Table I.
Characteristics of the studies included in the final meta-analysis (n=23).
| First author/s, year | Type of study | Country | Study period | Population (sex and age) | Type of cancer | Definition of PPI exposure | OR/RR/HR (95% CI) | Adjusted variables | (Refs.) |
|---|---|---|---|---|---|---|---|---|---|
| Nguyen et al, 2009 | Retrospective cohort study | USA | 1982-2005 | 344 individuals (men and women; mean age, 61 years) | Esophageal cancer | Received a dispensed prescription for PPIs vs. non-users | 0.40 (0.16–0.97) | Sex, age, Barrett's esophagus length and NSAIDs/COX-2/aspirin | (27) |
| Poulsen et al, 2009 | Retrospective cohort study | Denmark | 1990-2003 | 18,790 individuals | Gastric cancer | Patients who received ≥2 PPI prescriptions during the study period vs. non-users | 1.20 (0.80–2.00) | Calendar period, sex, age, history of H. pylori eradication therapy, gastroscopy, COPD, alcohol-related admission or therapy and ever using NSAIDs | (28) |
| Boursi et al, 2017 | Retrospective cohort study | UK | 1995-2013 | 19,146 individuals | Pancreatic cancer | PPI users vs. non-users | 1.89 (1.52–2.36) | Age, smoking, insulin, oral hypoglycemics, metformin, HbA1C, Hb, total cholesterol, creatinine and alkaline phosphatase | (29) |
| Brusselaers et al, 2017 | Prospective cohort study | Sweden | 2005-2012 | 797,067 individuals | Gastric cancer | PPI users vs. non-users | 3.38 (3.25–3.53) | Age, sex, calendar and categories | (30) |
| Hwang et al, 2017 | Prospective cohort study | South Korea | 2002-2013 | 451,284 individuals (men and women aged ≥40 years) | Colorectal cancer | Patients who consumed >60 DDDs of PPIs vs. non-users | 0.98 (0.78–1.24) | Age, male sex, obesity, current smoking, frequent drinking, low physical activity, comorbid conditions (including type 2 diabetes), concurrent drug use, (aspirin, metformin, statin) and low socioeconomic status | (31) |
| Wennerström et al, 2017 | Retrospective cohort study | Denmark | 1995-2011 | 1,563,860 individuals | Gastric cancer | PPI users vs. non-users | 2.51 (2.26–2.79) | Age, sex and municipality | (32) |
| Cheung et al, 2018 | Retrospective cohort study | Hong Kong | 2003-2012 | 63,397 individuals (≥18-year-old male and female patients) | Gastric cancer | PPI users vs. non-users | 2.44 (1.42–4.20) | Age of receiving H. pylori eradication therapy, sex, smoking, alcohol use, comorbidities and concomitant medications | (33) |
| Hwang et al, 2018 | Prospective cohort study | South Korea | 2002-2013 | 453,655 individuals (men and women aged ≥40 years) | Pancreatic cancer | Patients who consumed >60 DDDs of PPIs vs. non-users | 1.32 (1.03–1.70) | Age, male sex, obesity, current smoking, frequent drinking, low physical activity, comorbid conditions (type 2 diabetes, chronic pancreatitis), Charlson Comorbidity Index score and low socioeconomic status | (34) |
| Li et al, 2018 | Prospective cohort study | USA | 2001-2015 | 11,526 individuals (men and women; median age, 53 years) | Liver cancer | PPI users vs. non-users | 2.01 (1.50–2.70) | Age, sex, ethnicity, smoking history, alcohol abuse history, body mass index, diabetes, baseline FIB-4 score, gastroesophageal reflux disease, HCV genotype, past completed anti-HCV treatment and attainment of SVR | (35) |
| Tran et al, 2018 | Prospective cohort study | UK | 1991-2004 | 475,768 individuals | Liver cancer | PPI users vs. non-users | 1.99 (1.34–2.94) | Age, sex, deprivation, BMI, alcohol, smoking, comorbidities (including GORD, peptic ulcer disease, cirrhosis, hepatitis and diabetes) and other medication use (statins, aspirin) | (36) |
| Brusselaers et al, 2019 | Prospective cohort study | Sweden | 2005-2012 | 796,492 individuals (≥18-year-old male and female patients) | Gastric cancer; esophageal cancer | ≥180 days of accumulated use of PPIs vs. non-users | 2.97 (2.83–3.10); 3.93 (3.63–4.24) | Age and calendar categories | (37) |
| Kao et al, 2019 | Retrospective cohort study | Taiwan | 2003-2013 | 14,984 individuals | Liver cancer | PPI users vs. non-users | HBV cohort, 1.25 (0.90–1.73) HCV cohort, 1.19 (0.88–1.61) | Age, sex, year of cohort entry, comorbidities (cirrhosis, nonalcoholic liver disease, alcoholic liver disease, hypertension, chronic kidney disease, hyperlipidemia, diabetes) and concomitant medication (interferon/nucleos(t)ides, nonaspirin NSAIDs, histamine 2 receptor antagonist, aspirin, statin, fibrate, insulin, metformin) | (38) |
| Babic et al, 2020 | Prospective cohort study | USA | 1988-2015 | 175,871 individuals (female nurses aged 25–55 years; male health professionals aged 40–75 years) | Colorectal cancer | PPI users vs. non-users | 1.12 (0.78–1.59) | Age, BMI, physical activity, family history of colorectal cancer, alcohol intake, pack-years of smoking, history of lower endoscopy, caloric intake, vitamin D, calcium intake, regular aspirin use, folate intake, menopausal hormone therapy use and red meat as main dish | (39) |
| Brusselaers et al, 2020 | Prospective cohort study | Sweden | 2005-2012 | 796,492 individuals (≥18-year-old male and female patients) | Pancreatic cancer | PPI users vs. non-users | 2.22 (2.12–2.32) | Age, sex and calendar period | (40) |
| Liu et al, 2020 | Prospective cohort study | UK | 2006-2014 | 471,779 individuals | Gastric cancer | PPI users vs. non-users | 1.28 (0.86–1.90) | Age, sex, socioeconomic status, alcohol, smoking, BMI, comorbidities (diabetes, GORD, oesophagitis and peptic ulcer) and other medication uses (statins and aspirin) | (41) |
| Kamal et al, 2021 | Prospective cohort study | Sweden | 2005-2012 | 738,881 individuals | Gallbladder cancer; extrahepatic bile ducts cancer; intrahepatic bile ducts cancer | PPI users vs. non-users | 1.58 (1.37–1.81); 1.77 (1.56–2.00); 1.88 (1.57–2.23) | Sex, age group and calendar period | (42) |
| Lei et al, 2021 | Retrospective cohort study | Taiwan | 1999-2011 | 90,764 individuals (men and women) non-users | Colorectal cancer | Patients who used PPIs ≥30 days vs. CVD, CAD, COPD, | 2.03 (1.56–2.63) | Age, sex, comorbidities (hypertension, diabetes, dyslipidemia, liver cirrhosis), and baseline medication (aspirin, NSAIDs, statin and metformin) | (43) |
| Ng et al, 2021 | Retrospective cohort study | Hong Kong | 2004-2017 | 13,476 individuals (men and women) | Gastric cancer | Patients who used PPIs for ≥30 days vs. non-users (exposed to PPIs <14 days) | 2.38 (1.20–4.76) | Age, sex, comorbidities and baseline medication | (44) |
| Seo et al, 2021 | Retrospective cohort study | South Korea | 2002-2013 | 23,482 individuals (men and women; age ≥19 years) | Gastric cancer | Patients who used PPIs for ≥30 consecutive days vs. non-users | General population cohort, 2.44 (1.17–5.16) Post H. pylori eradication cohort, 2.22 (1.05–4.67) | Age, sex, smoking, alcohol, comorbidities and baseline medication | (45) |
| Shin et al, 2021 | Retrospective cohort study | South Korea | 2004-2015 | 39,799 individuals (men and women; age ≥40 years) | Gastric cancer | PPI users vs. H2RA users | 1.01 (0.88–1.16) | Age, sex, calendar period of prescription, time from medication start to 180 cDDD-days (months), socioeconomic characteristics (income, smoking and alcohol use), indication for drug use (gastresophageal reflux disease or peptic ulcer), Charlson Comorbidity Index, Helicobacter pylori eradication and use of other medications (aspirin, metformin and statin) | (46) |
| Abrahami et al, 2022 | Prospective cohort study | UK | 1990-2018 | 973,281 individuals (men and women; mean age, 60.4 years) | Gastric cancer | PPI users vs. H2RA users | 1.45 (1.06–1.98) | Age, sex, alcohol-related disorders, smoking status, BMI, comorbidities and baseline medication | (47) |
| Abrahami et al, 2022 | Prospective cohort study | UK | 1990-2018 | 1,293,749 individuals (men and women; mean age, 52.6 years) | Colorectal cancer | PPI users vs. H2RA users | 1.02 (0.92–1.14) | Age, sex, alcohol-related disorders smoking status, BMI, comorbidities, baseline medication, mammographic screening, prostate-specific antigen testing, colorectal cancer screening and influenza vaccination | (48) |
| Gong et al, 2022 | Prospective cohort study | South Korea | 2002-2013 | 1,025,340 individuals (men and women; age ≥20 years) | Gastric cancer | PPI users vs. H2RA users | 1.30 (0.75–2.27) | Age, sex, residential area, household income and comorbidities | (49) |
NSAID, Non-steroidal anti-inflammatory drug; COX-2, cyclooxygenase-2; H2RAs, H-2 receptor antagonists; COPD, chronic obstructive pulmonary disease; GORD, gastro-esophageal reflux disease; OR, odds ratio; RR, relative ratio; CVD, cerebrovascular disease; CAD, coronary artery disease; HBV, hepatitis B virus; HCV, hepatitis C virus; SVR, sustained virologic response; FIB-4, fibrosis-4; cDDD, cumulative defined daily dose; DDD, defined daily dose; PPI, proton pump inhibitor; HR, hazard ratio; HbA1C, hemoglobin A1C; Hb, hemoglobin.