Low HDL cholesterol, metformin use, and cancer risk in type 2 diabetes: the Hong Kong Diabetes Registry.
OBJECTIVE
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.


METHODS
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.


RESULTS
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]).


CONCLUSIONS
The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol.
Yang
Xilin
X
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. yang.xilin@cuhk.edu.hk
So
Wing Yee
WY
Ma
Ronald C W
RC
Kong
Alice P S
AP
Lee
Heung Man
HM
Yu
Linda W L
LW
Chow
Chun-Chung
CC
Ozaki
Risa
R
Ko
Gary T C
GT
Chan
Juliana C N
JC
D000328:Adult; D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008505:Medical Staff, Hospital / Q000706:statistics & numerical data; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology* / Q000378:metabolism / Q000517:prevention & control; D011237:Predictive Value of Tests; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects
D008076:Cholesterol, HDL; D007004:Hypoglycemic Agents; D008687:Metformin