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To the Editor: Nagel et al. [1] raise a number of questions regarding the analyses in our paper [2]; these analyses, in their opinion, led to confounded measures of association. We agree that potential confounding plays an essential role and can never be completely ruled out in analyses of observational data. However, we do not agree that the possibility of confounding inevitably leads to the conclusion that such results are definitely wrong and cannot reflect real risks. The main concern of Nagel et al. [1] is their assumption of an unequal distribution of patients with type 1 and type 2 diabetes in the insulin glargine (A21Gly,B31Arg,B32Arg human insulin) and human insulin groups. They seem to have overlooked the sensitivity analysis reported in our article that included only patients with a history of prescription of oral glucose-lowering agents (Table 4 in [2]). There is a very high probability that this subgroup of patients consists solely of patients with type 2 diabetes. In this subgroup the main results were essentially unaltered. This fact rules out the suspicion that our results are caused by the presence of a higher percentage of type 1 diabetic patients in the human insulin group. Nagel et al. [1] further hypothesise that bias is introduced by ignoring intrinsic insulin production in patients in the insulin glargine group. However, in patients receiving high doses of insulin, intrinsic insulin production becomes negligible; hence, such a bias would be expected to be greatest in patients receiving relatively small doses of insulin. Our data are contrary to this anticipated result in that they show that the most pronounced difference in the risk of malignant neoplasms between insulin glargine and human insulin occurs for high doses. Additionally, the adjustment made for treatment dose is criticised. We found that the risk of cancer diagnosis increased with the dose of insulin. As the dose of insulin is essential for its biological effect, it must be taken into account in every analysis. Inclusion of the individual insulin dose as a covariate was pre-specified in the study protocol. The rationale for the analysis of exposure to a single type of insulin per group was described in the article. Nagel et al. [1] correctly state that a notable percentage of patients were not included because the date of study inclusion and the date of their first event was identical. This is explained by the fact that, in this context, censoring because of study end was also counted as an event. Additionally, the data had some fuzziness inasmuch as study entry and study end dates were given to the month rather than to the day. U. Grouven (*) : L. G. Hemkens : R. Bender : P. T. Sawicki Institute for Quality and Efficiency in Health Care (IQWiG), Dillenburger Str. 27, 51105 Cologne, Germany e-mail: ulrich.grouven@iqwig.de

diabetologia

Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues. Reply to Nagel JM, Mansmann U, Wegscheider K et al. [letter] and Simon D [letter]