Additive interaction between the renin-angiotensin system and lipid metabolism for cancer in type 2 diabetes.
OBJECTIVE
Clinical and experimental studies suggest cross-talk between lipid metabolism and the renin-angiotensin system (RAS) in atherogenesis. The aim of this study was to explore interactions between these two systems in mediating cancer risk in type 2 diabetes.


METHODS
A prospective cohort of 4,160 Chinese patients with type 2 diabetes, free of cancer at enrollment, were analyzed using Cox models. Interaction of RAS inhibitors (angiotensin I-converting enzyme inhibitors or angiotensin II receptor blockers) and statins was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates additive interaction between the two classes of drugs. Molecular mechanisms underlying these interactions were explored using a uninephrectomy (UNX) rat model with renal carcinogenesis.


RESULTS
During 21,992 person-years of follow-up, 190 patients developed cancer. Use of RAS inhibitors and statins in isolation or combination during follow-up was associated with reduced risk of cancer after adjustment for covariates. The multivariable RERI and AP for the additive interaction between these drug classes for cancer were significant (0.53 [95% CI 0.20-0.87] and 2.65 [0.38-4.91], respectively). In the UNX rat model, inhibition of the RAS prevented renal cell carcinoma by normalizing hydroxymethylglutaryl-CoA reductase (HMGCR) expression and the insulin-like growth factor-1 (IGF-1) signaling pathway.


CONCLUSIONS
Combined use of RAS inhibitors and statins may act synergistically to reduce cancer risk, possibly via HMGCR and IGF-1 signaling pathways in high-risk conditions such as type 2 diabetes.
Yang
Xilin
X
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China. yang.xilin@cuhk.edu.hk
Zhao
Hailu
H
Sui
Yi
Y
Ma
Ronald C W
RC
So
Wing Yee
WY
Ko
Gary T C
GT
Kong
Alice P S
AP
Ozaki
Risa
R
Yeung
Chun Yip
CY
Xu
Gang
G
Tong
Peter C Y
PC
Chan
Juliana C N
JC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000453:epidemiology; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D007297:Inpatients; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D007677:Kidney Function Tests; D007680:Kidney Neoplasms / Q000453:epidemiology; D008055:Lipids / Q000502:physiology*; D017706:Lisinopril / Q000627:therapeutic use; D009369:Neoplasms / Q000150:complications* / Q000453:epidemiology / Q000378:metabolism*; D010045:Outpatients; D051381:Rats; D017207:Rats, Sprague-Dawley; D012042:Registries; D012084:Renin-Angiotensin System / Q000502:physiology*; D012307:Risk Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D008055:Lipids; D007334:Insulin-Like Growth Factor I; D017706:Lisinopril