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

Abstract

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.

Research design and 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.

FIG. 1.

Kaplan-Meier plot showing the cumulative incidences of cancer in patients with type 2 diabetes stratified by a combination of use of statins and RAS inhibitors over the follow-period (P for log-rank test < 0.0001).

FIG. 2.

UNX-induced renal cell carcinoma in remnant kidney. Kidney tissues 10 months after the operation were obtained from sham rats (A), untreated UNX rats (B), and UNX rats treated with the ACEI lisinopril (C). Periodic acid Schiff stain demonstrates invasive renal cell carcinoma in remnant kidney of untreated UNX rats (B), but not of sham rats or UNX rats treated with the ACEI. Original magnification × 100. (A color representation of this figure is available in the online issue.)

FIG. 3.

Renal dysfunction and elevated LDL cholesterol after uninephrectomy. Compared with sham rats, UNX rats progressively developed renal dysfunction, as assessed by the urine protein-to-creatinine ratio (A) and hyperlipidemia (B), as reflected by the elevated LDL cholesterol level. The proteinuria and hyperlipidemia were largely attenuated by treatment with the ACEI lisinopril. Data are means ± SD. *P < 0.05 vs. sham and ACEI.

FIG. 4.

Changes in protein expression of HMGCR in renal cortex and the effects of treatment with an ACEI (lisinopril). Renal tissue specimens were obtained 10 months after the operation. Western blot assays revealed a fourfold increase of HMGCR protein expression in the remnant kidney cortex of untreated UNX rats. This overexpression of HMGCR was largely normalized by treatment with the ACEI lisinopril. *P < 0.05 vs. sham and ACEI.

FIG. 5.

Changes in protein expression of the IGF-1 signaling pathway in renal cortex and the effects of treatment with an ACEI (lisinopril). Renal tissue specimens were obtained 10 months after the operation. Compared with sham rats, protein expression of the cancer-suppressing IGFBP3 was substantially diminished, whereas the cancer-promoting signals of Akt and PKCζ were increased in the untreated UNX rats. Treatment with an ACEI largely normalized the protein expression of these key molecules in the IGF-1 signaling pathway.