constituents require further validation. Consequently, future research should prioritize the identification of anti-dyslipidemia components in fruit as an urgent and significant objective, not only to elucidate the scientific mechanisms underlying dyslipidemia but also to develop strategies for controlling dyslipidemia through optimal fruit consumption.

In addition, a notable observation is the conflicting impact of high vegetable fiber intake. On one hand, it was associated with reduced cardiovascular risk, evident from the negative correlation with DBP. On the other hand, it had adverse effects on glycemic control, as indicated by a positive correlation with HbA1c. Moreover, a positive association was observed between whole grain fiber intake and DBP within the metformin group, suggesting that whole grain fiber intake enhances cardiovascular risk. Contrary to this observation, Du et al. [41] reported that total dietary fiber, vegetable/fruit fiber, and grain fiber are negatively correlated with DBP in middle-aged women. This observation could be attributed to differences in population, food consumption patterns, and sources of dietary fiber. Moreover, the level of dietary fiber intake in our study population was quite low, possibly below the amounts associated with considerable health benefits (corresponding to the current recommended about 25–30 g of dietary fiber per day [42]). This could account for the conflicting associations. Therefore, a more comprehensive understanding of these associations necessitates further studies that can delve into these dynamics in greater detail.

As a component of dietary carbohydrates, the ratio of dietary fiber to total carbohydrate intake is also important for metabolic benefits. Such benefits are often observed when a high proportion of total carbohydrates is derived from foods rich in dietary fiber. In our study, we observed inverse S-shaped associations between the carbohydrate-to-fiber ratio and 2hPPG as well as HDL-C within the acarbose group. Similarly, S-shaped associations were observed between the carbohydrate-to-fiber ratio and AUC for serum insulin as well as BMI within the metformin group. These findings collectively suggest that a diet characterized by a high carbohydrate and low fiber content is associated with poor glycemic control and low HDL-C levels following acarbose treatment. Conversely, such a diet is associated with high insulin sensitivity and weight loss following metformin treatment when compared to a diet characterized by a low carbohydrate and high fiber diet. Consistent with our results, the American Heart Association recommends at least 1.1 g of fiber per 10 g of carbohydrate for protection against CVD [43]. Moreover, Fontanelli et al. [44] reported that grain consumption meeting the <10:1 ratio (1 g of fiber per 10 g of carbohydrate) is associated with high nutritional quality and low cardiometabolic risk. However, we demonstrated the dose-response effect in terms of the relationships between carbohydrate-to-fiber ratio and clinical outcomes following intensive drug therapy in patients with T2DM. We observed that the relationships were not linear, suggesting that the quality of carbohydrates appears to play a more critical role in metabolic health rather than total carbohydrate as a percentage of dietary energy. Given that dietary carbohydrates constitute a heterogeneous class of nutrients, carbohydrate quality index (CQI) was developed as a novel index to offer a more comprehensive assessment of dietary carbohydrate quality, by taking dietary total fiber consumption, dietary glycemic index, whole grains-to-total grains ratio, and the ratio of solid carbohydrates to total carbohydrates into account [45]. Several studies have demonstrated a positive association between CQI and metabolic risk factors; however, the current evidence remains insufficient to draw definitive conclusions [46]. To comprehensively elucidate this association, additional observational and interventional research is required.

The effective management of T2DM requires an integrated approach that takes patient characteristics and available pharmacological options into consideration. It is common to use a combination of medications to optimize treatment outcomes in T2DM. The influence that lifestyle modifications, specifically dietary factors, might have on the action of those oral antidiabetic medications has received much less attention. However, some pioneering clinical trials and animal studies [13, 47] have demonstrated that the coadministration of certain types of fiber with certain drugs could reduce hyperglycemia more than monotherapy of the drug. These observations may be attributed to the interaction between the fibers and the orally administered drugs, potentially modifying the pharmacokinetic or pharmacodynamic profile of the drug. These interactions could involve the enhancement of the viscosity of gastrointestinal contents, trapping the drugs inside the viscous gel formed, increasing the amount of absorbed drug, and slowing the rate of absorption [15].

Several limitations in our study need to be acknowledged. First, the assessment of dietary fiber consumption was based on a 24-h recall, a method prone to misreporting and probably not representative of the typical diet. Although this method has provided valuable dietary results for several epidemiologic investigations, a more extensive dietary intake data collection would likely have reduced measurement errors. Second, as the current study only included 551 Chinese patients newly diagnosed with T2DM, our findings should be interpreted with caution when generalizing to other populations. Last but not least, the further exclusion of the original participants according to the diet record may bring some concerns about selection bias and further observation studies or clinical trials need to be conducted with full consideration of both drug treatment and dietary consumption.

In conclusion, we demonstrated the additional metabolic benefits of combining metformin or acarbose with dietary fibers from different sources in newly diagnosed patients with T2DM. We observed that consuming high amounts of total fiber and whole grain fiber can positively affect β-cell function, insulin sensitivity, and postprandial glycemic control in those T2DM taking acarbose. Moreover, in both acarbose and metformin groups, a high intake of legume fiber was associated with favorable glycemic control. Therefore, this suggests that whole grain and legume fibers can provide protective effects on glycemic control in newly diagnosed patients with T2DM. In addition, the drugs could act synergistically with certain types of fibers to improve glycemic control, insulin sensitivity, and weight loss. Thus, we predict that optimizing drug/dietary fiber combinations may provide greater success than monotherapy with antidiabetic agents, considering the significant interactions between the dietary fibers and the drugs.