The number of patients with type 2 diabetes mellitus (T2DM) is increasing annually, which poses a global health threat and causes high health care costs, especially in the Asian region (1). It has been reported that the prevalence of diabetes in Asian countries, ranging from 3 to 47%, continues to surge despite therapeutic advances, with more than 60% of patients with diabetes worldwide living in Asia (2). T2DM is also reaching epidemic proportions in China, a country with the largest number of patients with diabetes (3), and thus there is an urgent need for more effective or targeted treatment strategies for it.

Nowadays, the treatment for T2DM is based on lifestyle changes, especially diet and antidiabetic oral agents, according to the needs of the patients. The treatment aims to achieve and maintain the optimal glycemic control, prevent acute diabetic complications, and reduce the risk of chronic complications, which require a combination of diabetic diet and conventional medications (4). Although numerous clinical trials are helpful in comparing different treatment strategies or medication regimens, the results of these trials should be considered in combination with patients' specific conditions, the availability and cost of drugs, and physicians' judgment in decision-making.

Metformin has been recommended as a first-line drug for monotherapy or combination therapy by Western authoritative clinical practice guidelines when lifestyle interventions can no longer achieve glycemic control (5). In China, acarbose has been taken as one of the first-line drugs in treatment for diabetes because acarbose can slow down the digestion and absorption of dietary carbohydrates in small intestines by inhibiting brush-border α-glucosidase, and Chinese diet is characterized by a higher percentage of carbohydrates (6). Zhu et al. have confirmed that the hypoglycemic effect of acarbose in patients with T2DM consuming an Eastern diet is superior to that in those consuming a Western diet by a systematic meta-analysis of studies (7). Because of the specific mechanism of glycemic control and weight loss, dietary components may alter the hypoglycemic effect of acarbose.

In fact, in addition to pharmacological interventions, dietary interventions are another cornerstone therapy for diabetes prevention and management (8, 9). The essential therapeutic approach to reducing the incidence and severity of T2DM focuses on the nature and quality of nutrients, especially consumed energy and macronutrients (10). The macronutrients in the diet are utilized by the body as sources of energy, including carbohydrate, protein, and fat. Restriction on any one of these macronutrients will have to be compensated by increase in the proportion of energy derived from the other two (11). Diets have evolved with changes in time, cultural traditions, as well as geographic and economic factors, all of which interact in a complex manner to shape different dietary consumption patterns among countries and regions (12). It has been reported that most Asians follow an Eastern diet pattern, characterized by higher intakes of whole grains, legumes, vegetables, fruits, and fish, thus making dietary carbohydrates the major source of energy (13). Evidence has suggested that the macronutrient composition of the diet also plays a key role in the postprandial and diurnal glucose excursions in patients with T2DM, and its changes may contribute to reducing postprandial glycemia, HbA1c, and diabetic complications (14).

However, there is a lack of information on Chinese dietary patterns and the efficacy of acarbose. The metformin and acarbose in Chinese as the initial hypoglycemic treatment (MARCH) trial was thus conducted to compare the effects of acarbose and metformin as the initial therapy for Chinese patients newly diagnosed with T2DM. It became the first and unique trial to investigate the effect of dietary macronutrients on glycemic control in the context of intensive drug therapy (ClinicalTrial.gov, number ChiCTR-TRC-08000231) (15–17). The trial showed that acarbose has a similar efficacy to metformin, making it a viable option for Chinese patients. Nevertheless, no previous studies of drug–diet interaction were conducted by systematic analysis of the diet and clinical data from MARCH. In this study, data from the MARCH trial were used to examine whether the effects of two classic antidiabetic medications, namely, acarbose and metformin, on glycemic control and cardiometabolic risk factors are related to dietary macronutrient intakes in patients with T2DM.

Recent studies have drawn attention to the potential interactive effects of chronic medication use with nutrient intakes on chronic noncommunicable diseases (20, 21). Drug-nutrient interactions are of great clinical and public health significance, especially in patients with T2DM. The treatment for T2DM involved dietary manipulation that can reduce both glucose and insulin aberrant levels, and cardiovascular complications. This study first showed two classic antidiabetic medications of acarbose and metformin and their interaction with macronutrient intakes in the context of MARCH clinical trial. Among the included Chinese patients being treated for T2DM, metformin and acarbose mainly exerted different interactive effects with dietary energy, carbohydrate, and protein intakes on GLP-1 secretion, insulin release, and SBP.

The results of this study have shown that the daily intake of total energy, carbohydrates, protein, and fat for included newly diagnosed patients with T2DM fell into the normal range before treatment, and total energy intake remained relatively stable in both two groups during treatment. Even so, independent and positive associations were still found between total energy and FBG, as well as 2hPPG during treatment, suggesting additional benefits of glycemic control from total energy restriction even under antidiabetic oral agent therapy, which was also observed among Korean patients (22). Meanwhile, different oral drugs may change the association between total energy intake and treatment outcomes due to different mechanisms of action related to the gastrointestinal tract. In the subgroup analysis, total energy intake and AUC for plasma GLP-1 showed inverse associations under metformin and acarbose treatment, indicating that total energy intake stimulates distinct patterns of GLP-1 release. The incretin hormone of GLP-1 plays a critical role in regulating glucose homeostasis and dietary intakes of nutrients are a primary stimulus to the release of intestinal GLP-1 (23). In generally, carbohydrate, lipid, and protein digestion, also known as sources of total energy, can induce postprandial glycemic and GLP-1 secretion through different pathways, to promote the absorption of glucose and maintain the level of blood glucose (24). Consequently, strategies to slow down the digestion of these macronutrients are needed to achieve a sustained release of GLP-1 for improvement of the glucose homeostasis. It has been confirmed that postprandial GLP-1 secretion under acarbose treatment is stimulated in patients with T2DM by induction of transfer of carbohydrates to the distal parts of the intestine (25). Therefore, under acarbose treatment, a sustained release of GLP-1 can still be achieved even following an increase in total energy intake by slowing down the digestion and absorption of dietary carbohydrates in small intestine, suggesting a positive association between total energy intake and AUC for plasma GLP-1. However, under metformin treatment, a higher total energy intake was associated with lower AUC for plasma GLP-1. It has also been showed that metformin increases plasma GLP-1 concentrations in healthy controls and patients with T2DM (26). Nevertheless, it has been reported that metformin does not directly stimulate GLP-1 secretion in vitro, suggesting that its effect observed in vivo are indirect (27). It may be speculated that the GLP-1 secretion induced by metformin can be disturbed by total energy intake, which deserves further investigation.

Contrary to relatively stable intake of total energy, carbohydrate intake significantly decreased at 24 weeks but increased at 48 weeks in the acarbose group and significantly increased at 48 weeks in the metformin group. Considering that the staple food is rich in carbohydrate in most Asian countries, the changes in quantity of dietary carbohydrates indicated a gradually loose restriction on carbohydrate and a relative imbalance between dietary desires and adherence to diet modification in disease management. Dietary carbohydrates are one of fundamental macronutrients in terms of their capacities to affect blood glucose and insulin levels (28). In linear mixed-effect models, higher intake of carbohydrates was independently associated with higher BMI, HbA1c, 2hPPG, and AUC for serum insulin, which was also observed in Saudi patients (29), suggesting that carbohydrate restriction is essential for the achievement of good glycemic control, weight loss, and reduced insulin secretion. In addition, under acarbose and metformin treatment, significant and comparable effects on reduction of BMI and HbA1c were still achieved, while under acarbose treatment, significantly lower postprandial blood glucose was achieved after 48 weeks, and AUC for serum insulin decreased to a greater extent than under metformin treatment, demonstrating that acarbose is superior to metformin in reducing postprandial hyperglycemia and hyperinsulinemia in patients with T2DM consuming an Asian diet. Meanwhile, the association between dietary carbohydrates and AUC for serum insulin was only significant under acarbose but not metformin treatment, which may contradict the insulin-sparing effect of acarbose (30). However, it also reflected, from another perspective, beneficial effects of acarbose on preserving β-cell function (31).

Finally, synergetic effects of protein intake and metformin treatment on lowering SBP were found. Some intervention studies have proved that a high protein intake can significantly decrease SBP and DBP in patients with T2DM (32). Furthermore, Garnett et al. (33) also observed that the SBP and DBP of metformin-treated prediabetic adolescents significantly decreased over time when receiving an increased-protein diet, all of which may suggest that consuming more proteins may help metformin users feel more at ease over time.

Since total energy and protein intake remained relatively stable in this study, the increase in the proportion of energy from carbohydrates was accompanied by the decrease in energy from fat. Not surprisingly, this led to the positive associations of higher dietary fat intake with better glycemic control, weight loss, the improvement of insulin secretion, and higher WBISI, an indicator of insulin sensitivity. In spite of contradicting the results reported in most studies that a reduction in dietary fat can promote weight loss benefiting blood lipid and glucose profiles (34–36), the result of association between a relatively higher fat intake and better treatment outcomes may reflect interactions between macronutrients, which make it difficult to interpret the individual contributions of each source to clinical outcomes. Moreover, aside from the quantity of dietary fat and carbohydrates, growing evidence suggests that the quality of dietary fat and carbohydrates (with a preference for foods with natural unsaturated fat, high fiber, low glycemic index, and whole grain instead of those with trans or saturated fat) are stronger determinants of the effects of diet on metabolic control than the quantity of each macronutrient in the diet (37), which may be further investigated in the following studies.

The MARCH trial provided evidence that both acarbose and metformin have a similar effect as initial therapy on HbA1c reduction in Chinese patients with T2DM. Shortly after, a meta-analysis systematically searched the Chinese and English literature for eligible randomized controlled trials to compare glucose-lowering effects of metformin and acarbose, which also implied that the effect of metformin is at least as good as that of acarbose (38). In this study, it was also found that acarbose treatment was not inferior to metformin treatment in view of most clinical outcomes. However, linear mixed-effect models showed metformin treatment was associated with higher TG and 2hPPG but lower LDL-C compared with acarbose treatment. Although none of these outcomes was affected by interaction of drug and dietary macronutrients, the superior effect of acarbose on postprandial plasma glucose still demonstrated a stronger response to dietary intakes compared with metformin. The research results only showed three significant interactions. Perhaps, due to a relatively shorter observation, there were limited changes in dietary macronutrients over time and relatively overwhelming effects of intensive drug therapy. Although there is little evidence of drug–diet interaction, the potential mechanism may be explainable or incidental in this study. Therefore, great importance should be attached to drug–diet interaction, and further investigation should be conducted in physiological studies and clinical solutions.

To the best of our knowledge, this study is the first of its kind to document the interaction of between pharmacotherapies and dietary intakes of macronutrients in patients with T2DM. However, there are several limitations to consider. First, all participants were Chinese patients newly diagnosed with T2DM, which may limit the application to other patients to some extent, and the association may be largely different in patients with longer duration of diabetes or following Western dietary patterns. However, the results may be applicable to other Chinese populations with diabetes, with characteristics similar to the sample in this study. Second, only limited food and beverage items were evaluated by the 24-h dietary recall method, which may lead to an underestimation of energy and macronutrients intake. Third, measurement errors in self-reported dietary behaviors were inevitable. Finally, the fat type and quality of carbohydrates were not considered in this study.

The MARCH trail provided a unique opportunity to investigate the drug–diet interactive effect on treatment outcomes in patients with T2DM. Metformin and acarbose mainly exerted different interactive effects with dietary macronutrients on GLP-1 secretion, insulin release, and SBP, suggesting that the complexities of drug-diet therapies may confer distinct benefits of glycemic control.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and the protocol was approved by an Ethics Committee from each clinical site. The patients/participants provided their written informed consent to participate in this study.

GW and JL conceptualized and designed the study, obtained, and supervised data collection. YA and YL conducted the data analysis and drafted the manuscript. NB, XD, and XC helped perform data processing and analysis. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.