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Review article 1
0959-4973 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/CAD.0000000000001345
The effect of angiotensin receptor blockers and angiotensin-
converting enzyme inhibitors on progression of gastric
cancer: systematic review and meta-analysis
Seyed Ali Mehrdada, Farshad Mirzavib,
Seyed Mohammad Reza Seyedic and Ahmad Asoodehc
Angiotensin receptor blockers (ARB), as well as
angiotensin-converting enzyme inhibitors (ACEI),
are mostly used as therapy for hypertension and
cardiovascular disease. However, they can increase the
risk of cancer progression including gastric cancer. Here
we aimed to analyze the assessment between ARB and
ACEI on the progression of gastric cancer. Cochrane
Library, PubMed and EMBASE were searched for articles
and abstracts describing ARBs, ACEIs, and incidence of
gastric cancer. Risk ratio, hazard ratio and 95% confidence
interval (CI) were extracted from each outcome by using
a random-effects model. Six studies met our inclusion
criteria. These results demonstrated that there is a
significant association between ARB with gastric cancer
progression (risk ratio = 0.63; 95% CI, 0.5–0.7; P = 0.00;
I2 = 27.299; df (Q) = 2; Q -value = 2.75). However, there
was not any link between ACEIs and gastric cancer
development (risk ratio = 1.1; 95% CI, 0.92–1.31; P = 0.26;
I2 = 0.00; df (Q) = 3; Q -value = 1.26). All these findings
indicated that using the ARBs has raised the progression
of gastric cancer in these patients. Anti-Cancer Drugs
XXX: 000–000 Copyright © 2022 Wolters Kluwer Health,
Inc. All rights reserved.
Anti-Cancer Drugs XXX, XXX:000–000
Keywords: Gastric cancer; Angiotensin receptor blockers; angiotensin-con-
verting enzyme inhibitors
aDepartment of Biology, Faculty of Science, Hakim Sabzevari University,
Sabzevar, bCardiovascular Diseases Research Center, Birjand University of
Medical Sciences, Birjand, Iran cDepartment of chemistry, Faculty of Science,
Ferdowsi University of Mashhad, Mashhad, Iran
Correspondence to Ahmad Asoodeh, PhD, Department of Chemistry, Faculty of
Science, Ferdowsi University of Mashhad, Mashhad, Iran
Tel: +98 051 3880 5525; e-mail: Asoodeh@um.ac.ir
Received 19 March 2022 Revised form accepted 19 March 2022
Introduction
Gastric malignancy is also known as stomach cancer with
more than seven hundred thousand deaths in both sexes.
Moreover, about 1.09 million new cases of this cancer
have been reported in 2020 [1,2]. In this type of cancer,
cancerous cells mostly are present in the lining of the
stomach [3]. Gastric cancer also can develop from the
stomach to the other organs including liver, lungs, bones,
the lining of the abdomen and lymph nodes [4,5].
Blood pressure and water balance are regulated by the
renin-angiotensin system (RAS) [6]. When a person is
bleeding or their blood pressure drops, the system will
activate. Juxtaglomerular cells in the kidney produce
renin when blood volume is low. By cleaving angioten-
sinogen into its inactive decapeptide form, AngI is pro-
duced by RAS (Fig. 1). The active octapeptide AngII
is formed by the cleavage of AngI by ACE or chymase.
The AngII molecule binds to AT1R and AT2R subtypes
of G-protein coupled receptors, which are subtypes of
AT1R and AT2R, respectively. There is a higher afn-
ity of AT1R binding to AngII and a greater abundance of
AT1R proteins. A primary function of the AngII-AT1R
signaling pathway is to modulate aldosterone synthesis,
vasopressin secretion, cardiac hypertrophy, proliferation
of vascular smooth muscle cells, decrease in renal blood
ow, inhibition of renal renin, as well as central osmoreg-
ulation [7].
Currently used to treat cardiovascular diseases, RAS
inhibitors (RASI) have considerable potential in oncol-
ogy as well. Cancer biology is greatly inuenced by RAS,
which is both directly and indirectly involved in cancer
growth and dissemination [8]. A signicant link between
RAS function and cancer progression has been observed
with AngII, type 1 and type 2 receptors (AT1R, AT2R)
overexpressed in several types of cancer cells and tissues
[6].
Several types of cancer cells and tissues have been shown
to overexpress RAS components, including brain, lung,
breast, prostate, skin and cervical carcinomas, as well as
gastrointestinal malignancies and normal tissues (e.g.
stomach, pancreas and colon) [9].
Currently, some evidence suggests that using angioten-
sin receptor blockers (ARB) and angiotensin-converting
enzyme inhibitors (ACEI) can increase the incidence of
different types of cancers including gastric cancer [10,11].
In fact, ARbs are angiotensin II receptor antagonists that
are used to treat high blood pressure and heart attacks
[12,13]. ACEIs are another common therapy for high
blood pressure and heart failure patients. The main target
Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2 Anti-Cancer Drugs XXX, Vol XXX No 00
for both of these medications is angiotensin II which are
critical in developing the different types of malignancy
[14,15].
The present meta-analysis was aimed to comprehen-
sively assess the link between ARBs and ACEIs in gastric
cancer progression (Fig.1).
Methods
Strategy of search
Searched have been performed comprehensively via two
people individually by using the following databases:
EMBASE, PubMed and the Cochrane library to identify
the studies describing ARB, ACE inhibitors and inci-
dence of gastric cancer. Our search strategy was as fol-
lows: “Angiotensin-Converting Enzyme Inhibitors” OR
“Lisinopril” OR “Cilazapril” OR “Enalaprilat” OR “angi-
otensin converting enzyme inhibitor” OR “angiotensin-
converting enzyme inhibitor” OR “ACE inhibitor” OR
“captopril” OR “ACEI” OR “ramipril” OR “fosinopril”
OR “perindopril” OR “imidapril” OR “moexipril” OR
“quinapril” OR “trandolapril” OR “angiotensin receptor
antagonist” OR “angiotensin receptor blocker” OR “angi-
otensin receptor antagonist” OR “angiotensin receptor
blockade” OR “angiotensin-receptor blocker” OR “angi-
otensin-receptor antagonist” OR “angiotensin-receptor
blockade” OR “renin-angiotensin system inhibitor” OR
“ARB” OR “ARBs” OR “irbesartan” OR “eprosartan”
OR “losartan” OR “renin angiotensin system inhibitor”
OR “RAS inhibitor” OR “telmisartan” OR “valsartan”
OR “olmesartan” OR “candesartan” AND “Gastric can-
cer” OR “Gastric neoplasm” OR “ Gastric carcinoma”
OR “Gastric adenoma” OR “Gastric tumor” OR “Gastric
tumour” OR “Gastric malignan” OR “Gastric polyp” OR
“Gastric lesion” OR “Stomach cancer” OR “Stomach
neoplasm” OR “Stomach carcinoma” OR “Stomach ade-
noma” OR “Stomach tumor” OR “Stomach tumour” OR
“Stomach malignan” OR “Stomach polyp” OR “Stomach
lesion”. A total of six studies met our inclusion criteria.
Databases were scanned from all years of study, until
December 2021 (Fig.2) (Table1).
Data extraction
The author’s name, country, study duration, and study
type were extracted from each article. Risk ratio (RR),
odds ratio (OR), hazard ratios and 95% condence inter-
vals (CIs) also were extracted from the studies. However,
the articles not in English were excluded from the study.
Statistical analysis
A comprehensive meta-analysis (CMA, version 2.2.064) was
used to calculate pooled association of ARBs as well as ACEIs
on the progression of gastric cancer. OR, hazard ratio, as well
Fig. 1
Renin-Angiotensin System (RAS) pathways. RAS pathways can be divided into two types: circulatory and local.
Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Effect of ARB and ACE inhibitors on the progression of gastric cancer Mehrdad et al. 3
Fig. 2
Flowchart of the studies included in meta-analyses.
Table 1 Characteristics of included studies
Study Country Study period Study type Adjustments
Chang, et al.,
[16]
Taiwan July 2000 to
Dec. 2000
Case-Control Age, sex, use of ARB, antihypertensive drugs, insulin, oral hypoglycemic agents, statins, underlying diseases
Kim, et al.,
[17]
South Korea May 2002 to
May 2010
Cohort Physical examination, surgical, pathologic reports, imaging, chemotherapy regimens, response, date of pro-
gression, last follow-up, death, use of hypertension
medications (ACEIs or ARBs).
Kumekawa,
et al., [18]
Japan Jan. 2007 to
Dec. 2011
Cohort Not applicable
Ryo, et al.,
[19]
Japan June 2001 to
April 2004
Cohort Age, BMI, diagnosis, acute coronary syndrome, dyslipidemia, diabetes mellitus, cerebrovascular disease,
current smoker, Previous myocardial infarction, total cholesterol, use of aspirin/NSAIDs, statin
Sjöberg, et
al., [20]
Spain 1994–2001 Cohort Esophageal cancer, gastric cancer, other cancer, age of 85 years, death or end of study period
Wang, et al.,
[21]
Taiwan Jan. 1997 to
Dec. 2009
Cohort Hypertension, statin, diuretics, use of ACEI/ARB, diabetes mellitus, heart failure
ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.
Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
4 Anti-Cancer Drugs XXX, Vol XXX No 00
as 95% CI were extracted from all studies, and we consid-
ered hazard ratio and OR as a risk ratio because according to
the references when the frequency of outcomes isare lower
than 10% they are very similar to the risk ratio [22–24]. The
I2 value and P value of heterogeneity also were calculated.
Results
The effects of RAS inhibitors on the risk of gastric can-
cer progression were evaluated together and individu-
ally. In the case of assessment of both ACEIs and ARBs
together our result demonstrated that there was no sig-
nicant between RAS inhibitors as well as the incidence
of gastric cancer (risk ratio = 0.837; 95% CI, 0.64–1.083;
P = 0.176, I2 = 65.06; df (Q) = 8, Q-value = 22.9) (Fig. 3).
However, our results demonstrated that ARBs signi-
cantly increased the incidence of gastric cancer progres-
sion (risk ratio = 0.63; 95% CI, 0.5–0.7; P = 0.00; I2 = 27.299;
df (Q) = 2; Q-value = 2.75) (Fig.4), while there was not
any signicant association between ACEIs and gastric
cancer development (risk ratio = 1.1; 95% CI = 0.92–1.31;
P = 0.26; I2 = 0.00; df (Q) = 3; Q-value = 1.26) (Fig. 5).
Moreover, we investigated the heterogeneity by using
the random-effects model. In addition, in the present
study, Egger’s test and checking the symmetry of fun-
nel plots were used for evaluating the publication bias
of each group.
Fig. 3
Forrest plot for showing the association between using ACEIs and ARBs and risk of gastric cancer progression. ARB, angiotensin receptor block-
ers, ACEI, angiotensin-converting enzyme inhibitors.
Fig. 4
Forrest plot for showing the association between using ARBs and risk of gastric cancer progression. ARB, angiotensin receptor blockers.
Copyright © 2022 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Effect of ARB and ACE inhibitors on the progression of gastric cancer Mehrdad et al. 5
Discussion
ACEIs and ARBs are well known as two common antihy-
pertensive medications that target RAS which regulates
arterial pressure. However, current studies suggested
that these two drugs affect the development of different
malignancy including gastric cancer [10,11].
ARBs are mostly used as an alternative to ACEI to
decrease cardiovascular risks, while previous reports
indicated that ARBs are linked with the incidence of
different malignancy. A study demonstrated the effect
of the different classes of ARBs on malignancy inci-
dence in individuals who live with type 2 diabetes.
This research indicated that losartan reduced the inci-
dence (OR = 0.78; 95% CI, 0.63–0.97), whereas cande-
sartan (OR = 1.79; 95% CI, 1.05–3.06) and telmisartan
(OR = 1.54; 95% CI, 0.97–2.43) were associated with
incidence of cancer in patients with diabetes. However,
there was no signicant link between ACE inhibitors
and chance of malignancy development [16]. Moreover,
the result of another study indicated that patients who
received telmisartan as a class of ARBs had a higher risk
of malignancy incidence (risk ratio = 1.08; 95% CI, 1.01–
1.15; P = 0.016) [25]. In line with the previous reports,
our result also indicated that ARBs signicantly raised
the progression risk of gastric cancer (risk ratio = 0.63;
P = 0.00).
Another study indicated that using telmisartan (ARBs)
in combination with ramipril (ACEIs) signicantly raised
the risk of malignancy in comparison to when ramipril
was used as a monotherapy [824 (9·7%) vs. 735 (8·6%);
hazard ratio = 1·14; 95% CI, 1·03–1·26]. Moreover, result
of this study indicated that the risk of malignancy inci-
dence was signicantly higher in patients who had no his-
tory of cancer and received telmisartan therapy (hazard
ratio = 1·24; 95% CI, 1·01–1·52) [26].
However, a study investigated the incidence risk of
cancer after using ARBs for less than 180 days and
had no previous history of cancer. This study demon-
strated that the risk of malignancy in ARBs users
was 4% whereas it was 6% in the group who did not
receive ARB (hazard ratio = 0.58; 95% CI, 0.55–0.62;
P < 0.001) [21].
Another study on 63 individuals who had advanced
gastric cancer suggested that therapy with ACEI/ARB
affects the survival rate of these patients. Results of this
study indicated that using ACEI/ARB along with con-
ventional chemotherapy can increase the survival rate
to 5.5 months (95% CI, 3.71–7.29) for these patients in
comparison to people that do not receive ACEI/ARB
(survival rate: 8.2 vs. 13.9; P = 0.0095). All these ndings
suggest that combination therapy of ACEI/ARB with
conventional chemotherapy probably can improve sur-
vival in gastric cancer patients [17].
ACEIs are other drugs that directly targeted RAS by
inhibiting the producing angiotensin II [27]. A study
with the aim of the protective effect of ACEIs toward
esophageal and gastric cancer demonstrated that this
drug reduces the incidence of esophageal cancer by
29% (OR = 0.71; 95% CI, 0.43–1.17) whereas there
was not any association with squamous cell skin can-
cer (OR = 1.27; 95% CI, 0.71–2.28). Moreover, this
study indicated that using the high daily dose of this
drug decreased the chance of both cancers by 45%
(OR = 0.55; 95% CI, 0.33–0.93). In addition, the result of
this study demonstrated that there was not any associa-
tion between ACEIs and the incidence of gastric cancer
(OR = 1.07; 95% CI, 0.84–1.36) [20]. Same as previous
reports our result also demonstrated that there was not
any signicant link between ACEIs and the progres-
sion of gastric cancer (Risk ratio = 1.1; P = 0.26).
Fig. 5
Forrest plot for showing the association between using ACEIs and risk of gastric cancer progression. ACEI, angiotensin-converting enzyme
inhibitors.
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6 Anti-Cancer Drugs XXX, Vol XXX No 00
Conclusion
In conclusion, all these ndings indicate probably the
link between using ARBs and gastric cancer progression.
However, limited data in this eld conrm the exact asso-
ciation between the incidence of cancer and different
ARBs. Therefore, there is a need for more future studies
to declare the role of ARBs in different malignancy pro-
gression as well as gastric cancer.
Conflicts of interest
There are no conicts of interest.
Author Contributions
SAM, FM, SMRS and AA designed this study. SAM and
SMRS performed statistical analysis. SAM, FM, SMRS and
AA interpreted the data. SAM and SMRS wrote the rst
draft. FM and AA revised the manuscript. All authors have
reviewed and approved the nal version of the manuscript.
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