Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and cancer risk: an updated meta-analysis of observational studies

Shin, Kayeong; Yang, Jiwoo; Yu, Yeuni; Son, Eunjeong; Kim, Ki‐Hun; Kim, Yun Hak

doi:10.1177/20420986221129335

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…Lee SH et al (2022) conducted a population-based cohort study in Korea and indicated that RAAS inhibitors use was not associated with gynecologic cancers [ 44 ]. A meta-analysis of observational studies found no preventive effect of RAAS against gynecologic cancers [ 45 ]. Inconsistences between our finding and other studies may be due to the differences in study design, and adjusted confounders.…”

Section: Discussionmentioning

confidence: 99%

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study

Nguyen

Huang

et al. 2023

IJMS

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The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan’s Health and Welfare Data Science Center (2000–2016) and linked with Taiwan Cancer Registry (1979–2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85–0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20–39 years (aOR: 0.70, 95% CI: 0.58–0.85), 40–64 years (aOR: 0.77, 95% CI: 0.74–0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83–0.91), and overall (aOR: 0.81, 95% CI: 0.79–0.84). Ovarian cancer risk was significantly lower in the groups aged 40–64 years (aOR: 0.76, 95% CI: 0.69–0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75–092), and overall (aOR: 0.79, 95% CI: 0.74–0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20–39 years (aOR: 2.54, 95% CI: 1.79–3.61), 40–64 years (aOR: 1.08, 95% CI: 1.02–1.14), and overall (aOR: 1.06, 95% CI: 1.01–1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40–64 years (aOR: 0.88, 95% CI: 0.84–0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83–0.90), and overall (aOR: 0.88, 95% CI: 0.85–0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86–0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.

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Section: Discussionmentioning

confidence: 99%

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study

Nguyen

Huang

et al. 2023

IJMS

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“…Also, in all cancer group the overall risk was reduced [ 54 ]. Other research team, in turn, reported an increased risk of melanoma [relative risk (RR): 1.09, 95% CI: 1.00–1.19] and kidney cancer (RR: 1.50, 95% CI 1.01–2.23) in ACE-I-treated patients, but a decreased risk of oesophageal cancer (RR: 0.73, 95% CI: 0.57–0.94) [ 55 ]. Furthermore, a reduced survival from malignant diseases among hypertensive individuals emerged in two randomized controlled trials: with enalapril (OR = 1.59, 95% CI: 0.90–2.820) and benazepril (OR = 1.52, 95% CI: 0.45–5.42).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Regulska,

Michalak,

Kolenda

et al. 2023

Rep Pract Oncol Radiother.

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Background Ovarian cancer is a huge therapeutic and financial problem for which approved treatments have already achieved their limit of efficiency. A cost-effective strategy to extend therapeutic options in this malignancy is drug repurposing aimed at overcoming chemoresistance. Here, angiotensin-converting enzyme inhibitors (ACE-I) are worth considering. Materials and methods We searched literature for publications supporting the idea of adjuvant application of ACE-Is in ovarian malignancy. Then, we searched The Cancer Genome Atlas databases for relevant alternations of gene expression patterns. We also performed in silico structure-activity relationship evaluation for predicting ACE-Is’ cytotoxicity against ovarian cancer cell lines. Finally, we reviewed the potential obstacles in ACE-Is repurposing process. Results The alternation of angiotensin receptor expression in ovarian cancer translates into poorer patient survival. This confirms the participation of the renin-angiotensin system in ovarian carcinogenesis. In observational studies, ACE-Is were shown synergize with both, platinum-based chemotherapy as well as with antiangiogenic therapy. Consistently, our in silico simulation showed that ACE-Is are probably cytotoxic against ovarian cancer cells. However, the publications on their chemopreventive properties were inconclusive. In addition, some reports correlated ACE-Is use with increased general cancer incidence. We hypothesized that this effect could be associated with mutagenic nitrosamine formation in ACE-Is’ pharmaceutical formulations, as was the case with angiotensin receptor blockers (ARBs) and other well-established pharmaceuticals. Conclusions Available data warrant further research into repositioning ACE-Is to ovarian cancer as chemosensitizers. Prior to this, however, a special research program is needed to detect possible genotoxic contaminants of ACE-Is.

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“…Safety concerns, in particular, relate to their pro-carcinogenic potential, evidenced by increased incidence of malignancy among ACE-Is users [3,4]. Specifically, the risk regards common neoplastic conditions such as: endometrial [5,6], melanoma, kidney and female reproductive cancers [7][8][9][10][11]. Furthermore, their capacity to stimulate lung cancer, which is the most common human neoplastic condition [12][13][14], was implied.…”

Section: Introductionmentioning

confidence: 99%

Impact of ramipril nitroso-metabolites on cancer incidence — in silico and in vitro safety evaluation

Regulska,

Kolenda,

Michalak

et al. 2023

Rep Pract Oncol Radiother.

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Background Angiotensin-converting enzyme inhibitors (ACE-I) and their pharmacologically related sartans have been associated with an increased cancer incidence in several clinical observations. In 2018, sartans were revealed as being significantly contaminated with nitrosamines. Nitrosamines are potent human mutagens that can be formed ex vivo and, more concerningly, also in vivo from nitrosatable drug precursors. Their formation in sartans may justify the reported cancer risk and, by analogy, this may also apply to ACE-Is. Materials and methods We investigated a commonly used ACE-I, ramipril (RAM). We checked its susceptibility to in vivo interaction with nitrite, potentially resulting in the generation of mutagenic N-nitrosamines. To that end, in silico simulation of mutagenicity of RAM nitroso-derivatives was performed using VEGA-GUI software. Then, the Nitrosation Assay Procedure was conducted which served as a model of endogenous reaction. The resulting post-nitrosation mixtures were subjected to a bacterial reverse mutation test employing Salmonella typhimurium strains TA98 and TA100 with and without metabolic activation. Results Our results showed that studied samples did not induce point mutations in the test bacteria, regardless of the catalytic cytochrome activity. Conclusion We concluded that RAM endogenous nitrosation is not the reason for increased cancer incidence. However, other ACE-Is must be verified in a similar manner.

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Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and cancer risk: an updated meta-analysis of observational studies

Cited by 7 publications

References 23 publications

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study

Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study

Angiotensin-converting enzyme inhibitors for ovarian cancer? — a new adjuvant option or a silent trap

Impact of ramipril nitroso-metabolites on cancer incidence — in silico and in vitro safety evaluation

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