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 2015 年 1 月 22 日 8:30-8:55 ８階 医局 Liao WC, Tu YK, Wu MS, Lin JT, Wang HP, Chien KL. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. BMJ Jan 2;349:g7371. doi: /bmj.g7371.

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) Letter Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study （ J. Rosenstock, V. Fonseca, J. B. McGill, M. Riddle, J.-P. Hallé, I. Hramiak, P. Johnston, M. Davis ）

Metformin monotherapy carried the lowest risk of cancer. metformin metformin & SU Diabetologia Sep;52(9):

因果関係を検証する研究方法として、大規模コホート研究はバイアスを避けて 実証データを得るために最も有用な疫学研究であるが、 1 つの研究から得られた 関連からは、偶然・バイアス・交絡による可能性を否定できない。したがって、 複数の疫学研究からのエビデンスに基づき、動物実験などのデータも参考にし ながら因果関係の 有無を判断しなくてはならない。 津金昌一郎（国立がん研究センター） ;Diabetes Frontier,22,1,2011. 糖尿病 糖負荷試験 空腹時血糖 HbA1c 自己申告糖尿病 無作為化比較試験 コホート研究 症例対照研究 癌 罹患・死亡 因果関係 交絡 肥満、喫煙、飲酒、 運動不足、肝疾患など バイアス 診断、因果逆転、 対象・対照の選 択、思い出しな ど 偶然 α- エラー、検出 力不足など 糖尿病と癌／関連と因果関係

RECORD study Lancet Jun 20;373(9681): Epub 2009 Jun 6.

There was no difference in the overall incidence of malignant neoplasms. There were some imbalances in the incidence of individual tumours. There were more bladder tumours (14 vs six) and fewer cases of breast cancer (three vs 11) reported in the pioglitazone group compared with placebo. アクトス群(n=2605)プラセボ群(n=2633) p イベント例数患者例数イベント例数患者例数 新生物118112(4%)117113(4%)NS 悪性新生物‡10397(4%)10399(4%)NS 結腸直腸癌 16(1%) 15(1%)0.834 肺癌 15(1%) 12(1%)0.544 膀胱癌 14(1%) 6(<1%)0.069 膀胱癌(除外後)§ 6(<1%) 造血器癌 6(<1%) 10(<1%)0.327 乳癌 3(<1%) 11(<1%)0.034 その他 47(2%) 46(2%)0.876 Dormandy J.A. et al:Lancet,366,1279,2005. PROactive 試験における癌患者発生率 悪性新生物の全体的な発生率に差は認められなかった。個々の腫瘍の発生率のいくつかの不 均衡があった。プラセボと比較してピオグリタゾン群で膀胱腫瘍（14対6）が多く、乳がんは （3対11）有意に低下していた。 ‡：症例の中には複数種の腫瘍も認められている §：盲検解除後に検討した例

Objective To evaluate potential linear and non-linear dose- response relations between blood glucose and risk of pancreatic cancer.

Design Systematic review and dose-response meta- analysis of prospective observational studies. Data sources Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. Eligibility criteria Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. Data extraction and synthesis Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations.

Fig 1 Flow chart of literature search for studies investigating association between blood glucose concentration and risk of pancreatic cancer

Table 2 Rate ratios for pancreatic cancer in studies included in systematic review and dose-response meta-analysis on blood glucose concentration and rate of pancreatic cancer

Fig 2 Summary rate ratio of pancreatic cancer, highest v lowest blood glucose category. Weights from random effects analysis. *Estimated from reported post-load blood glucose or haemoglobin A1c concentrations. †Pooled from rate ratios for men and women. ‡Pooling of rate ratios for men and women not feasible because categorisation of blood glucose differed between sexes

Fig 3 Summary linear trend of rate ratio per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose. Weights from random effects analysis

Fig 4 Dose-response relation between fasting blood glucose and rate ratio for pancreatic cancer, showing point estimates and 95% confidence interval for non-linear analysis and point estimates for linear analysis. Circles indicate adjusted rate ratios in individual studies; size of bubble is proportional to precision (inverse of variance) of rate ratio [mg/dl]

Fig 5 Dose-response relation between fasting blood glucose and rate ratio for pancreatic cancer, excluding categories with assigned fasting blood glucose concentration >7.0 mmol/L. Graph shows point estimates and 95% confidence interval for non-linear analysis and point estimates for linear analysis. Circles indicate adjusted rate ratios in individual studies; size of bubble is proportional to precision (inverse of variance) of rate ratio [mg/dl]

Results Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer.

Conclusions Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer.

Message 前向き観察研究 9 件（膵臓癌患者 2408 人）を対 象に、血糖値と膵臓癌リスクの関連をシステマ ティックレビューおよび用量反応メタ解析で検討。 前糖尿病状態および糖尿病において空腹時血糖値 と膵臓癌の発症率に強力な線形の用量反応関係が 見られた。空腹時血糖値 0.56mmol/L (10mg/dl) 上昇ごとに膵臓癌の発症率が 14 ％増 加することが示された。 IGT で血糖を低下させると介入が影響あるかは？ RECORD 研究では rosiglitazone は膵癌を顕著 に減らしている！