Table 5.
Major putative adverse effects of chronic PPI therapy
| Putative adverse effect | Meta-analysis reference numbers |
HRa or ORb (95% CI) found in recent RCT (94) |
Major proposed mechanisms |
|---|---|---|---|
| Cardiovascular events | (237-240) | 1.04a (0.93–-1.15) | PPIs block metabolism of ADMA, which accumulates and inhibits NO synthase, thus blocking endothelial production of NO needed for vascular homeostasis |
| (All) MI | 0.94a (0.79–1.12) | ||
| Stroke | 1.16a (0.94–1.44) | ||
| Cardiovascular death | 1.03a (0.89–1.20) | ||
| Cardiovascular events in patients on clopidogrelc | (241-260) | NA | PPIs are metabolized by the same enzyme needed to activate clopidogrel (CYP2C19), so concomitant use of these drugs might decrease the antiplatelet effect of clopidogrel |
| Kidney disease | (261-265) | NA | AIN develops as an idiosyncratic drug reaction and progresses to chronic kidney disease |
| (All) AIN | NA | ||
| Chronic kidney disease | 1.17b (0.94–1.45) | ||
| Enteric infection (other than Clostridium. difficile) | (266,267) | 1.33b (1.01–1.75) | Reduced gastric acid enables ingested enteric pathogens to survive passage through the stomach |
| C. difficile | (268-276) | 2.26b (0.70–7.34) | Reduced gastric acid enables survival of ingested C. difficile vegetative forms and prevents conversion of salivary nitrite to ROS that suppress C. difficile spores; PPIs may enhance C. difficile toxin expression and cause microbiome alterations that promote C. difficile colitis |
| SIBO | (277,278) | NA | Reduced gastric acid enables increased bacterial colonization of the UGI tract |
| Spontaneous bacterial peritonitis in patients with cirrhosis | (279-283) | NA | Increased bacterial colonization of the UGI tract and PPI-induced increases in UGI tract permeability predispose to bacterial translocation; PPIs also might interfere with inflammatory cell functions that ordinarily would prevent infection |
| Pneumonia | (284-289) | 1.02b (0.87–1.19) | Reduced gastric acid enables UGI tract colonization with pulmonary pathogens that can be aspirated; PPIs also might interfere with inflammatory cell functions that ordinarily would prevent infection |
| Dementia | (290-293) | 1.20b (0.81–1.78) | PPIs block vacuolar H+-ATPase needed to acidify microglial lysosomes, thereby preventing their degradation of cerebral amyloid-β peptide; PPI-induced B12 deficiency also might contribute to dementia |
| Bone fracture | (294-302) | 0.96b (0.79–1.17) | Reduced gastric acid causes calcium malabsorption leading to decreased bone mineral density; PPIs might reduce bone resorption by blocking vacuolar H+-ATPase in osteoclasts; PPIs cause hypergastrinemia that might cause parathyroid hyperplasia |
| Gastric atrophy | (303-305) | 0.73b (0.40–1.32) | PPIs promote corpus-predominant H. pylori gastritis that results in gastric atrophy with loss of parietal cells |
| Gastric cancer | (306-308) | NA | PPIs promote gastric atrophy and inflammation in H. pylori–infected patients, resulting in intestinal metaplasia predisposed to malignancy; reduced gastric acid enables overgrowth of bacteria that convert dietary nitrates to potentially carcinogenic N-nitroso compounds; PPI-induced hypergastrinemia causes gastric epithelial cell proliferation that promotes carcinogenesis |
| Vitamin B12 deficiency | (309) | NA | Reduced gastric acid results in malabsorption of protein-bound cobalamin; gastric atrophy results in decreased intrinsic factor production |
| Hypomagnesemia | (310-312) | NA | PPI effects in elevating intestinal pH may interfere with magnesium absorption, perhaps because the affinity of the enterocyte magnesium transporter TRPM6/7 for magnesium decreases in a higher pH environment |
| All-cause mortality | (313) | 1.03a (0.92–1.15) | Potentially all of above |
a
Hazard ratio.
b
Odds ratio
c
The US Food and Drug Administration recommends avoiding the concomitant use of clopidogrel and omeprazole.
ADMA, asymmetric dimethylarginine; AIN, acute interstitial nephritis; ATP, adenosine triphosphate; CI, confidence interval; HR, hazard ratio; MI, mucosal integrity; NA, not available; NO, nitric oxide; OR, odds ratio; PPI, proton pump inhibitor; RCT, randomized controlled trial (94); ROS, reactive oxygen species; SIBO, small intestinal bacterial overgrowth; TRPM6/7, transient receptor potential melastatin 6 and 7.