CVDやがんは、交絡？という感じもしますが。更なる研究の蓄積が必要ですね。
・骨折
https://www.ncbi.nlm.nih.gov/pubmed/17190895
JAMA. 2006 Dec 27;296(24):2947-53.
Long-term proton pump inhibitor therapy and risk of hip fracture.
There were 13,556 hip fracture cases and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons).
Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study
BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e372 (Published 31 January 2012)Cite this as: BMJ 2012;344:e372Results During 565 786 person years of follow-up, we documented 893 incident hip fractures. The absolute risk of hip fracture among regular users of PPIs was 2.02 events per 1000 person years, compared with 1.51 events per 1000 person years among non-users. Compared with non-users, the risk of hip fracture among women who regularly used PPIs for at least two years was 35% higher (age adjusted hazard ratio 1.35 (95% confidence interval 1.13 to 1.62)), with longer use associated with increasing risk (Ptrend<0.01). Adjustment for risk factors, including body mass index, physical activity, and intake of calcium did not materially alter this association (hazard ratio 1.36 (1.13 to 1.63)). These associations were also not changed after accounting for reasons for PPI use. The relation between PPI use and fracture differed by smoking history (Pinteraction=0.03). Among current and former smokers, PPI use was associated with greater than 50% increase in risk of fracture, with a multivariate hazard ratio for fracture of 1.51 (1.20 to 1.91). In contrast, among women who never smoked there was no association (multivariate hazard ratio 1.06 (0.77 to 1.46)). In a meta-analysis of these results with 10 prior studies, the pooled odds ratio of hip fracture associated with PPI use was 1.30 (1.25 to 1.36).
Lewis JR, Barre D, Zhu K.et.al. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res. 2014;29(11):2489-97.
Targownik LE, Leslie WD, Davison KS,et.al. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol. 2012;107(9):1361-9.
Arch Intern Med. 2010 May 10;170(9):765-71. doi: 10.1001/archinternmed.2010.94.
Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.
RESULTS:
During 1 005 126 person-years of follow-up, 1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures, and 21 247 total fractures occurred. The multivariate-adjusted hazard ratios for current PPI use were 1.00 (95% confidence interval [CI], 0.71-1.40) for hip fracture, 1.47 (95% CI, 1.18-1.82) for clinical spine fracture, 1.26 (95% CI, 1.05-1.51) for forearm or wrist fracture, and 1.25 (95% CI, 1.15-1.36) for total fractures. The BMD measurements did not vary between PPI users and nonusers at baseline. Use of PPIs was associated with only a marginal effect on 3-year BMD change at the hip (P = .05) but not at other sites.
CONCLUSION:
Use of PPIs was not associated with hip fractures but was modestly associated with clinical spine, forearm or wrist, and total fractures.
・心筋梗塞
Results
In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.
・CKD
J Am Soc Nephrol. 2016 Oct;27(10):3153-3163. Epub 2016 Apr 14.
Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.
In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.
・肺炎
スタチンやACEIは肺炎減少と関連していたけど、PPIは増加と関連していた。
After adjusting for potential confounders, a current prescription for statins was associated with a significant reduction in the risk of pneumonia (adjusted OR 0.78, 95% CI 0.65-0.94). Similarly, a current prescription for ACEI was associated with a reduction in the risk of pneumonia (adjusted OR 0.75, 95% CI 0.65-0.86). Contrary to previous study results we did not find a significant association between current prescription for histamine 2 receptor antagonist (H(2)RA) and pneumonia risk (adjusted OR 1.14, 95% CI 0.92-1.40) but current prescriptions for proton pump inhibitors (PPI) were associated with an increased risk of pneumonia (adjusted OR 1.55, 95% CI 1.38-1.77).
メタアナ
PLoS One. 2015 Jun 4;10(6):e0128004. doi: 10.1371/journal.pone.0128004. eCollection 2015.
Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis.
Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31).
DISCUSSION:
Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.
Gut. 2018 Jan;67(1):28-35. doi: 10.1136/gutjnl-2017-314605. Epub 2017 Oct 31.
Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study.
RESULT:
Among the 63 397 eligible subjects, 153 (0.24%) developed GC during a median follow-up of 7.6 years. PPIs use was associated with an increased GC risk (HR 2.44, 95% CI 1.42 to 4.20), while H2RA was not (HR 0.72, 95% CI 0.48 to 1.07). The risk increased with duration of PPIs use (HR 5.04, 95% CI 1.23 to 20.61; 6.65, 95% CI 1.62 to 27.26 and 8.34, 95% CI 2.02 to 34.41 for ≥1 year, ≥2 years and ≥3 years, respectively). The adjusted absolute risk difference for PPIs versus non-PPIs use was 4.29 excess GC (95% CI 1.25 to 9.54) per 10 000 person-years.
CONCLUSION:
Long-term use of PPIs was still associated with an increased GC risk in subjects even after HP
・認知症
Clin Pharmacol Ther. 2019 Mar 12. doi: 10.1002/cpt.1430. [Epub ahead of print]
Does Long-Term Proton Pump Inhibitor Use Increase Risk of Dementia? Not Really! Results of the Group-Based Trajectory Analysis.
A group-based trajectory modeling was used to identify distinct groups with regard to longitudinal PPI use over 3 years and to further examine the association between the trajectories of PPI use and dementia in a 5-year follow-up. Among 10,533 older adults who initiated PPIs, three distinct trajectories of longitudinal PPI use were identified: short-term (n = 7,406, 70.3%), intermittent (n = 1,528, 14.5%), and long-term users (n = 1,599, 15.2%). Long-term (hazard ratio (HR) = 0.99 (95% confidence interval (CI), 0.93-1.17)) and intermittent PPI users (HR = 0.91 (95% CI, 0.76-1.09)) were not associated with an increased risk of incident dementia compared with short-term users. Regardless of pattern of use, PPIs did not appear to significantly increase the risk of dementia over a mean follow-up period of 4 years.
・貧血
Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency
Gastroenterology. 2017 Mar;152(4):821-829.e1. doi: 10.1053/j.gastro.2016.11.023. Epub 2016 Nov 24.
Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.
Abstract
BACKGROUND & AIMS:
Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency.
METHODS:
A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression.
RESULTS:
Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs <0.75 PPI pills/d; P value interaction = .004) and decreased after medication discontinuation (P-trend < .001). Some of the strongest associations were among persons taking >1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications.
CONCLUSIONS:
Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation.
https://www.bmj.com/content/365/bmj.l1580
・総死亡
Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1580 (Published 30 May 2019)Cite this as: BMJ 2019;365:l1580https://www.bmj.com/content/365/bmj.l1580
Abstract
Objective To estimate all cause mortality and cause specific mortality among patients taking proton pump inhibitors (PPIs).
Design Longitudinal observational cohort study.
Setting US Department of Veterans Affairs.
Participants New users of PPIs (n=157 625) or H2 blockers (n=56 842).
Main outcome measures All cause mortality and cause specific mortality associated with taking PPIs (values reported as number of attributable deaths per 1000 patients taking PPIs).
Results There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases. Analyses of subcauses of death suggested that taking PPIs was associated with an excess mortality due to cardiovascular disease (15.48, 5.02 to 25.19) and chronic kidney disease (4.19, 1.56 to 6.58). Among patients without documented indication for acid suppression drugs (n=116 377), taking PPIs was associated with an excess mortality due to cardiovascular disease (22.91, 11.89 to 33.57), chronic kidney disease (4.74, 1.53 to 8.05), and upper gastrointestinal cancer (3.12, 0.91 to 5.44). Formal interaction analyses suggested that the risk of death due to these subcauses was not modified by a history of cardiovascular disease, chronic kidney disease, or upper gastrointestinal cancer. Taking PPIs was not associated with an excess burden of transportation related mortality and death due to peptic ulcer disease (as negative outcome controls).
Conclusions Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use. Heightened vigilance in the use of PPI may be warranted.
