Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Diabetes Care. 2011 Feb;34(2):375-80. doi: 10.2337/dc10-1509. Epub 2010 Oct 27.
The AMP-activated protein kinase (AMPK) pathway is a master regulator in energy metabolism and may be related to cancer. In type 2 diabetes, low HDL cholesterol predicts cancer, whereas metformin usage is associated with reduced cancer risk. Both metformin and apolipoprotein A1 activate the AMPK signaling pathway. We hypothesize that the anticancer effects of metformin may be particularly evident in type 2 diabetic patients with low HDL cholesterol.
In a consecutive cohort of 2,658 Chinese type 2 diabetic patients enrolled in the study between 1996 and 2005, who were free of cancer and not using metformin at enrollment or during 2.5 years before enrollment and who were followed until 2005, we measured biological interactions for cancer risk using relative excess risk as a result of interaction (RERI) and attributable proportion (AP) as a result of interaction. A statistically significant RERI >0 or AP >0 indicates biological interaction.
During 13,808 person-years of follow-up (median 5.51 years), 129 patients developed cancer. HDL cholesterol <1.0 mmol/L was associated with increased cancer risk among those who did not use metformin, but the association was not significant among those who did. Use of metformin was associated with reduced cancer risk in patients with HDL cholesterol <1.0 mmol/L and, to a lesser extent, in patients with HDL cholesterol ≥ 1.0 mmol/L. HDL cholesterol <1.0 mmol/L plus nonuse of metformin was associated with an adjusted hazard ratio of 5.75 (95% CI 3.03-10.90) compared with HDL cholesterol ≥ 1.0 mmol/L plus use of metformin, with a significant interaction (AP 0.44 [95% CI 0.11-0.78]).
The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol.
AMP 激活的蛋白激酶（AMPK）途径是能量代谢的主要调节剂，可能与癌症有关。在 2 型糖尿病中，低 HDL 胆固醇预示着癌症，而二甲双胍的使用与降低癌症风险相关。二甲双胍和载脂蛋白 A1 均可激活 AMPK 信号通路。我们假设，二甲双胍的抗癌作用在低 HDL 胆固醇的 2 型糖尿病患者中可能更为明显。
在 1996 年至 2005 年期间连续入组的 2658 例中国 2 型糖尿病患者队列中，这些患者在入组时或入组前 2.5 年内无癌症且未使用二甲双胍，并随访至 2005 年，我们使用交互超额相对危险度（RERI）和交互归因比例（AP）来衡量癌症风险的生物学交互作用。统计学上显著的 RERI>0 或 AP>0 表明存在生物学交互作用。
在 13808 人年的随访期间（中位数 5.51 年），有 129 例患者发生癌症。在未使用二甲双胍的患者中，HDL 胆固醇<1.0mmol/L 与癌症风险增加相关，但在使用二甲双胍的患者中无显著相关性。在 HDL 胆固醇<1.0mmol/L 的患者中，使用二甲双胍与降低癌症风险相关，在 HDL 胆固醇≥1.0mmol/L 的患者中相关性较弱。与 HDL 胆固醇≥1.0mmol/L 且使用二甲双胍相比，HDL 胆固醇<1.0mmol/L 且未使用二甲双胍的患者调整后的 HR 为 5.75（95%CI3.03-10.90），存在显著的交互作用（AP0.44[95%CI0.11-0.78]）。
二甲双胍的抗癌作用在低 HDL 胆固醇的 2 型糖尿病患者中最为明显。
