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      Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study

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          The aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin analogues.


          Data were provided by the largest German statutory health insurance fund (time-frame: January 1998 to June 2005 inclusive), on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin, aspart, lispro or glargine. The primary outcome was the diagnosis of a malignant neoplasm. Data were analysed by multiple Cox regression models adjusting for potential confounders.


          A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years. A positive association between cancer incidence and insulin dose was found for all insulin types. Because patients receiving combined therapy with insulin analogues and human insulin were excluded, the mean daily dose was much lower for glargine than for human insulin, and a slightly lower cancer incidence in the glargine group was found. After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin ( p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart ( p = 0.30) or lispro ( p = 0.96) compared with human insulin.


          Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogues, especially glargine.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-009-1418-4) contains supplementary material, which is available to authorised users.

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          Most cited references 22

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          Metformin and reduced risk of cancer in diabetic patients.

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            Adjusting for multiple testing--when and how?

            Multiplicity of data, hypotheses, and analyses is a common problem in biomedical and epidemiological research. Multiple testing theory provides a framework for defining and controlling appropriate error rates in order to protect against wrong conclusions. However, the corresponding multiple test procedures are underutilized in biomedical and epidemiological research. In this article, the existing multiple test procedures are summarized for the most important multiplicity situations. It is emphasized that adjustments for multiple testing are required in confirmatory studies whenever results from multiple tests have to be combined in one final conclusion and decision. In case of multiple significance tests a note on the error rate that will be controlled for is desirable.
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              Diabetes mellitus and risk of colorectal cancer: a meta-analysis.

              Diabetes has been associated with an increased risk of colorectal cancer in most, but not all, studies. Findings have also been inconclusive with regard to sex and subsite in the colorectum. To resolve these inconsistencies, we conducted a meta-analysis of published data on the association between diabetes and the incidence and mortality of colorectal cancer. We identified studies by a literature search of Medline from January 1, 1966, through July 31, 2005, and by searching the reference lists of pertinent articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. All statistical tests were two-sided. Analysis of 15 studies (six case-control and nine cohort studies), including 2 593 935 participants, found that diabetes was associated with an increased risk of colorectal cancer, compared with no diabetes (summary RR of colorectal cancer incidence = 1.30, 95% CI = 1.20 to 1.40), without heterogeneity between studies (P(heterogeneity) = .21). These results were consistent between case-control and cohort studies and between studies conducted in the United States and in Europe. The association between diabetes and colorectal cancer incidence did not differ statistically significantly by sex (summary RR among women = 1.33, 95% CI = 1.23 to 1.44; summary RR among men = 1.29, 95% CI = 1.15 to 1.44; P(heterogeneity) = .26) or by cancer subsite (summary RR for colon = 1.43, 95% CI = 1.28 to 1.60; summary RR for rectum = 1.33, 95% CI = 1.14 to 1.54; P(heterogeneity) = .42). Diabetes was positively associated with colorectal cancer mortality (summary RR = 1.26, 95% CI = 1.05 to 1.50), but there was evidence for heterogeneity between studies (P(heterogeneity) = .04). Our findings strongly support a relationship between diabetes and increased risk of colon and rectal cancer in both women and men.

                Author and article information

                Springer-Verlag (Berlin/Heidelberg )
                30 June 2009
                September 2009
                : 52
                : 9
                : 1732-1744
                [1 ]Institute for Quality and Efficiency in Health Care (IQWiG), Dillenburger Straße 27, D-51105 Cologne, Germany
                [2 ]Hannover Medical School, Hannover, Germany
                [3 ]Faculty of Medicine, University of Cologne, Cologne, Germany
                [4 ]AOK Research Institute (WIdO), Berlin, Germany
                © The Author(s) 2009
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                © Springer-Verlag 2009


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