Investigation of interaction between sodium-glucose cotransporter 2 inhibitors and FOLFOX with colorectal cancer and type 2 diabetes

Abstract

BACKGROUND

For stage III colorectal cancer (CRC) patients with type 2 diabetes mellitus (T2DM), the standard mFOLFOX6 adjuvant chemotherapy is often challenged by disease recurrence and chemotherapy-induced toxicities. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, beyond glycemic control, exhibit potential antitumor properties in preclinical studies, yet robust clinical evidence for their combination with FOLFOX is scarce. We hypothesized that adding the SGLT2 inhibitor dapagliflozin to mFOLFOX6 would improve glycemic control, enhance oncological outcomes, and not significantly increase chemotherapy-related toxicities in this comorbid patient population.

AIM

To investigate the efficacy and safety of dapagliflozin combined with mFOLFOX6 in stage III CRC patients with T2DM.

METHODS

This single-center, randomized controlled trial at a tertiary hospital enrolled 160 patients with stage III CRC and T2DM post-R0 resection. They were assigned to receive either dapagliflozin plus mFOLFOX6 (experimental group) or mFOLFOX6 with standard non-SGLT2 inhibitors glucose management (control group) for 12 cycles. Key outcomes included 3-year disease-free survival (DFS), tumor markers (carcinoembryonic antigen, carbohydrate antigen 19-9), glycemic control (glycated hemoglobin, fasting blood glucose), and adverse events. Data were analyzed using t-tests, χ² tests, and Kaplan-Meier with log-rank test.

RESULTS

The experimental group (n = 80) showed superior glycemic control (post-treatment glycated hemoglobin: 6.79% ± 0.79% vs 7.75% ± 0.59%, P < 0.001) and greater reductions in tumor markers (post-treatment carcinoembryonic antigen: 3.59 ± 1.24 ng/mL vs 4.52 ± 1.15 ng/mL, P < 0.001) compared to the control group (n = 80). The 3-year DFS was significantly higher (43.75% vs 22.5%, P = 0.004), with a prolonged median DFS (31.6 months vs 19.0 months, P < 0.001). The incidence of grade ≥ 3 chemotherapy-related adverse events was not significantly different between groups (56.25% vs 47.5%, P = 0.268). Specific SGLT2 inhibitor-associated events (e.g., acute kidney injury, diabetic ketoacidosis) occurred but were manageable.

CONCLUSION

Adding dapagliflozin to mFOLFOX6 improves glycemic control, tumor marker response, and survival in stage III CRC patients with T2DM, without significantly increasing chemotherapy-specific toxicities.

Key Words: Sodium-glucose cotransporter 2 inhibitors; Colorectal cancer; mFOLFOX6; Type 2 diabetes mellitus; Survival rate; Dapagliflozin

Core Tip: In this study, we evaluated the addition of the sodium-glucose cotransporter 2 inhibitor dapagliflozin to standard mFOLFOX6 chemotherapy in patients with stage III colorectal cancer and type 2 diabetes mellitus after curative resection. The combination significantly improved glycemic control, reduced carcinoembryonic antigen levels, and enhanced 3-year disease-free survival without increasing severe chemotherapy-related toxicity. These findings suggest that sodium-glucose cotransporter 2 inhibitor may offer dual metabolic and oncological benefits in this high-risk comorbid population, supporting its repurposing as an adjunct to adjuvant chemotherapy.

INTRODUCTION

Colorectal cancer (CRC) is the world’s third largest common gastrointestinal malignancies and contributes significantly to global morbidity and mortality each year[1]. It is defined by a high postoperative rate of recurrence and high cancer-related mortality rate, which together constitute a serious clinical and economic burden on families and society[2]. Although diagnostic techniques, early screening programs, and multimodal treatment methods continuously improve, the high recurrence rate of the disease and development of chemotherapy resistance remain major unresolved challenges in clinical treatment and often result in a poor prognosis for advanced cases[3]. At the same time, there is mounting study increased risk of different cancers, specifically CRC, breast cancer, and esophageal cancer[4]. The relationship between these two diseases is due to the common pathophysiological mechanisms involved; particularly, chronic hyperglycemia, hyperinsulinemia, persistent low-grade inflammation, and obesity all create a procarcinogenic microenvironment and influence the carcinogenesis themselves, from initiating cancer to growth and death, invasion, and metastasis[5].

For patients with stage III CRC, postoperative adjuvant chemotherapy is an indispensable and crucial step toward achieving radical treatment and long survival. The mFOLFOX6 regimen, which includes oxaliplatin and fluorouracil/Leucovorin as its basic constituents, is currently the established adjuvant chemotherapy standard of international clinical guidelines. It has been demonstrated that its administration can significantly reduce the possibility of tumor recurrence and distant metastasis, thus leading to improved overall survival rates[6,7]. However, the therapeutic benefit of these cytotoxic drugs is very often counterbalanced by their considerable toxic side effects. Among them, peripheral neurotoxicity associated with oxaliplatin represents one of the major dose-limiting toxicities. Indeed, this condition may induce different kinds of structural and functional damage to sensory neurons, impairing signal transduction in the peripheral and central nervous systems, with consequent chronic, often debilitating, symptoms such as paresthesia and pain[8]. Such adverse events not only sharply diminish the patients’ quality of life but also frequently cause dose reductions or postponements in chemotherapy treatments, thus compromising the overall safety and efficacy of clinical management. It is, therefore, of utmost importance to explore adjuvant therapies with the aim of mitigating these challenges. In such a context, investigating hypoglycemic drugs capable of effectively managing blood glucose while exerting a concomitant positive influence on tumor prognosis either through a direct anti-neoplastic action or a chemo-sensitizing effect has become one of the most important research hotspots within this emerging interdisciplinary field of oncoendocrinology.

In the past few years, sodium-glucose cotransporter 2 (SGLT2) inhibitors, as a new class of glucose-lowering medicines, have not only effectively controlled blood glucose but also have protective effects on the cardiovascular system and kidneys[9]. Studies have shown that SGLT2 inhibitors can suppress the reuptake of glucose in the kidneys and promote the urine sugar excretion, thereby improving the metabolic disorder state of patients with type 2 diabetes mellitus (T2DM). Given that tumor cells predominantly depend on glycolysis for energy production, SGLT2 inhibitors may indirectly deprive them of their metabolic supply and inhibit tumor proliferation by reducing circulating glucose levels. In addition, SGLT2 inhibitors promote the excretion of glucose in urine, high sugar environment may promote specific proliferation of intestinal flora. The short-chain fatty acid produced by them has antitumor activity, which may inhibit CRC cell proliferation and further affect the prognosis of CRC patients[10]. Furthermore, SGLT2 inhibitors may also further improve the tumor microenvironment by inhibiting cancer-related chronic inflammatory responses[11].

Although anti-tumor potential has been preliminarily confirmed with SGLT2 inhibitors in preclinical and some observational studies, robust clinical evidence with respect to their specific interaction with the FOLFOX chemotherapy regimen among patients with concurrent CRC and T2DM remains scarce. Synergistic efficacy, potential pharmacokinetic influences, and long-term safety of such a combination have not been well-characterized. Against this backdrop, our study was conducted as a prospective, randomized controlled trial aimed at investigating in a systematic way the efficacy and safety of the addition of the SGLT2 inhibitor dapagliflozin to the mFOLFOX6 chemotherapeutic regimen in stage III CRC patients with T2DM. The control group received mFOLFOX6 regimen plus routine glucose management with hypoglycemic agents without any SGLT2 inhibitors. The primary goals are to ascertain whether such a combination can promote tumor response, decrease recurrence rates, and mitigate chemotherapy-related toxicities without adding significant additional risks, thereby providing a high level of evidence-based medical data for optimal clinical treatment decisions regarding this specific and challenging patient population.

MATERIALS AND METHODS

General information

One hundred and sixty patients with stage III colorectal adenocarcinoma and T2DM who were diagnosed and underwent radical surgery (R0 resection) in the gastrointestinal surgery of our hospital from January 2021 to November 2022 were stochastically assigned to a control group (80 cases) and an experimental group (80 cases) by random number table method.

Inclusion criteria: (1) Diagnosed with colorectal adenocarcinoma by colonoscopy and pathological examination, and the postoperative pathology was stage III[12]; (2) Met the diagnostic criteria for T2DM [glycated hemoglobin (HbA1c) value > 6.5% or fasting blood glucose (FBG) ≥ 7.0 mmol/L or 2 hours blood glucose after meal ≥ 11.1 mmol/L][13]; (3) Electrocorticography performance status score of 0 and 1; (4) Baseline liver and kidney function were basically normal: Child-Pugh grade A, epidermal growth factor receptor ≥ 45 mL/minute/1.73 m²; and (5) Signing informed consent is for both patients and their families.

Exclusion criteria: (1) Type 1 diabetes or other types of diabetes; (2) Distant metastasis (M1); (3) Severe heart failure (New York Heart Association class III-IV) or autoimmune disease; (4) Previous adjuvant chemoradiotherapy; and (5) Allergy to SGLT2 inhibitors or mFOLFOX6 regimen drugs.

Treatment methods

Both groups of patients underwent standard radical resection for CRC. The surgery was performed laparoscopically by a fixed team of specialists, using the appropriate standard radical surgical technique based on the tumor location, and completing D3 lymph node dissection. The entire procedure strictly followed the treatment guidelines to ensure pathological R0 resection was achieved.

Chemotherapy regimen

All patients began adjuvant chemotherapy 4-8 weeks post-surgery, using the mFOLFOX6 regimen, planned for a total of 12 cycles. The specific dosing regimen was as follows: (1) Oxaliplatin 85 mg/m² was intravenously infused for 2 hours on the first day; (2) Leucovorin 400 mg/m² was intravenously infused for 2 hours on the first day; and (3) Fluorouracil 400 mg/m² was intravenously pushed on the first day, followed by continuous intravenous infusion of 2400 mg/m² for 46 hours. Every two weeks constitutes a cycle.

Glucose-lowering treatment regimen

Glucose control target: A uniform glycemic control target was set for all patients (FBG 4.4-7.0 mmol/L, non-FBG < 10.0 mmol/L). This study did not interfere with the choice of glucose-lowering regimen in the control group, only prohibiting the use of SGLT2 inhibitors. The actual glucose-lowering regimens of both groups were recorded in detail throughout the treatment process.

Control group: Received mFOLFOX6 chemotherapy regimen plus routine glucose management with hypoglycemic agents. Their glucose-lowering treatment was implemented by an endocrinologist based on the patient’s specific condition, and the regimen may include lifestyle interventions, the use of various oral hypoglycemic agents other than SGLT2 inhibitors, and insulin therapy. For patients with good glycemic control, drug intervention may be temporarily withheld.

Experimental group: Dapagliflozin 5 mg orally once daily, starting on the day chemotherapy began, continued until the end of chemotherapy or the criteria for discontinuation were met.

Observation indicators

Survival indicators: The main observation indicators were 3-year disease-free survival (DFS) rate. DFS refers to the interval between randomization and tumor progression or death from all causes.

Tumor marker indicators: Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were detected before and after treatment, respectively, using electrochemiluminescence immunoassay. The normal reference range of CEA was less than 5 ng/mL, and that of CA19-9 was less than 37 U/mL[14].

Glycemic control indicators: HbA1c and FBG were measured before and after treatment, respectively.

Treatment-related adverse reactions: Serious adverse events during treatment [risk of acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary/reproductive system infection, etc.] were recorded and graded according to the CTCAE 5.0 standard.

Statistical analysis

Data analysis was conducted using SPSS 21.0 software. Continuous data were expressed as mean ± SD, and the independent samples t-tests were used for inter-group comparison. Counting data were expressed as the n (%), and comparisons between groups were conducted using the χ² test or Fisher’s exact test. The survival curves were plotted using the Kaplan-Meier method, and the survival rates between groups were compared using the Log-rank test. P < 0.05 was considered statistically significant.

Randomization and blinding methods

The random sequence was generated by a professional statistician using computerized random number generation software, and the allocation sequence was concealed using sequentially numbered, opaque, sealed envelopes. The envelopes were opened by an independent nurse who was not involved in patient enrollment, treatment implementation, or outcome assessment to assign patients to the experimental group or control group. Given the obvious differences in hypoglycemic treatment methods between the two groups, patient blinding was not feasible. However, outcome assessors (including those responsible for tumor marker detection, imaging evaluation, and adverse event recording) and statisticians were blinded to the group assignments throughout the study. Detailed records of all hypoglycemic agents used in the control group were maintained, including drug types, dosages, and adjustment timelines, to facilitate subsequent subgroup analysis of potential confounding factors.

RESULTS

Comparison of baseline data between the two groups

Table 1 indicated that there was no statistically significant difference in age, gender, tumor location, TNM stage, HbA1c, FBG, epidermal growth factor receptor, CEA, and CA19-9 between the two groups (P > 0.05).

Table 1 Comparison of baseline data between the two groups, mean ± SD.

Indicators	Control group (n = 80)	Experimental group (n = 80)	t/χ2	P value
Age (years)	61.21 ± 8.49	60.75 ± 9.13	0.330	0.742
Gender (male/female)	45/35	47/33	0.102	0.749
Tumor location			0.120	0.989
Transverse colon	9	10
Right colon	25	24
Left colon	16	17
Sigmoid colon	30	29
TNM staging			0.332	0.847
III A	15	16
III B	46	48
III C	19	16
Glycated hemoglobin (%)	8.06 ± 0.84	8.02 ± 0.83	0.310	0.757
Fasting blood glucose (mmol/L)	7.81 ± 1.93	7.85 ± 1.89	-0.130	0.896
Epidermal growth factor receptor (ml/minute/1.73 m²)	87.92 ± 13.24	86.59 ± 14.52	0.605	0.546
Carcinoembryonic antigen	15.95 ± 3.53	16.83 ± 3.49	-1.587	0.115
Carbohydrate antigen 19-9	86.48 ± 3.99	87.35 ± 3.85	-1.405	0.162

It compares the continuous variables (e.g., age, glycated hemoglobin, fasting blood glucose, epidermal growth factor receptor, carcinoembryonic antigen, carbohydrate antigen 19-9) between the two groups by independent samples t-tests, and the categorical variables (e.g., gender, tumor location, TNM stage) by χ² test. The results show that there is no statistically significant difference between the two groups (P > 0.05).

Comparison of glycemic control between the two groups

Table 2 demonstrated that the experimental group showed a significant advantage in glycemic control. The mean HbA1c and FBG levels after treatment in the experimental group were significantly lower than those in the control group (both P < 0.001).

Table 2 Comparison of glycemic control between the two groups, mean ± SD.

Indicators	Time	Control group (n = 80)	Experimental group (n = 80)	t/χ2	P value
Glycated hemoglobin (%)	Before treatment	8.06 ± 0.84	8.02 ± 0.83	0.310	0.757
	After treatment	7.75 ± 0.59	6.79 ± 0.79	8.671	< 0.001
Fasting blood glucose (mmol/L)	Before treatment	7.81 ± 1.93	7.85 ± 1.89	-0.130	0.896
	After treatment	7.45 ± 1.29	6.75 ± 1.56	3.106	0.002

It compares glycated hemoglobin and fasting blood glucose levels before and after treatment between the control and experimental groups using paired sample t-tests. The results show that while no significant differences existed at baseline (P > 0.05), the experimental group achieved significantly greater reductions in both glycated hemoglobin and fasting blood glucose levels after treatment compared to the control group (P < 0.05).

Comparison of tumor marker indicators between the two groups

Table 3 displayed that the levels of CEA and CA19-9 decreased significantly after treatment in both groups, with a greater reduction observed in the experimental group compared to the control group (both P < 0.05), indicating superior tumor marker response in patients receiving dapagliflozin.

Table 3 Comparison of tumor marker indicators between the two groups, mean ± SD.

Indicators	Time	Control group (n = 80)	Experimental group (n = 80)	t/χ2	P value
Carcinoembryonic antigen	Before treatment	15.95 ± 3.53	16.83 ± 3.49	-1.587	0.115
	After treatment	4.52 ± 1.15	3.59 ± 1.24	4.942	< 0.001
Carbohydrate antigen 19-9	Before treatment	86.48 ± 3.99	87.35 ± 3.85	-1.405	0.162
	After treatment	34.57 ± 7.23	31.51 ± 6.43	2.833	0.005

It compares the levels of tumor markers (carcinoembryonic antigen and carbohydrate antigen 19-9) before and after treatment between the control and experimental groups using independent samples t-tests. The results show that while no significant differences existed at baseline (P > 0.05), the experimental group exhibited significantly greater reductions in both carcinoembryonic antigen and carbohydrate antigen 19-9 levels after treatment compared to the control group (P < 0.05).

Comparison of survival indicators between the two groups

Table 4 and Figure 1 displayed that the experimental group had significantly higher 1-year (85.00% vs 62.50%, P = 0.001), 2-year (60.00% vs 37.50%, P = 0.004), and 3-year survival rates (43.75% vs 22.50%, P = 0.004), as well as a longer median DFS (31.6 months vs 19.0 months, Log-rank P < 0.001), compared to the control group.

Figure 1 Comparison chart of survival curves of the two groups of patients. DFS: Disease-free survival.

Table 4 Comparison of survival indicators between the two groups.

Survival indicators (%)	Control group (n = 80)	Experimental group (n = 80)	Statistics	P value
Survival rate for one year	62.50	85.00	χ2= 10.460	0.001
Survival rate for two years	37.50	60.00	χ2= 8.105	0.004
Survival rate for three years	22.50	43.75	χ2= 8.154	0.004
Median disease-free survival (months)	19.00	31.60	Log-rank = 12.898	< 0.001

It compares the 1-year, 2-year, and 3-year survival rates, as well as the median disease-free survival (DFS), between the control and experimental groups using the χ² test (for survival rates) and the Log-rank test (for median DFS). The results showed that the experimental group had significantly higher survival rates at all time points and a significantly longer median DFS compared to the control group (all P < 0.05).

Comparison of adverse events between the two groups

Treatment-related adverse events:Table 5 showed a similar profile of treatment-related adverse events – primarily gastrointestinal reactions, myelosuppression, and neurotoxicity – in both groups, with no statistically significant difference in the incidence of grade ≥ 3 events (56.25% vs 47.50%, P > 0.05).

Table 5 Comparison of treatment-related adverse events between the two groups of patients, n (%).

Adverse reaction type	Control group (n = 80)		Experimental group (n = 80)		χ2	P value
	Any level	≥ 3 level	Any level	≥ 3 level
Gastrointestinal reaction	50 (62.50)	10 (12.50)	53 (66.25)	12 (15.00)	0.245	0.620
Myelosuppression	58 (72.50)	22 (27.50)	61 (76.25)	25 (31.25)	0.295	0.587
Neurotoxicity	49 (61.25)	6 (7.50)	52 (65.00)	8 (10.00)	0.242	0.623
Total ≥ level 3		38 (47.50)		45 (56.25)	1.227	0.268

It compares the incidence of treatment-related adverse events between the two groups using the χ² test. The results show no statistically significant differences in the incidence rates of gastrointestinal reactions, myelosuppression, neurotoxicity, or the total incidence of grade ≥ 3 adverse events between the control and experimental groups (all P > 0.05).

Serious adverse events: The occurrence of serious adverse effects was higher in the experimental group than in the control group, mainly including AKI (9 cases), DKA (2 cases), genital fungal infection (3 cases), and symptomatic urinary tract infection (4 cases). A detailed review of the nine AKI cases in the experimental group revealed that most occurred during the first 2-3 cycles of chemotherapy. All patients had received adequate intravenous hydration per protocol before oxaliplatin infusion. None were on concurrent nephrotoxic medications like non-steroidal anti-inflammatory drugs at the time of AKI. All AKI events were grade 1-2, with serum creatinine levels 1.2-1.5 times the baseline value, and returned to normal within 1-2 weeks after discontinuing dapagliflozin, strengthening hydration, and discontinuing non-steroidal anti-inflammatory drugs. The 2 DKA cases occurred when complicated by severe infection and difficulty eating, and were cured after active anti-infection, fluid replacement, and insulin therapy. No treatment-related deaths occurred.

DISCUSSION

CRC is the world’s third largest common gastrointestinal malignancies and the second largest cause of cancer-associated death. According to statistics, there were more than 1.9 million new cases of CRC worldwide and about 904,000 deaths in 2022, accounting for about approximately one-tenth of all cancer cases and deaths, resulting in a heavy disease burden[1]. Despite advanced treatments like screening, surgery, and chemotherapy, CRC remains a major global health challenge[3]. Meanwhile, T2DM is the most prevalent type of diabetes, affecting 90% of cases worldwide with its prevalence continuing to rise[15]. Studies have indicated that T2DM is a known risk element for CRC[16]. In addition, T2DM has been shown to have a adverse impact on the prognosis of CRC patients. Studies have shown that all-cause and cancer-specific mortality risks are elevated in CRC patients with T2DM, and have a worse DFS and shorter OS than patients without diabetes[17]. Hyperglycemia, insulin resistance, and a chronic inflammatory microenvironment are considered key factors promoting tumor proliferation, invasion, and metastasis[18]. Therefore, optimizing glycemic management and improving DFS in the comprehensive treatment of CRC patients with T2DM has become an important topic of clinical research.

As an alternative to CRC III, standard treatment based on mFOLFOX6 (including fluorouracil, leucovorin, and oxaliplatin) is used to significantly reduce the risk of postoperative recurrence and increase survival rates[6,19]. In China, mFOLFOX6 is the first-line treatment for advanced CRC[20]. Nevertheless, the clinical application of mFOLFOX6 is limited, and its side effects include bone marrow suppression, neurotoxicity and gastric sedation. For type 2 diabetes, chemotherapy can further deteriorate glucose levels, increase the risk of infection, and undermine the tolerance and effectiveness of chemotherapy[21]. Therefore, exploring novel hypoglycemic drugs that combine good hypoglycemic effects with potential antitumor activity holds significant importance improving the treatment outcomes of CRC patients with T2DM.

Sodium-dependent glucose transporters 2 inhibitors have recently been one of the most attractive new classes of types hypoglycemic drugs. Over the last couple of years, SGLT2 inhibitors have demonstrated considerable clinical benefits in the prevention and treatment of diabetes mellitus. This is achieved through targeting and inhibiting the expression of SGLT2 in the proximal tubules, thereby reducing sodium and glucose reabsorption and subsequently lowering blood glucose levels[22]. Hence, this can ameliorate various cell damages and reduce the symptoms of diabetes[23]. Moreover, apart from lowering blood glucose, SGLT2 inhibitors have also been found to have cardiovascular protective effects and renal protection[24]. More importantly, preclinical studies and some observational studies suggest that SGLT2 inhibitors may have direct or indirect antitumor effects by multiple mechanisms, including but not limited to: (1) SGLT2 inhibitors suppress tumor growing by restricting glucose ingestion in tumor cells, and glucose is a crutial energy source for the progression of cancer[25]; (2) SGLT2 inhibitors inhibit cervical cancer cell migration and induce apoptosis by activating AMP-activated protein kinase to regulate Sonic Hedgehog Signaling Molecule expression[26]; and (3) SGLT2 inhibitors also reduce the breast cancer cells proliferation through high membrane polarization and mitochondrial membrane instability[27]. For example, studies have established that dapagliflozin can suppress the growth and migration of gastric cancer cells in vitro and inhibit tumor growth in the body[28]. In addition, studies have shown that the SGLT2 inhibitor dapagliflozin can inhibit the inflammatory response by inhibiting the activity of nucleotide oligomerization domain-like receptor protein 3 inflammasomes containing pyridine structures in the kidney and reducing the release of proinflammatory cytokines such as interleukin-1 beta[29]. Therefore, based on a kidney disease model, SGLT2 inhibitors may inhibit intestinal inflammation, delay the progression of CRC precursor lesions, and thus reduce the risk of CRC. However, clinical studies on the combined use of SGLT2 inhibitors with standard chemotherapy regimens (such as mFOLFOX6), especially data on their influence on the long-term survival of CRC patients, are still very limited.

While the anti-tumor effects of SGLT2 inhibitors in CRC remain under investigation, their action likely intersects with CRC-specific biology. Notably, constitutive activation of the Wnt/β-catenin pathway drives most CRC cases and promotes stemness and immune evasion[30,31]. SGLT2 inhibitors may indirectly modulate this axis by ameliorating hyperinsulinemia – a known Wnt activator – and reducing chronic inflammation that fuels tumor progression within the CRC microenvironment[32]. Furthermore, given the critical role of gut microbiota and butyrate-producing bacteria in suppressing CRC[32], SGLT2 inhibitors-induced metabolic shifts could favorably reshape the colonic microbial landscape. Future studies should directly assess SGLT2 inhibitors effects on Wnt signaling, immune contexture, and microbiome composition in CRC.

This randomized controlled trial investigated the efficacy and safety of dapagliflozin combined with mFOLFOX6 adjuvant chemotherapy (experimental group) and mFOLFOX6 adjuvant chemotherapy plus routine glucose management with hypoglycemic agents excluding SGLT2 inhibitors (control group) in stage III CRC patients with T2DM. Regarding glycemic control, the experimental group showed significantly lower mean HbA1c and FBG levels than the control group (both P < 0.001). This result confirms the potent and stable glucose-lowering ability of SGLT2 inhibitors, demonstrating excellent performance even under chemotherapy stress. Secondly, in terms of oncology prognostic indicators, the experimental group showed significantly greater reductions in CEA and CA19-9 levels after treatment compared to the control group (both P < 0.05). As for survival indicators, after three years of follow up the experimental group had significantly greater 3-year DFS than the control group (P < 0.05), with a median of nearly 12 months of DFS improvement. These data continue to suggest that the addition of dapagliflozin to mFOLFOX6 chemotherapy provides meaningful survival benefit for this group of patients.

Despite these positive findings, there are several limitations in this study. The first relates to the single-center investigation with a comparatively restricted sample size of 160 cases, which may prevent accurate assessment of the risk of rare adverse reactions such as ketoacidosis, further limiting the generalizability of results and introducing a potential for selection bias. A key methodological limitation is the heterogeneous nature of glucose-lowering therapy in the control group (routine glucose management), which could include various agents (e.g., metformin, sulfonylureas, dipeptidyl peptidase 4 inhibitors, insulin) with potentially different effects on insulin levels, inflammation, and cancer progression. This heterogeneity makes it challenging to definitively attribute the observed survival benefits solely to the specific effects of dapagliflozin, as opposed to differences in the intensity or mechanism of glycemic control between the groups. Future trials should consider more standardized comparator arms. The second limitation is that mechanisms are still insufficient. While advantages have been demonstrated in both tumor marker reduction and survival outcome improvements in the experimental group, there is still a shortage of direct biological evidence on whether SGLT2 inhibitors enhance chemotherapy sensitivity through mechanisms of regulating glucose metabolism in tumor cells, affecting the insulin/insulin-like growth factor 1 axis, or altering the tumor microenvironment. In addition, CRC patients often use other treatments such as targeted therapies and immunotherapy. Courses of diabetes and the combined use of other hypoglycemic agents may also act as confounding factors and influence the accurate judgment of the independent effect of SGLT2 inhibitors. According to the above-mentioned deficiencies, the following aspects must be further explored in future research. First, large-scale, dedicated randomized controlled trials for CRC patients T2DM are recommended, strictly controlling confounding factors with prespecified subgroup analysis to identify the advantageous population. At the mechanistic level, model experiments in and out of body should be used to systemically study the influence of SGLT2 inhibitors on CRC cell chemosensitivity, regulation of the tumor microenvironment, and the expression of drug transport protein, and to elucidate their mechanism of action from multiple perspectives. A comprehensive monitoring system must be established in the clinical setting to guarantee safety medication use. Meanwhile, differences in different SGLT2 inhibitors need further study regarding their efficacy, optimal timing of initiation, and duration of treatment, so as to establish evidence-based personalized treatment strategies. It is necessary to actively develop the research in these directions to elucidate the rule of SGLT2 inhibitors in CRC comprehensive treatment and thus create new ways to improve prognosis.

CONCLUSION

In summary, this research has shown that the combination of SGLT2 inhibitor (dapagliflozin) and mFOLFOX6 regimen (experimental group) compared with mFOLFOX6 regimen plus routine glucose management with hypoglycemic agents excluding SGLT2 inhibitors (control group) in patients with stage III CRC comorbid with T2DM appears to be trending towards improved oncological outcomes potentially through higher rates of tumor response and recurrence-free survival, together with a potentially tolerable and predictable safety profile. All adverse events were consistent with the expected spectra of both chemotherapeutic agents, as well as SGLT2 inhibitors. Importantly, these findings are preliminary; the precise biological mechanisms, including possible effects on tumor metabolism and the tumor microenvironment, are unknown, which emphasizes the pressing need for higher quality, multicentre studies and concept-specific mechanistic studies. Confirmation would involve a systematic validation study involving larger cohorts, and the setting of a new therapeutic target could develop into new integrated and personalized approaches to CRC patients with T2DM.