Incident Type 2 Diabetes Duration and Cancer Risk

A Prospective Study in Two US Cohorts

Yang Hu, ScD; Xuehong Zhang, MD, ScD; Yanan Ma, PhD; Chen Yuan, ScD; Molin Wang, PhD; Kana Wu, MD, PhD; Fred K. Tabung, MSPH, PhD; Deirdre Tobias, ScD; Frank B. Hu, MD, PhD; Edward Giovannucci, MD, ScD; Mingyang Song, MD, ScD


J Natl Cancer Inst. 2021;113(4):381-389. 

In This Article


Leveraging data from 2 large prospective cohorts, we found around 21% increased risk of total cancer, 28% increased risk of obesity-related cancer, and 25% increased risk of diabetes-related cancer comparing participants with and without diabetes. For individual cancers, incident T2D was associated with increased incidence of colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, esophagus cancer, breast cancer, and endometrial cancer. The cancer risks reached highest levels at 4–8 years after T2D diagnosis after which the risk elevation was no longer increased. Through analyzing key diabetes-related biomarkers, we found that C-peptide level was on average lower among participants with more than 8 years of diabetes duration than diabetes patients with shorter disease duration, whereas HbA1c level was generally higher for patients with longer diabetes duration. With careful adjustment of important confounders in all analyses, these 2 lines of evidence collectively favor the insulin resistance and hyperinsulinemia hypothesis that indicates T2D as a direct risk factor in the cancer etiology, rather than a spurious association confounded by common risk factors between T2D and cancer.

Results from the current study were largely in line with a previous meta-analysis of 12 cohorts consisting of 257 222 participants, which found 10% increased risk of cancer incidence among diabetes patients compared with those without diabetes.[22] We observed a slightly stronger association for cancer incidence, which could result from the exclusion of prostate cancer, the only type of cancer inversely associated with T2D. In addition, to our knowledge, this is the first study to specifically examine the association between T2D and obesity-related cancer as a single group. However, our data suggest that not all included individual obesity-related cancers were positively associated with T2D. The positive associations were primarily driven by colorectal cancer, pancreatic cancer, thyroid cancer, esophagus cancer, liver cancer, breast cancer, and endometrial cancer. Additional adjustment for BMI attenuated associations for all obesity-related cancer, suggesting that overall body fatness could partially explain the increased cancer risk among diabetics.

Through categorical modeling and spline analysis of diabetes duration, our study demonstrated that the cancer risk gradually reduced after 8.0 years of diabetes duration when the risks were highest during the diabetes duration. Ascertainment bias was unlikely to explain the positive association because similar increased cancer risks were found between 0–2.0 years and 4.1–6.0 or 6.1–8.0 years of diabetes duration. It is notable that even though different cancers have distinct etiologic factors, the pattern of relationship with T2D duration was remarkably similar for individual cancers (colorectal, breast, endometrial, pancreatic), suggesting shared underlying biological mechanisms linking T2D to these cancers. These findings may imply that hyperinsulinemia in early diabetes plays a greater role than hyperglycemia in promoting cancer development because the hazard ratios of cancer decreases after reaching a certain diabetes stage when endogenous insulin secretion is gradually depleted because of exhaustion of β cell function. Our data on C-peptide and HbA1c support this hypothesis because we found the decline of the C-peptide level approximately coincided with the decrease of cancer risk, whereas the HbA1c level keeps increasing during the extended course of diabetes.

The strengths of the current study included a large sample size with long term of follow-up, use of incident T2D only, comprehensive repeated assessments of lifestyle and dietary factors, and a high follow-up rate. We also explicitly addressed the reverse causality, ascertainment bias, and influence of cancer screening. Our study also had some limitations. First, although our analysis included several major types of cancer, we did not have data to examine the associations for certain uncommon cancers such as bile duct cancers, which have been associated with T2D.[23] Second, despite meticulous adjustment for potential confounders, we could not rule out residual confounding in our analysis particularly for BMI, which is closely related with T2D. However, given the consistent positive associations observed for most included cancers, residual confounding is unlikely to fully account for these statistically significant associations. Third, despite that we adjusted for the hypoglycemic drug use, detailed information on specific drug use such as sulphonylurea, metformin, and thiazolidinediones were lacking. However, it is difficult to assess the influence of such incomplete adjustment on the diabetes-cancer associations because of substantial heterogeneity in the effects of different hypoglycemic drugs on cancer risk.[24–26] Additional long-term prospective cohort studies with comprehensive information on insulin and oral hypoglycemic drug use are needed to clarify the associations between individual diabetes drugs and cancer risk. Fourth, we were unable to directly examine the prospective association between circulating insulin level and diabetes duration because the repeatedly measured insulin was not available in our cohorts. Nonetheless, our biomarker analysis on C-peptide and HbA1c could still provide some insights to further understand the mechanisms underlying the diabetes-cancer associations. Finally, because the study participants were mostly White health professionals, whether our findings could be generalized to other populations remains unclear. However, the association between diabetes and major cancers incidence did not appear to differ substantially by ethnicity groups.[27–29]

In conclusion, the cancer risks were statistically significantly increased after diabetes diagnosis, but the increased risk appeared to plateau or decrease after 8 years of diabetes duration, which coincided with the change of plasma C-peptide level over time. Our findings support a role of hyperinsulinemia in cancer development.