Additive interaction between renin-angiotensin system and lipid metabolism for cancer in type 2 diabetes mellitus

  1. Xilin Yang, PhD (yang.xilin{at}cuhk.edu.hk)1,
  2. Hailu Zhao, PhD (zhaohailu{at}cuhk.edu.hk)1,
  3. Yi Sui, PhD1,
  4. Ronald CW Ma, MBBChir, MRCP1,
  5. Wing Yee So, MD, FRCP1,
  6. Gary TC Ko, MD, FRCP2,
  7. Alice PS Kong, MBChB, FRCP1,
  8. Risa Ozaki, MBChB, MRCP1,
  9. Chun Yip Yeung, MBBS, MRCP1,
  10. Gang Xu, PhD1,
  11. Peter CY Tong, PhD, FRCP1,2,3 and
  12. Juliana CN Chan, MD, FRCP1,2,3
  1. 1Department of Medicine and Therapeutics
  2. 2Hong Kong Institute of Diabetes and Obesity
  3. 3Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    Abstract

    Objective– Clinical and experimental studies suggest cross-talk between lipid metabolism and the renin-angiotensin system (RAS) in atherogenesis. This study aimed to explore interactions between these two systems in mediating cancer risk in Type 2 diabetes mellitus (T2DM).

    Research design and methods - A prospective cohort of 4160 Chinese patients with T2DM, free of cancer at enrolment, was 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 during follow-up was associated with reduced risk of cancer after adjusting for covariates. The multivariable RERI and AP for the additive interaction between these drug classes in cancer patients were significant (0.53, 95% confidence interval: 0.18 to 0.86; and 2.37, 95%CI: 0.27 to 4.48, respectively). In the UNX rat model, inhibition of the RAS prevented renal cell carcinoma by normalizing HMG-CoA reductase (HMGCR) expression and insulin-like growth factor-1(IGF-1) signaling pathway.

    Conclusion 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 T2DM.

    Footnotes

      • Received January 23, 2009.
      • Accepted April 15, 2009.

    This Article

    1. Published online before print April 28, 2009, doi: 10.2337/db09-0105
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