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


The age-standardized characteristics of participants are shown according to T2D status in Table 1. In both cohorts, compared with participants without T2D during the follow-up, participants diagnosed with T2D had older age, higher BMI, higher proportion of non-White race, higher prevalence of hypertension and hypercholesterinemia, less physical activity and alcohol intake, and higher proportion of family history of diabetes but slightly lower proportion of family history of cancer. Women participants diagnosed with T2D were also more likely to use oral contraceptive but less so for postmenopausal hormone. Similar diet quality and total energy intake were found for participants with and without diabetes.

During 4 294 078 person-years of follow-up, we documented in the 2 cohorts a total of 43 849 cancer cases of which 21 977 (50.1%) were obesity-related cancer and 26 904 (61.4%) were diabetes-related cancer. After adjusting for demographic, lifestyle, dietary factors, and BMI, T2D was associated with statistically significantly increased risk of all 3 composite cancer outcomes (Table 2). The pooled hazard ratios were 1.21 (95% CI = 1.16 to 1.26) for total cancer, 1.28 (95% CI = 1.21 to 1.35) for obesity-related cancer, and 1.25 (95% CI = 1.19 to 1.32) for diabetes-related cancer. For individual cancers, T2D was statistically significantly associated with increased risk of colorectal cancer (HR = 1.21, 95% CI = 1.06 to 1.38), lung cancer (HR = 1.27, 95% CI = 1.12 to 1.45), pancreatic cancer (HR = 2.07, 95% CI = 1.70 to 2.52), esophagus cancer (HR = 1.85, 95% CI = 1.28 to 2.69), liver cancer (HR = 3.39, 95% CI = 2.24 to 5.12), thyroid cancer (HR = 1.49, 95% CI = 1.03 to 2.15), breast cancer (HR = 1.26, 95% CI = 1.17 to 1.37), and endometrial cancer (HR = 1.26, 95% CI = 1.06 to 1.50). No statistically significant heterogeneity was found between the 2 cohorts. The associations for postmenopausal breast cancer, estrogen receptor– and progesterone receptor (ER/PR)–positive breast cancer, and ER/PR-negative breast cancer were similar to that for total breast cancer (Supplementary Table 1, available online).

The cancer risks were statistically significantly elevated right after T2D diagnosis, and such risk elevation did not further increase after 8 years of diabetes duration. This risk trajectory was observed for both composite cancer outcomes and most individual cancers that were associated with T2D listed in Table 3. For example, the hazard ratio for developing any cancer increased from 1.29 (95% CI = 1.19 to 1.38) in patients with 0–2.0 years of diabetes duration to 1.37 (95% CI = 1.25 to 1.50) in patients having diabetes for 6.1–8.0 years. The total cancer risk then decreased to 1.21 (95% CI = 1.09 to 1.35) for 8.1–10.0 years of diabetes duration and further down to 1.04 (95% CI = 0.95 to 1.14) after 15.0 years of diabetes duration. The spline analysis revealed statistically significant (P < .05 for all included cancer outcomes) nonlinear relation between diabetes duration and cancer risks; cancer risk appeared to culminate around 6.5–7.5 years after T2D diagnosis and then gradually decreased afterward (Figure 1; Supplementary Figure 1, available online).

Figure 1.

Dose-response relationship between duration of type 2 diabetes and risk of cancer incidence. Data were combined from 2 cohorts. Spline regression adjusted for age (month), ethnicity (White, African American, Asian, others), smoking status (never smoked; past smoker; currently smoke 1–14 cigarettes per day, 15–24 cigarettes per day, or ≥25 cigarettes per day), alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–14.9, 15.0–29.9, and ≥30.0 g/d), multivitamin use (yes, no), physical activity (quintiles), total energy (quintiles), alternative healthy eating index (quintiles), family history of diabetes (yes, no), family history of cancer (yes, no), endoscopy screening (yes, no), and fasting glucose screening (yes, no). For women, insulin use (yes, no), oral hypoglycemic drug use (yes, no), mammography screening (yes, no), postmenopausal hormone use (never, former, or current hormone use, or missing), and oral contraceptive use (yes, no) were further adjusted. P value for nonlinearity <.001 for panels A, B, and C. A) Total cancer incidence; (B) obesity-related cancer incidence; (C) diabetes-related cancer incidence.

In the stratified analysis (Supplementary Table 2, available online), men younger than 60 years had statistically significantly (P interaction = .04) higher risk (HR = 1.75, 95% CI = 1.11 to 2.75) of developing obesity-related cancer than their older counterparts (HR = 1.36, 95% CI = 1.18 to 1.56). However, such effect modification was not found for women. No other statistically significant interactions were detected. The sensitivity analysis that adjusted for the baseline covariates produced similar estimates as in the main models (Supplementary Table 3, available online).

In the secondary analysis (Table 4), we observed that, compared with participants without T2D, participants with prevalent T2D of 8 years or less had higher C-peptide levels, whereas those with longer duration of T2D had lower C-peptide level. The least square geometric mean of plasma C-peptide for participants with T2D duration of 4.1–8.0 years was 2.85 ng/mL (95% CI = 2.43 to 3.34) but 1.73 ng/mL (95% CI = 1.48 to 2.03) in those with 8.1–10.0 years. On the contrary, the HbA1c level was consistently higher among participants with longer diabetes duration, although a slightly lower level was observed for participants with a diabetes duration of more than 15.0 years compared with those with 10–15 years.