Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract, the early diagnosis rate is low (1, 2). In recent years, the diagnosis of CRC has increased significantly due to advances in diagnostic techniques and cancer screening (3). According to the World Health Organization, there were 1,926,425 new cases with CRC and 904,019 new deaths associated with CRC in 2022. By 2035, the global incidence of CRC is expected to increase to 2.5 million new cases (4). The prognosis for treatment of patients with early-stage CRC is significantly better than that of patients with intermediate and late-stage disease (5). Therefore, early detection, screening and treatment can effectively reduce the burden of CRC and decrease the mortality rate of CRC.

While CRC arises from a complex interplay of genetic and environmental factors, emerging evidence highlights metabolic dysregulation—particularly hyperglycemia—as a critical driver of CRC progression. Traditional risk factors such as hereditary syndromes and lifestyle behaviors (e.g., smoking, alcohol consumption) contribute to CRC pathogenesis (6, 7). However, the escalating global prevalence of type 2 diabetes mellitus (T2DM) has drawn attention to hyperglycemia as a modifiable metabolic risk factor. Clinical studies indicate that CRC patients with T2DM exhibit an 18% reduction in 5-year survival compared to non-diabetic counterparts (8), while mechanistic research reveals that hyperglycemia promotes tumor proliferation via BMP4 and PI3K/AKT/mTOR pathways (9, 10). These findings underscore the need to quantify the disease burden specifically attributable to hyperglycemia, independent of other confounders.

Previous study have indicated a notable increase in CRC deaths and disease burden linked to metabolic risks (11, 12), particularly hyperglycemia (12), and highlight the significance of targeted cancer screening for high risk populations and the growing impact of hyperglycemia on CRC burden. However, these studies primarily focused on mortality and DALYs, with less emphasis on other dimensions of disease burden such as years lived with disability (YLDs) and years of life lost (YLLs). Furthermore, they did not extensively explore health inequality issues related to hyperglycemia-associated CRC across different countries.

To bridge these gaps, the present study provides a more nuanced analysis of the hyperglycemia-related CRC burden. Using a similar dataset, this study goes further in its analysis by incorporating not only deaths and DALYs but also YLDs and YLLs, offering a multi-faceted view of the disease’s impact. Additionally, the study introduces a novel perspective on global health inequality regarding hyperglycemia-associated CRC. Importantly, the study also employs hierarchical clustering to reveal variation in disease burden across different regions and countries, providing further evidence of the disparities that exist.

This study provides a systematic and comprehensive description of the global burden of hyperglycemia-associated CRC disease based on the GBD 2021 dataset, and gives the global burden of disease for different SDI levels, geographic regions, sexes, and age groups over a 30-year period from 1990 to 2021, with cross-national inequality analysis. The burden of hyperglycemia-associated CRC was also projected for the years 2022 to 2040.

Previous studies have revealed a notable increase in CRC deaths and disease burden associated with hyperglycemia (12), and underscored the significance of targeted cancer screening for high risk populations and the growing impact of hyperglycemia on CRC burden. Consistently, we found that the ASR of deaths, YLDs, YLLs, and DALYs attributed to hyperglycemia-associated CRC increased significantly globally between 1990 and 2021, with an overall upward trend despite fluctuating in recent years. Mechanically, hyperglycemia triggers counter-regulatory upregulation of insulin and insulin-like growth factor levels, which promotes neoplastic proliferation primarily through PI3K/AKT/mTOR signaling pathway (19). In addition, hyperglycemia can facilitate CRC tumorigenesis via the induction of inflammatory responses, oxidative stress, immunomodulation, and angiogenesis (20). Moreover, elevated blood glucose levels has been demonstrated to increase oxaliplatin chemo-resistance in CRC patients, potentially through the phosphorylation of SMAD3 and MYC and the upregulation of EHMT2 expression (21). Given the ongoing significance of hyperglycemia-associated CRC, these findings offer a mechanistic rationale for developing more effective clinical management strategies to address the public health concern.

In terms of gender differences, the results showed that the four ASRs were higher in male than in female, and that female showed flat or decreasing levels of ASRs compared to 1990, while the increase in male was still greater, suggesting that the male population is at higher risk for CRC. Evidence from population-based studies also suggests that hyperglycemia or diabetes is significantly associated with the risk of CRC in male. It has also been shown that alcohol consumption and smoking have a greater impact on CRC DALYs in men than in women (22–26). This gender difference may be related to differences in the tumor microenvironment, immune response levels and hormone levels, such as the expression of immune-related genomes in female patients is higher than that in males, and endogenous estrogen secretion in females has a protective effect on the development of CRC (27, 28). These results suggest that gender-regulated biological clocks differ significantly in males and females, and that in-depth studies of the mechanisms that contribute to the gender differences in disease burden are needed to provide gender-differentiated pathways for disease prevention, diagnosis, and treatment.

Similar to previous results, our age-stratified analysis of the burden of hyperglycemia-associated CRC in 2021 showed that the burden of disease increased significantly with age (29), with the highest number of death- and disability-adjusted years in the age group 65–74 years. This positive correlation of disease burden with age implies a cumulative effect of hyperglycemic risk exposure. These results illustrate the value of timely control of risk factors in effectively reducing the overall disease burden of CRC, especially in the elderly population.

This study also analyzed the burden of disease of hyperglycemia-associated CRC in different SDI regions. The burden of disease indicators (ASRs of deaths, YLDs, YLLs, and DALYs) had a positive association with SDI levels. The reason for this is hypothesized to be that high SDI regions have fast economic and medical development and more early detection of CRC through screening, cancer registries, and technological improvements, resulting in a higher number of diagnosed cases in High SDI regions, and a higher burden of disease at the time of the data count. However, the overall trend of ASR in these areas is slowly decreasing and the burden is decreasing due to early detection, intervention and treatment. Conversely, in contrast to the overall trend, there is a slow upward trend in disease ASR in Low-middle SDI and Low SDI regions. This may be due to horizontal developmental constraints, as these regions are experiencing a prevariant phase of disease burden in High SDI regions. To further analyze changes in burden trends across districts, we conducted a cluster analysis of burden across the 21 GBD districts. Our findings show that the countries with the highest number of hyperglycemia-associated CRC deaths and increased disease burden are Lesotho and Egypt, in large part because the burden of disease caused by diabetes or hyperglycemia is increasing significantly in these regions. According to a survey, Egypt ranks first in the MENA region in terms of the number of people with diabetes, which itself has the highest prevalence of diabetes in the world. Singapore, on the other hand, has the highest level of decline in ASR. This decline may be largely attributed to the widespread use of early screening programs such as fecal occult blood tests and colonoscopy. Screening programs aim to identify CRCs in the precancerous polyp stage and early malignant stage, which can help reduce CRC morbidity and mortality by removing precancerous lesions before malignant transformation or at an early stage (4, 30). In a meta-analysis of observational studies, screening colonoscopy was associated with a 70% reduction in CRC risk and 68% reduction in mortality. While the efficacy of screening colonoscopy in reducing CRC burden is clear, maximizing its benefit hinges on accurate and efficient histological assessment of detected lesions. Accumulating evidence suggests that deep learning algorithms, particularly convolutional neural networks, play a transformative role in the automated tissue classification and diagnosis of CRC histopathology images (31). These models demonstrate high accuracy in distinguishing between benign and malignant tissues, grading tumor malignancy, and identifying specific histological features related to prognosis, thus assisting pathologists by increasing diagnostic efficiency and reducing subjectivity (31, 32). Leveraging deep learning to automate CRC histopathological diagnosis represents a promising avenue for advancing cancer screening strategies. Overall, it is crucial to develop and implement CRC screening strategies and procedures, which are essential for early detection and improved prognostic survival (33).

To develop more effective treatment options for hyperglycemia-associated CRC, we projected the burden of disease from 2022-2040. According to the results, the ASR of YLDs for hyperglycemia-associated CRC will increase yearly, but other indicators are more stable. As the burden of diabetes is currently increasing and the impact of disability due to diabetes-related complications is growing, there is an urgent need for more complete strategies to mitigate the threat.

In the past 30 years, the health inequality index of hyperglycemia-related CRC has not improved. It implies that there has been a persistent neglect in addressing the uneven distribution of disease burden across different populations, which has contributed to the lack of progress in reducing these health disparities. Moreover, this study shows a split trend: while death-related burdens have lessened, disability burdens, measured by YLDs, are rising, even in high-SDI regions. This highlights the urgent need for targeted interventions. The increase in YLDs suggests more long-term disability from hyperglycemia-related CRC, possibly due to delayed diagnosis, suboptimal treatment, and the disease’s biological traits. Despite advanced medical resources in high-SDI areas, persistent disability burdens may stem from an aging population with higher hyperglycemia and CRC rates and challenges in managing chronic conditions. Current strategies may not effectively prevent or manage this disability, necessitating the development of better interventions to improve overall prognosis.

Different common preventive approaches have been suggested for both diabetes and CRC, focusing on modifiable lifestyle factors, including dietary interventions (e.g. lower dietary glycemic load and total carbohydrate intake) and the promotion of physical activity, as well as the hypoglycemic drugs (34). However, evidence of the effects of the hypoglycemic drugs, for instance, metformin, for chemoprevention remains controversial (35). Notably, a recent large-scale cohort study revealed a significant inverse association between optimal glycemic control (HbA1c <7%) and the risk of left-sided CRC, as well as both non-advanced and advanced colonic adenomas, in diabetic patients (36). Thus, incorporating glycemic management into preventive frameworks for CRC screening may represent a viable strategy for mitigating the associated disease burden. In clinical settings, managing CRC patients with hyperglycemia is often complicated and there are little agreed evidence based guidelines on the best management on this issue (37). The co-existence of both conditions poses a challenge to determining an appropriate glycemic target and the optimal combination therapy due to heterogeneity in patient status and drug-drug reactions. Multidisciplinary collaboration among surgeons, medical oncologists, and endocrinologists is essential for developing effective patient management strategies.

Beyond the imperative for integrated management of hyperglycemia and CRC, other pivotal issues, influencing the long term quality of life and functional outcomes of CRC patients, need to be addressed (38). Specifically, mental health disorders, particularly depression and anxiety, are increasingly recognized as significant predictors of adverse postoperative outcomes in CRC patients (39, 40). A growing body of evidence from observational studies suggests that pre-existing and post-diagnosis depression is associated with a higher risk of postoperative complications, including wound infections and paralytic ileus, potentially through dysregulation of the hypothalamic-pituitary-adrenal axis and impaired immune function (40–42). Therefore, systematic screening for psychological distress and integrating psychosocial interventions into standard perioperative care pathways are not merely supportive measures but crucial components for improving overall prognosis of CRC.

There are some limitations in this study. First, the data for GBD were obtained from cancer registries, among others, but the completeness of the data varies from country to country due to differences in the level of development. Second, due to the wide time frame covered by the study, changes in diagnostic and therapeutic approaches to CRC, and many social and economic factors, the incidence of the disease is more likely to be underestimated in its early stages, and this should be taken into account. Third, despite the finding of a significant increase in the burden of CRC associated with hyperglycemia, the analysis should be interpreted in conjunction with a comprehensive interpretation of multidimensional data to improve the accuracy and robustness of the predictions.

In summary, hyperglycemia-associated CRC poses a growing global burden, with YLDs rising even in high-SDI regions, indicating increasing long-term disability. Despite declining mortality, persistent health inequalities remain across SDI levels and countries. These findings underscore the urgent need for improved glycemic control, early CRC screening, and targeted interventions to reduce disability and address cross-national disparities in disease burden.