We thank Zhang and Giovannucci (1) for their interest in our article (2) and their comments, which allow us to further clarify some epidemiological and analytical details we mentioned in the article.
The main finding of our analysis is the lack of evidence of an association, which does not indicate the absence of it. While previous studies have robustly shown a higher risk of some cancers in individuals with versus without type 2 diabetes, the association between duration of diabetes and cancer risk is sparser and contrasting. After our publication, investigators of a large multicohort study found evidence of a greater risk of cancer-related mortality in individuals with versus without type 2 diabetes adjusting for age and several risk factors; however, in line with our results, there was no evidence of an association between duration of diabetes and cancer mortality (3).
Regarding the epidemiological design, in view of the available evidence we did not include a nonexposed population as our aim was not to compare the risk of cancer in individuals with versus without type 2 diabetes. Importantly, a higher risk of cancer incidence in individuals with type 2 diabetes, compared with those without, does not necessarily imply a greater risk in individuals with a longer versus shorter diabetes duration: as highlighted in your letter and in our manuscript, the excess in cancer risk in individuals with type 2 diabetes is likely related to hyperinsulinemia/insulin resistance, which commonly occurs earlier than hyperglycemia, which plays a pivotal, and potentially duration-dependent, role in the risk of vascular complications.
From an analytical perspective, we note that all regression models included attained age and age at diagnosis; rather than unadjusted, estimated rates are model-based predictions conditional on specific values of attained age and diabetes duration, a well-known methodological approach in epidemiology and demography (4). Furthermore, as attained age is, by definition, a linear combination of age at diagnosis and duration of diabetes (attained age = age at diagnosis + duration), it is not clear how this statistical transformation would result in a “selection” bias. In addition, our survival models included a spline not only for duration but also for attained age, the two timescales that were modeled simultaneously: the advantages of this approach, compared with the further suggestion of categorizing duration or using diabetes duration in the model as time-fixed covariate (i.e., duration at “baseline”), have been discussed in the article and previously investigated in detail both from a general methodological perspective (5,6) and in the specific context of diabetes duration, where the effect of diabetes duration likely changes for different ages (7). Lastly, our cohort comprised individuals with early-onset type 2 diabetes (inclusion criteria: age ≥35 years at diagnosis) but the low event rates resulted in imprecise predictions for people with diabetes diagnosed between 35 and 50 years; we, therefore, agree with Zhang and Giovannucci that future studies would require larger cohorts and longer follow-ups for wider ranges of age at diagnosis.
Article Information
Funding. This study was partly funded by Hope Against Cancer (grant no. RM60G0690). Work of M.D. is co-funded by the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre and University of Leicester. K.K. and F.Z. are supported by the NIHR Applied Research Collaboration East Midlands and the NIHR Leicester Biomedical Research Centre. Work of S.L. is funded by the Cancer Research UK program “Inequalities in Cancer Outcomes” (EPNCZS34).
The funding bodies had no role in the study design, data collection, data analysis, interpretation of results, or writing of the manuscript.
Duality of Interest. K.K. has acted as a consultant or speaker or received grants for investigator-initiated studies for AstraZeneca, Novartis, Novo Nordisk, Sanofi, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, and Bayer. M.D. has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk, and Sanofi; advisory board member and speaker for AstraZeneca; advisory board member for Janssen, Lexicon, Pfizer, Medtronic, and ShouTi Pharma; and speaker for Napp Pharmaceuticals, Novartis, and Takeda Pharmaceuticals International. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim, AstraZeneca, and Janssen. No other potential conflicts of interest relevant to this article were reported.
