Association between Time in Range and Cancer Mortality among Patients with Type 2 Diabetes: A Prospective Cohort Study
The relationship between diabetes and cancer has been a subject of significant interest in medical research. Both diseases share common risk factors such as obesity, metabolic disorders, physical inactivity, unhealthy diet, alcohol consumption, and smoking. Diabetes has been associated with an increased risk of cancer mortality, with some studies suggesting a 25% higher risk among diabetic patients. However, the specific role of glycemic control, particularly metrics like time in range (TIR), in cancer mortality remains underexplored. This study aimed to investigate the association between TIR, time above range (TAR), time below range (TBR), and the risk of cancer mortality among patients with type 2 diabetes.
The study was conducted as a prospective cohort analysis involving 6,225 patients with type 2 diabetes in Shanghai, China. These patients were recruited between January 2005 and December 2015 and followed up until December 31, 2018. The primary outcome was cancer mortality, with secondary outcomes focusing on site-specific cancer mortality. TIR was measured using continuous glucose monitoring (CGM) at baseline, defined as the average percentage of time spent within the target glucose range of 70 to 180 mg/dL (3.9–10.0 mmol/L) during a 24-hour period. TAR and TBR were similarly defined as the percentage of time spent above and below this range, respectively.
Baseline characteristics of the study population revealed that patients with TIR greater than 70% were younger, had a shorter duration of diabetes, and exhibited better metabolic profiles compared to those with TIR of 70% or less. The mean age of the participants was 61.7 years, and the mean follow-up duration was 7.10 years. During this period, 237 cancer-related deaths were confirmed. Multivariable-adjusted Cox proportional hazards regression analysis was used to determine the association between TIR and cancer mortality.
The results showed that patients with TIR of 70% or less had a 32% higher risk of cancer mortality compared to those with TIR greater than 70%, with a hazard ratio (HR) of 1.32 (95% confidence interval [CI]: 1.01–1.75). When TIR was analyzed as a continuous variable, each 10% decrease in TIR was associated with a 7% increase in the risk of cancer mortality (HR: 1.07; 95% CI: 1.02–1.14). These findings suggest a significant inverse relationship between TIR and cancer mortality among patients with type 2 diabetes.
In site-specific analyses, a notable association was observed between TIR and the risk of hepatocellular cancer mortality. The HR for hepatocellular cancer mortality associated with each 10% decrease in TIR was 1.24 (95% CI: 1.09–1.41). However, no significant relationship was found between hemoglobin A1c (HbA1c) and overall cancer mortality (HR: 1.04; 95% CI: 0.97–1.10), indicating that TIR may be a more robust marker for cancer risk than HbA1c in this population.
Sensitivity analyses were conducted by excluding patients with a prior history of cancer, and the results remained consistent. The multivariable-adjusted HR for cancer mortality in patients with TIR of 70% or less was 1.25 (95% CI: 0.92–1.70), and each 10% decrease in TIR was associated with an 8% increase in cancer mortality risk (HR: 1.08; 95% CI: 1.01–1.15). Subgroup analyses further confirmed these findings across different age groups, sexes, body mass index (BMI) categories, smoking status, and medication use.
The study also explored the associations between TAR, TBR, and cancer mortality. TAR, which reflects hyperglycemia, was significantly associated with cancer mortality in both the major analysis (HR: 1.08; 95% CI: 1.02–1.14) and sensitivity analysis (HR: 1.08; 95% CI: 1.01–1.14). In contrast, TBR, which indicates hypoglycemia, showed no significant association with cancer mortality. This suggests that hyperglycemia, rather than hypoglycemia, may be a more critical factor in cancer mortality among patients with type 2 diabetes.
The findings of this study add to the growing body of evidence supporting the use of TIR as a valuable metric for glycemic control and its association with diabetic complications. Unlike HbA1c, which provides a single measure of average glucose levels, TIR captures glycemic variability and exposure to both hyperglycemia and hypoglycemia. This makes TIR a more comprehensive marker for assessing the risk of comorbidities in diabetic patients.
The potential mechanisms underlying the association between hyperglycemia and cancer mortality are multifaceted. Hyperglycemia may promote tumor progression by enhancing glucose uptake, upregulating glycolysis, and disrupting cell cycle regulation. Additionally, hyperinsulinemia and insulin resistance, common in type 2 diabetes, can stimulate the proliferation and metastasis of cancer cells through insulin and insulin-like growth factor (IGF) receptors. Chronic inflammation and hormonal imbalances associated with diabetes may also contribute to cancer progression.
The strengths of this study include its large sample size, long follow-up duration, and the use of CGM to measure TIR. However, there are limitations to consider. Socioeconomic and lifestyle factors were not accounted for, which could influence cancer mortality. Additionally, TIR was measured only once at baseline, and the study population consisted of inpatients, which may introduce selection bias. Future research should explore the impact of multiple TIR measurements and include a broader population to validate these findings.
In conclusion, this study provides strong evidence of an inverse association between TIR and the risk of cancer mortality among patients with type 2 diabetes. TIR emerges as a superior marker for assessing cancer risk compared to HbA1c, highlighting its potential as an optimal target for glycemic control in diabetic patients. These findings underscore the importance of maintaining optimal glucose levels to reduce the risk of cancer mortality in individuals with type 2 diabetes.
doi.org/10.1097/CM9.0000000000001740
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