Use of RAS inhibitors associated with lower cancer risk in T2D

A real-world study of over 250,000 type 2 diabetes (T2D) patients from Hong Kong has found that use of renin-angiotensin-system inhibitors (RASIs) is independently associated with reduced risk of cancer, including diabetes-related cancers and cancer-specific mortality in diabetes.

Compared with the general population, T2D patients are 1.3–3 times more likely to develop cancer. [N Engl J Med 2011;364:829-841] However, RASIs, which are commonly prescribed to diabetes patients for cardiovascular (CV) and renal protection, are thought to have anticancer effects through blocking the angiotensin II pathway associated with angiogenesis, cellular adhesion, invasion and proliferation. [Sci Rep 2019;9:8565; BMC Cancer 2021;21:1338; Curr Cancer Drug Targets 2005;5:307-323]

“Despite this biological plausibility, compared with the large body of evidence on the benefits of RASIs on CV disease, their anti-cancer benefits in diabetes remain controversial,” wrote the researchers from the Chinese University of Hong Kong. “In this study, we used real-world data from a territory-wide electronic medical record system and evaluated the time-varying risk associations of RASI use with cancer events and related mortality.” [EBioMedicine 2022;doi:10.1016/j.ebiom.2022.10421]

The researchers curated a cohort of 253,491 patients with T2D (mean age, 61.1 years; male, 47.5 percent) from the Hong Kong Diabetes Surveillance Database, including 133,730 (52.8 percent) new RASI users, of whom 73,596 were angiotensin-converting enzyme inhibitor (ACEI) only users, 21,103 were angiotensin receptor blocker (ARB) only users, and 39,031 were ACEI/ARB users.

During a mean follow-up of 6.5 years, 15,030 (5.9 percent) and 6,863 (2.7 percent) patients were diagnosed with all-site cancer and diabetes-related cancers, respectively. A total of 24,768 (9.8 percent) patients died, with 6,590 (2.6 percent) deaths due to cancer and 2,845 (1.1 percent) deaths due to diabetes-related cancer.

Time-varying RASI use was associated with reduced risk of all-site and diabetes-related cancers vs nonuse of RASIs (all-site: hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.74–0.79; diabetes-related: HR, 0.79; 95 percent CI, 0.75–0.84). “For site-specific cancers, RASI use was associated with lower risk of liver [HR, 0.71; 95 percent CI, 0.63–0.81], lung [HR, 0.64; 95 percent CI, 0.59–0.71], colorectal [HR, 0.82; 95 percent CI, 0.76–0.90] and pancreatic cancers [HR, 0.63; 95 percent CI, 0.52–0.76], and neutral risk of breast [HR, 0.93; 95 percent CI, 0.82–1.06] and prostate cancers [HR, 0.86; 95 percent CI, 0.72–1.02],” pointed out the researchers.

In addition, RASI use was associated with lower risk of all-cause mortality (HR, 0.52; 95 percent CI, 0.50–0.53), cancer-specific mortality (HR, 0.50; 95 percent CI, 0.47–0.53), and diabetes-related cancer mortality (HR, 0.49; 95 percent CI, 0.45–0.54).

Compared with ACEI-only use, ARB-only use was associated with lower risk of all-site cancer (HR, 0.90; 95 percent CI, 0.81–0.99), all-cause mortality (HR, 0.71; 95 percent CI, 0.66–0.78), cancer-specific mortality (HR, 0.77; 95 percent CI, 0.66–0.91), and diabetes-related cancer mortality (HR, 0.73; 95 percent CI, 0.57–0.94).

“Due to the more complete blockade of RAS with ARBs, the larger effect size with ARBs vs ACEI is plausible,” commented the researchers. “In addition to directly blocking the effects of angiotensin-II on AT1 receptor, ARBs [but not ACEIs] increase angiotensin-II level. This increase is accompanied by upregulation of ACE2, which converts angiotensin-II to angiotensin that possesses anti-proliferative, anti-inflammatory and anti-cancer effects. Besides, side effects, such as cough, are more common with ACEIs vs ARBs, which may lead to poorer adherence.”