We read with great interest in Diabetes Care the study by Zaccardi et al. (1), which has provided novel information for a critical research question. The authors concluded that there is no association between type 2 diabetes (T2D) duration and cancer risk. They argued that cancer risk elevation observed for longer T2D duration may simply be an epiphenomenon of aging, since longer disease duration necessarily results in an older age. However, we encourage a few additional considerations.
First, the authors included only individuals with T2D in the analytic population. This “case-only” analytic strategy precludes demonstrating the relative risk estimates in comparing T2D patients with those without the condition. As shown in Figs. 1C and 2C, the absolute cancer risk decreased significantly during the initial several years following the onset of T2D. This observation appears to align with findings from a previous prospective study, where it was reported that the age-adjusted relative risk of cancer peaked shortly after the diagnosis of T2D, and then leveled off, but remained higher throughout follow-up in comparison with those without T2D (2). Up to the time of diagnosis for T2D, insulin levels generally are high. With increasing duration after diagnosis, insulin levels decrease, while hyperglycemia tends to worsen. The patterns for cancer consistently suggest that insulin resistance and hyperinsulinemia may play a more significant role in the underlying etiology, as opposed to hyperglycemia. This hypothesis is substantiated by a Mendelian randomization analysis, where a causal effect was reported of elevated fasting insulin levels on tumorigenesis—rather than glucose-related traits (3). This contrasts with other sequelae of T2D, such as cardiovascular and renal disease, where cumulative long-term effects of hyperglycemia contribute to the pathogenesis.
Second, attention to the following methodological issues may further strengthen inferences: 1) The majority of the main analyses were conducted based on participants “attaining” a certain age (as shown in Figs. 1B–D, 2B–D, 3, etc.). This analytic strategy may be susceptible to selection bias. 2) This article only demonstrates crude (unadjusted) effect estimates, raising concerns about confounding from a range of factors such as race, BMI, diet quality, smoking, alcohol consumption, physical activity, and family history of diabetes and cancer. 3) Early-onset T2D (diagnosed at <40 years of age) typically exhibits a more severe and aggressive disease profile (4). The impact of early-onset T2D on cancer risk might be more substantial compared with that of later-onset T2D, extending beyond solely the accumulation of a longer disease duration (5). As for the initial analytical group studies commenced at age 50 years, the opportunity was missed to identify the relative risk of cancer associated with early-onset T2D. 4) We encourage the authors to perform multivariable-adjusted restricted cubic spline analysis to explore the dose-response association between T2D duration and the relative risk of cancer. Displaying multivariable-adjusted relative risk estimates for refined disease duration categories (e.g., 0–5, 6–10, 10–15, and 15–20 years) would also be valuable (2). 5) Finally, it would also be meaningful to demonstrate effect estimates for T2D duration beyond 20 years in future studies when data based on extended follow-up are available.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
