Abstract
Aims/hypothesisThe aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies.MethodsNational Health Registries from Denmark (1996–2010), Finland (1996–2011), Norway (2005–2010) and Sweden (2007–2012) and the UK Clinical Practice Research Datalink database (1987–2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (≤0.5, 0.5–1, 1–2, 2–3, 3–4, 4–5, 5–6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin.ResultsA total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for ≤0.5 years of treatment and for malignant melanoma for 2–3 years (RR 1.92, 95% CI 1.02, 3.61) and 4–5 years (RR 3.55, 95% CI 1.68, 7.47]); among men, a lower risk was observed for pancreatic cancer for 2–3 years (RR 0.34, 95% CI 0.17, 0.66) and for liver cancer for 3–4 years (RR 0.36, 95% CI 0.14, 0.94) and >6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences.Conclusions/interpretationThe present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.
Highlights
Diabetes mellitus and cancer are common diseases with rising incidence and prevalence globally [1, 2]
Ever-use of insulin glargine and insulin detemir was most common in the Finnish cohort, as was the baseline use of non-insulin glucose-lowering therapy
For any cancer in women, we found an elevated risk for 0.5 year of insulin glargine use relative to human insulin (RR 1.17, 95% CI 1.03, 1.32); in men, there was a lower risk for 0.5–1 year (RR 0.87, 95% CI 0.77, 1.00), 1–2 years (RR 0.84, 95% CI 0.73, 0.95) and >6 years (RR 0.61, 95% CI 0.48, 0.78) of exposure (Figs 1, 2 and ESM Table 1)
Summary
Diabetes mellitus and cancer are common diseases with rising incidence and prevalence globally [1, 2]. Diabetes is associated with an increased risk for certain cancers [3] and the pattern and magnitude of the excess risk are generally similar for type 1 and 2 diabetes [4, 5]. It has been suggested that certain diabetes risk factors, as well as glucose-lowering medications, may contribute to this association [6]. In 2009, the publication of four observational studies [7,8,9,10] sparked concerns about insulin glargine as a potential modifier of cancer risk [11]. Initial observational studies [7,8,9,10] were criticised for limitations and biases [11, 13, 14] such as short follow-up, inclusion of prevalent insulin users and time-lag bias [15]. Further attempts to rule out or confirm the association yielded inconsistent findings, emphasising the importance of properly designed and conducted observational studies [16]
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