Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study
Abstract
:1. Introduction
2. Methods
2.1. Data Source
2.2. Study Population
2.3. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Herman, L.L.; Bashir, K. Angiotensin Converting Enzyme Inhibitors (ACEI) [Updated 2019 Oct 22]. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2019. Available online: https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/books/NBK431051/ (accessed on 25 February 2020).
- Amann, B.; Tinzmann, R.; Angelkort, B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 2003, 26, 2421–2425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Opelz, G.; Döhler, B. Treatment of kidney transplant recipients with ACEi/ARB and risk of respiratory tract cancer: A collaborative transplant study report. Am. J. Transplant. 2011, 11, 2483–2489. [Google Scholar] [CrossRef] [PubMed]
- Hallas, J.; Christensen, R.; Andersen, M.; Friis, S.; Bjerrum, L. Long term use of drugs affecting the renin-angiotensin system and the risk of cancer: A population-based case-control study. Br. J. Clin. Pharmacol. 2012, 74, 180–188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bangalore, S.; Kumar, S.; Kjeldsen, S.E.; Makani, H.; Grossman, E.; Wetterslev, J.; Gupta, A.K.; Sever, P.S.; Gluud, C.; Messerli, F.H. Antihypertensive drugs and risk of cancer: Network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011, 12, 65–82. [Google Scholar] [CrossRef]
- Hicks, B.M.; Filion, K.B.; Yin, H.; Sakr, L.; Udell, J.A.; Azoulay, L. Angiotensin converting enzyme inhibitors and risk of lung cancer: Population based cohort study. BMJ 2018, 363, k4209. [Google Scholar] [CrossRef] [Green Version]
- Bahaj, W.; Albawaliz, A.; Qureini, A.; Abughanimeh, O.K.M.; Younis, M.; Tahboub, M.; Noman, A.; Abdulhak, A.A.B. Angiotensin converting enzyme inhibitors use and development of lung cancer: A systematic review and meta-analysis. J. Clin. Oncol. 2019, 37, e13093. [Google Scholar] [CrossRef]
- Pasternak, B.; Svanström, H.; Callréus, T.; Melbye, M.; Hviid, A. Use of angiotensin receptor blockers and the risk of cancer. Circulation 2011, 123, 1729–1736. [Google Scholar] [CrossRef] [Green Version]
- Lever, A.F.; Hole, D.J.; Gillis, C.R.; McCallum, I.R.; McInnes, G.T.; MacKinnon, P.L.; Meredith, P.A.; Murray, L.S.; Reid, J.L.; Robertson, J.W.K. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 1998, 352, 179–184. [Google Scholar] [CrossRef]
- Friis, S.; Sørensen, H.T.; Mellemkjaer, L.; McLaughlin, J.K.; Nielsen, G.L.; Blot, W.J.; Olsen, J.H. Angiotensin-converting enzyme inhibitors and the risk of cancer: A population-based cohort study in Denmark. Cancer 2001, 92, 2462–2470. [Google Scholar] [CrossRef]
- Chang, C.H.; Lin, J.W.; Wu, L.C.; Lai, M.S. Angiotensin receptor blockade and risk of cancer in type 2 diabetes mellitus: A nationwide case-control study. J. Clin. Oncol. 2011, 29, 3001–3007. [Google Scholar] [CrossRef]
- Gokhale, M.; Girman, C.; Chen, Y.; Pate, V.; Funk, M.J.; Stürmer, T. Comparison of diagnostic evaluations for cough among initiators of angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Pharmacoepidemiol. Drug Saf. 2016, 25, 512–520. [Google Scholar] [CrossRef] [Green Version]
- Pope, C.A., III; Burnett, R.T.; Thun, M.J.; Calle, E.E.; Krewski, D.; Ito, K.; Thurston, G.D. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA 2002, 287, 1132–1141. [Google Scholar] [CrossRef] [Green Version]
- Raaschou-Nielsen, O.; Andersen, Z.J.; Beelen, R.; Samoli, E.; Stafoggia, M.; Weinmayr, G.; Hoffmann, B.; Fischer, P.; Nieuwenhuijsen, M.J.; Brunekreef, B.; et al. Air pollution and lung cancer incidence in 17 European cohorts: Prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol. 2013, 14, 813–822. [Google Scholar] [CrossRef]
- Li, Y.F.; Zhu, X.M.; Liu, F.; Xiao, C.S.; Bian, Y.F.; Li, H.; Cai, J.; Li, R.-S.; Yang, X.-C. Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: A meta-analysis. PLoS ONE 2012, 7, e37396. [Google Scholar] [CrossRef] [Green Version]
- Chiang, Y.Y.; Chen, K.B.; Tsai, T.H.; Tsai, W.C. Lowered cancer risk with ACE inhibitors/ARBs: A population-based cohort study. J. Clin. Hypertens. Greenwich. 2014, 16, 27–33. [Google Scholar] [CrossRef] [Green Version]
- Kuba, K.; Imai, Y.; Rao, S.; Gao, H.; Guo, F.; Guan, B.; Huan, Y.; Yang, P.; Zhang, Y.; Deng, W.; et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 2005, 11, 875–879. [Google Scholar] [CrossRef]
- Fox, A.J.; Lalloo, U.G.; Belvisi, M.G.; Bernareggi, M.; Chung, K.F.; Barnes, P.J. Bradykinin-evoked sensitization of airway sensory nerves: A mechanism for ACE-inhibitor cough. Nat. Med. 1996, 2, 814–817. [Google Scholar] [CrossRef]
- Yang, C.M.; Chien, C.S.; Ma, Y.H.; Hsiao, L.D.; Lin, C.H.; Wu, C. Bradykinin B2 receptor-mediated proliferation via activation of the Ras/Raf/MEK/MAPK pathway in rat vascular smooth muscle cells. J. Biomed. Sci. 2003, 10, 208–218. [Google Scholar] [CrossRef]
- Gutkind, J.S. Regulation of mitogen-activated protein kinase signaling networks by G protein-coupled receptors. Sci. STKE 2000, 2000, re1. [Google Scholar] [CrossRef]
- Golias, C.; Charalabopoulos, A.; Stagikas, D.; Charalabopoulos, K.; Batistatou, A. The kinin system—Bradykinin: Biological effects and clinical implications. Multiple role of the kinin system—Bradykinin. Hippokratia 2007, 11, 124–128. [Google Scholar]
- Chee, J.; Naran, A.; Misso, N.L.; Thompson, P.J.; Bhoola, K.D. Expression of tissue and plasma kallikreins and kinin B1 and B2 receptors in lung cancer. Biol. Chem. 2008, 389, 1225–1233. [Google Scholar] [CrossRef]
- Da Costa, P.L.; Sirois, P.; Tannock, I.F.; Chammas, R. The role of kinin receptors in cancer and therapeutic opportunities. Cancer Lett. 2014, 345, 27–38. [Google Scholar] [CrossRef] [Green Version]
- Esteban, F.; Muñoz, M.; González-Moles, M.A.; Rosso, M. A role for substance P in cancer promotion and progression: A mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev. 2006, 25, 137–145. [Google Scholar] [CrossRef]
- Muñoz, M.; Coveñas, R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 2013, 48, 1–9. [Google Scholar] [CrossRef]
- Zhang, J.; Liu, J.; Chen, J.; Li, X.; Wu, Y.; Chen, H.; Wu, W.; Zhang, K.; Gu, L. Angiotensin receptor blockers (ARBs) reduce the risk of lung cancer: A systematic review and meta-analysis. Int. J. Clin. Exp. Med. 2015, 8, 12656–12660. [Google Scholar]
- Huang, C.C.; Chan, W.L.; Chen, Y.C.; Chen, T.J.; Lin, S.J.; Chen, J.W.; Leu, H.B. Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertension. Am. J. Cardiol. 2011, 107, 1028–1033. [Google Scholar] [CrossRef]
- Bhaskaran, K.; Douglas, I.; Evans, S.; van Staa, T.; Smeeth, L. Angiotensin receptor blockers and risk of cancer: Cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ 2012, 344, e2697. [Google Scholar] [CrossRef] [Green Version]
- Egami, K.; Murohara, T.; Shimada, T.; Sasaki, K.I.; Shintani, S.; Sugaya, T.; Ishii, M.; Akagi, T.; Ikeda, H.; Matsuishi, T.; et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J. Clin. Invest. 2003, 112, 67–75. [Google Scholar] [CrossRef] [Green Version]
- Fujiyama, S.; Matsubara, H.; Nozawa, Y.; Maruyama, K.; Mori, Y.; Tsutsumi, Y.; Masaki, H.; Uchiyama, Y.; Koyama, Y.; Nose, A.; et al. Angiotensin AT(1) and AT(2) receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (EGF)-mediated EGF receptor transactivation. Circ. Res. 2001, 88, 22–29. [Google Scholar] [CrossRef]
- Ino, K.; Shibata, K.; Kajiyama, H.; Yamamoto, E.; Nagasaka, T.; Nawa, A.; Nomura, S.; Kikkawa, F. Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br. J. Cancer 2006, 94, 552–560. [Google Scholar] [CrossRef] [Green Version]
- Batra, V.K.; Gopalakrishnan, V.; McNeill, J.R.; Hickie, R.A. Angiotensin II elevates cytosolic free calcium in human lung adenocarcinoma cells via activation of AT1 receptors. Cancer Lett. 1994, 76, 19–24. [Google Scholar] [CrossRef]
- Arrieta, O.; Villarreal-Garza, C.; Vizcaíno, G.; Pineda, B.; Hernández-Pedro, N.; Guevara-Salazar, P.; Wegman-Ostrosky, T.; Villanueva-Rodriguez, G.; Gamboa-Dominguez, A. Association between AT1 and AT2 angiotensin II receptor expression with cell proliferation and angiogenesis in operable breast cancer. Tumour Biol. 2015, 36, 5627–5634. [Google Scholar] [CrossRef]
- Feng, Y.; Wan, H.; Liu, J.; Zhang, R.; Ma, Q.; Han, B.; Xiang, Y.; Che, J.; Cao, H.; Fei, X.; et al. The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer. Oncol. Rep. 2010, 23, 941–948. [Google Scholar]
- Fujita, M.; Hayashi, I.; Yamashina, S.; Itoman, M.; Majima, M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem. Biophys. Res. Commun. 2002, 294, 441–447. [Google Scholar] [CrossRef]
- Suganuma, T.; Ino, K.; Shibata, K.; Kajiyama, H.; Nagasaka, T.; Mizutani, S.; Kikkawa, F. Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin. Cancer Res. 2005, 11, 2686–2694. [Google Scholar] [CrossRef] [Green Version]
- Fujimoto, Y.; Sasaki, T.; Tsuchida, A.; Chayama, K. Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett. 2001, 495, 197–200. [Google Scholar] [CrossRef]
- Gong, Q.; Davis, M.; Chipitsyna, G.; Yeo, C.J.; Arafat, H.A. Blocking angiotensin II Type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells. Pancreas 2010, 39, 581–594. [Google Scholar] [CrossRef]
- Makani, H.; Bangalore, S.; Desouza, K.A.; Shah, A.; Messerli, F.H. Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials. BMJ 2013, 346, f360. [Google Scholar] [CrossRef] [Green Version]
- Xing, Y.F.; Xu, Y.H.; Shi, M.H.; Lian, Y.X. The impact of PM2.5 on the human respiratory system. J. Thorac. Dis. 2016, 8, E69–E74. [Google Scholar]
- Lee, W.J.; Teschke, K.; Kauppinen, T.; Andersen, A.; Jäppinen, P.; Szadkowska-Stanczyk, I.; Pearce, N.; Persson, B.; Bergeret, A.; Facchini, L.A.; et al. Mortality from lung cancer in workers exposed to sulfur dioxide in the pulp and paper industry. Environ. Health Perspect. 2002, 110, 991–995. [Google Scholar] [CrossRef] [Green Version]
- Wilop, S.; von Hobe, S.; Crysandt, M.; Esser, A.; Osieka, R.; Jost, E. Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy. J. Cancer Res. Clin. Oncol. 2009, 135, 1429–1435. [Google Scholar] [CrossRef]
Covariate | ARB N = 22384 | ACEI N = 22384 | |||
---|---|---|---|---|---|
n | % | n | % | p-Value | |
Age, years | |||||
Mean ± SD a | 58.9 | 13.9 | 58.8 | 14.0 | 0.39 |
Sex | 0.98 | ||||
Women | 10225 | 45.7 | 10223 | 45.7 | |
Men | 12159 | 54.3 | 12161 | 54.3 | |
Monthly income (NTD) † | 0.001 | ||||
<15,000 | 6222 | 27.8 | 6010 | 26.9 | |
15,000−19,999 | 11791 | 52.7 | 12271 | 54.8 | |
≥ 20,000 | 4371 | 19.5 | 4103 | 18.3 | |
Urbanization level‡ | 0.001 | ||||
1 (highest) | 6666 | 29.8 | 6072 | 27.1 | |
2 | 6166 | 27.6 | 7005 | 31.3 | |
3 | 3812 | 17.0 | 3791 | 16.9 | |
4 (lowest) | 5740 | 25.6 | 5516 | 24.6 | |
Comorbidity | |||||
Hypertension | 19772 | 88.3 | 19776 | 88.4 | 0.95 |
Diabetes | 3347 | 15.0 | 3320 | 14.8 | 0.72 |
Tuberculosis | 434 | 1.94 | 450 | 2.01 | 0.59 |
Alcohol-related disease | 1199 | 5.36 | 1195 | 5.34 | 0.93 |
COPD | 3459 | 15.5 | 3474 | 15.5 | 0.84 |
Chronic liver disease | 5838 | 26.1 | 5782 | 25.8 | 0.55 |
Hyperlipidemia | 8819 | 39.4 | 8631 | 38.6 | 0.07 |
Asthma | 3044 | 13.6 | 2993 | 13.4 | 0.48 |
Stroke | 3148 | 14.1 | 3268 | 14.6 | 0.11 |
CAD | 8158 | 36.5 | 7900 | 35.3 | 0.01 |
Rheumatologic disease | 748 | 3.34 | 742 | 3.31 | 0.87 |
Medications | |||||
α-Blockers | 3359 | 15.0 | 3365 | 15.0 | 0.94 |
β-Blockers | 13300 | 59.4 | 13310 | 59.5 | 0.92 |
Potassium sparing diuretics | 3076 | 13.7 | 3087 | 13.8 | 0.88 |
Thiazides | 10450 | 46.7 | 10436 | 46.6 | 0.89 |
Loop diuretics | 5783 | 25.8 | 5767 | 25.8 | 0.86 |
CCB (non-DHP or DHP) | 15484 | 69.2 | 15603 | 69.7 | 0.22 |
Others | 4173 | 18.6 | 4245 | 19.0 | 0.38 |
Air pollutants | |||||
PM2.5 μg/m3 daily average (SD)a | 34.8 | 8.33 | 36.0 | 8.47 | < 0.001 |
PM10 μg/m3 daily average (SD)a | 59.1 | 13.0 | 61.1 | 13.2 | < 0.001 |
SO2 ppb daily average (SD)a | 4.72 | 1.93 | 4.82 | 1.99 | < 0.001 |
ARB | ACEI | |
---|---|---|
Variables | (N = 22384) | (N = 22384) |
Person-years | 141645 | 136981 |
Follow-up time (y), Mean ± SD | 6.33 ± 3.52 | 6.12 ± 3.47 |
Event, n | 173 | 228 |
Rate | 12.2 | 16.6 |
cHR (95% CI) | 1(Reference) | 1.36(1.11, 1.65) ** |
aHR (95% CI) a | 1(Reference) | 1.36(1.11, 1.67) ** |
Medication Exposed | N | Event | Person-Year | Rate | aHR (95% CI) a |
---|---|---|---|---|---|
ACEI # | |||||
Non-ACEI | 22384 | 173 | 141645 | 12.2 | 1.00 |
≤45 days | 11159 | 89 | 77982 | 11.4 | 0.97(0.75, 1.26) |
>45 days | 11225 | 139 | 58998 | 23.6 | 1.87(1.48, 2.36) *** |
Non-ACEI | 1.00 | ||||
≤540 mg | 11183 | 85 | 75254 | 11.3 | 0.98(0.75, 1.28) |
>540 mg | 11201 | 143 | 61726 | 23.2 | 1.80(1.43, 2.27) *** |
Non-ACEI | 1.00 | ||||
≤50 DDD | 11215 | 91 | 77329 | 11.8 | 0.99(0.76, 1.28) |
>50 DDD | 11169 | 137 | 59651 | 23.0 | 1.85(1.46, 2.34) *** |
ARB# | |||||
Non-ARB | 22384 | 228 | 136981 | 16.6 | 1.00 |
≤200 days | 11175 | 78 | 73104 | 10.7 | 0.61(0.47, 0.80) *** |
>200 days | 11209 | 95 | 68541 | 13.9 | 0.88(0.69, 1.13) |
Non-ARB | 1.00 | ||||
≤11200 mg | 5394 | 56 | 27325 | 20.5 | 1.17(0.86, 1.59) |
>11200 mg | 16990 | 117 | 114320 | 10.2 | 0.62(0.50, 0.79) *** |
Non-ARB | 1.00 | ||||
≤200 DDD | 11363 | 81 | 73414 | 11.0 | 0.63(0.48, 0.81) *** |
>200 DDD | 11021 | 92 | 68231 | 13.5 | 0.87(0.67, 1.11) |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Lin, S.-Y.; Lin, C.-L.; Lin, C.-C.; Hsu, W.-H.; Lin, C.-D.; Wang, I.-K.; Hsu, C.-Y.; Kao, C.-H. Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study. Cancers 2020, 12, 747. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030747
Lin S-Y, Lin C-L, Lin C-C, Hsu W-H, Lin C-D, Wang I-K, Hsu C-Y, Kao C-H. Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study. Cancers. 2020; 12(3):747. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030747
Chicago/Turabian StyleLin, Shih-Yi, Cheng-Li Lin, Cheng-Chieh Lin, Wu-Huei Hsu, Chia-Der Lin, I.-Kuan Wang, Chung-Y. Hsu, and Chia-Hung Kao. 2020. "Association between Angiotensin-Converting Enzyme Inhibitors and Lung Cancer—A Nationwide, Population-Based, Propensity Score-Matched Cohort Study" Cancers 12, no. 3: 747. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030747