1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2009 年７月２日 8:30-8:55 ８階 医局 L. G. Hemkens & U. Grouven & R. Bender & C. Günster & S. Gutschmidt & G. W. Selke & P. T. Sawicki Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study Diabetologia DOI 10.1007/s00125-009-1418-4, 2009 J. M. Jonasson, R. Ljung, M. Talbäck B. Haglund, S. Gudbjörnsdòttir, G. Steineck Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden Diabetologia, 2009

6. インスリングラルギン（ ® ランタス）に関する重要なお知らせ 平成 21 年 6 月 29 日 6 月 26 日、ヨーロッパ糖尿病学会 (EASD) は、インスリングラルギン（ ® ランタス）と発 癌の関連についての 4 つの論文が Diabetologia 誌に掲載されることになり、そのうちドイ ツ、スウェーデンで行われた研究でランタス単独使用者において、ヒトインスリン使用 者や他の超速効型アナログ製剤使用者などに比べて、癌の頻度が高かったと報告してい ると発表しました（ http://www.diabetologia-journal.org/cancer.html ）。一方、イギリス で行われた試験ではランタス治療と発癌との関連は認められませんでした。また、スウ ェーデンやスコットランドでの試験では、乳癌のみがランタス単独治療により増加ある いは増加傾向を示しており、他の癌では増加はありませんでした。 EASD は、現時点で はこれらの試験からランタスと発癌の関連について何らの結論をも導くことはできない としており、今後発売元であるサノフィ - アベンティス社および規制当局と協力して世 界規模での調査を続行していく必要があるとしています。また、更なる情報が得られる まではランタスの使用をやめないように注意を喚起しています。なお、インスリンデテ ミル（ ® レベミル）に関しては、発売からの期間が短いため、今回の試験では調査され ていません。 http://www.diabetologia-journal.org/cancer.html 本学会としては、今後サノフィ・アベンティス社に世界規模での特に発癌に関連する安 全性情報の提供を求めるとともに、厚生労働省など規制当局などとも協議の上、適宜そ の情報を提供していきたいと思います。添付の EASD 、 ADA などの見解も参照し、会員 の先生方の判断のもと、ランタスを使用されている患者さんあるいは今後使用する患者 さんに対して、必要に応じて上記のような発癌に関する論文が存在することやヒトイン スリン製剤などで治療する選択肢についても十分説明して頂きたく思います。 日本糖尿病学会 問い合わせ先 学術調査研究・教育担当 南條輝志男 広報担当 加来浩平 事務局長 植木浩二郎

9. Peter Kurtzhals, Lauge Schäffer, Anders Sørensen, Claus Kristensen, Ib Jonassen, Christoph Schmid, and Thomas Trüb : Correlations of Receptor Binding and Metabolic and Mitogenic Potencies of Insulin Analogs Designed for Clinical Use Diabetes 49:999– 1005, 2000 insulin aspart (B28Asp human insulin) insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin) insulin detemir (NN304) [B29Lys(«-tetradecanoyl),desB30 human insulin] cf. Insulin glulisine [3B-lysine-29B-glutamic human insulin] : insulin receptor 0.7, IGF-1 0.2-0.25

10. Editorial Does diabetes therapy influence the risk of cancer? (U. Smith, E. A. M. Gale) Articles Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study (L. G. Hemkens, U. Grouven, R. Bender, C. Günster, S. Gutschmidt, G. W. Selke, P. T. Sawicki):Germany Insulin glargine use and short-term incidence of malignancies–a population-based follow-up study in Sweden (J. M. Jonasson, R. Ljung, M. Talbäck, B. Haglund, S. Gudbjörnsdòttir, G. Steineck) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes (C. J. Currie, C. D. Poole, E. A. M. Gale) UK Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group (SDRN Epidemiology Group) Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open- label study (J. Rosenstock, V. Fonseca, J. B. McGill, M. Riddle, J.-P. Hallé, I. Hramiak, P. Johnston, M. Davis) Letter Results of a post-hoc analysis of tumour development during the diabetic retinopathy study R Perfetti http://www.diabetologia-journal.org/cancer.html

11. L. G. Hemkens (*) : U. Grouven : R. Bender : P. T. Sawicki Institute for Quality and Efficiency in Health Care (IQWiG), U. Grouven Hannover Medical School, Hannover, Germany R. Bender : P. T. Sawicki Faculty of Medicine, University of Cologne, Cologne, Germany C. Gunster : S. Gutschmidt : G. W. Selke AOK Research Institute (WIdO), Berlin, Germany

12. Background 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.

13. 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. Methods A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years.

14. Fig. 1 Flow diagram of the data analysed

18. Intermediate and final models with HRs (95% CIs) for insulin analogues (reference group: human insulin) for malignant neoplasms Table 2

19. Intermediate and final models with HRs (95% CIs) for insulin analogues (reference group: human insulin) for all-cause mortality Table 3

20. aspart lispro glargine

24. 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. Results

25. 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. Conclusion

28. BACKGROUND In the light of a report suggesting that insulin glargine may increase cancer occurrence, the EASD asked us to perform this study.

29. METHODS We followed 114,841 individuals who had a prescription dispensed for insulin between 1 July and 31 December 2005. From 1 January 2006 to 31 December 2007, we noted the occurrence of malignancies. Seven different nationwide registers were used to obtain information on insulin exposure, outcome and possible confounders; these were linked using the unique personal identity number assigned to every Swedish resident.

37. RESULTS After adjustment for age and, when appropriate, sex, users of insulin glargine monotherapy (no other types of insulin), compared with users of types of insulin other than insulin glargine, had an RR of 1.99 (95% CI 1.31-3.03) for breast cancer, 0.93 (95% CI 0.61-1.40) for gastrointestinal cancer, 1.27 (95% CI 0.89-1.82) for prostate cancer and 1.07 (95% CI 0.91- 1.27) for any type of malignancy. Adjustment for age, smoking, BMI, age at onset of diabetes, age at birth of first child, cardiovascular disease and oestrogen use gave an RR for breast cancer of 1.97 (95% CI 1.29-3.00). The 95% CIs crossed 1.0 for the RR calculated in all analyses of users of insulin glargine in combination with other types of insulin.

38. CONCLUSION In Sweden, during 2006 and 2007, women using insulin glargine monotherapy (no other types of insulin) had an increased incidence rate of breast cancer as compared with women using types of insulin other than insulin glargine. This result may be due to a random fluctuation; the possibilities for examining validity are limited, and no statistically significant results were obtained for any other individual cancer site or for the outcome ‘all malignancies’. No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurence of malignancies can be drawn from the results of this study.