Proton Pump Inhibitors – What Does the Research Say?

Here is a collection of information about proton pump inhibitors.

Widespread use of gastric acid inhibitors in infants: Are they needed? Are they safe? (World Journal of Gastrointestinal Pharmacology and Therapeutics)
“Previously assumed safety of these medications is being challenged with evidence of potential side effects including GI and respiratory infections, bacterial overgrowth, adverse bone health, food allergy and drug interactions.”
Infants are physiologically predisposed to GOR [gastro-oesophageal reflux] because of their shorter intra-abdominal oesophagus, frequent liquid feeds that distend the stomach, and supine position[2]. Infants with GOR have been found to have frequent transient lower oesophageal sphincter relaxations, which are thought to be the pathophysiological basis of the condition. Fifty-percent of infants reportedly experience daily regurgitation in the first 3 mo of life, which resolve by 12-14 mo in most healthy infants[3]. The pathogenic mechanism leading infant GOR to develop into GORD is unclear, although decreased neural protective reflexes and delayed gastric emptying are thought to play a role[1].”
“There is also mounting evidence that children are being exposed to unnecessarily high doses of PPI with doses of 1 mg/kg per day up to as high as 4 mg/kg per day used in clinical practice. Recent randomised trials have shown that although there is a dose-dependant reduction in acid production, for the treatment of erosive esophagitis there is no significant difference in healing between 5 mg/d and 10 mg/d for children < 20 kg[20,21].”
“However, PPIs have consistently failed to show efficacy in reducing infant GORD symptoms compared with placebo. Chen et al[23] reviewed four randomised control trials (RCTs) of PPIs in treating symptomatic GORD infants < 12 mo, conducted by pharmaceutical companies under formal requests by the Food and Drug Administration. The results of independent studies such as Moore et al[24] have corroborated with their results, which are summarised in Table ​Table11[2328]. Notably, Moore et al[24] enrolled infants with endoscopically confirmed GORD and found omeprazole significantly reduced the reflux index (percentage of total duration pH < 4) in these infants compared with placebo, but irritability improved regardless of treatment. In the most recent randomised controlled trial of PPI (Esomeprazole) for the treatment of symptomatic GORD, without endoscopy, all children were initially treated with PPI and then randomised to continuation of PPI or placebo[25]. It found no statistically significant difference in apparent treatment failure between the PPI or placebo group.
Headache, diarrhoea, constipation and nausea are idiosyncratic effects of PPIs that occur in 14% of children[1]. Acute interstitial nephritis, a rare, idiosyncratic hypersensitivity reaction to medications including PPIs, has also been reported in observational adult studies[29]. Increased risk of infection, for example, Clostridium Difficile, is increasingly being recognised[30]. Side effects related to the direct inhibition of gastric acid and reflex hypergastrinaemia, immunosuppression and drug metabolism have also been suggested (Table ​(Table22).”
“The human stomach has a median pH of 1.4, and a pH < 4 has a powerful bactericidal effect on ingested acid-sensitive bacteria[18]. PPIs often cause a gastric environment with pH > 4, inducing a state of hypochlorhydria which allows the overgrowth of bacteria in the stomach[18].”
“These microbial changes are thought to be due to the lack of the gastric acid barrier allowing bacteria to enter the intestine and also the effect of impaired protein digestion providing nutrients to facilitate bacterial growth[31]. Links have previously been made between these and similar changes to intestinal microbiome and the pathogenesis of inflammatory and malignant conditions of the bowel[33].”
“The pathogenic mechanism that allows enteric bacteria to cause gastrointestinal infections is multi-factorial. Gastric acid inhibition reduces the gastric microbiocidal barrier, delays gastric emptying, reduces gastric mucus viscosity thereby increasing the risk of bacterial translocation in addition to increasing the risk of colonisation by bacterial agents. Gastric acid inhibition also has an adverse effect on leukocyte function by decreasing adhesion to endothelial cells, reducing chemotactic response to bacterial proteins and inhibiting neutrophil phagocytosis by phagosome acidification[16]. This is potentially important in neonates and infants, who have immature humoral immunity[16]. A study on the numbers and type of bacteria in nasogastric tubes of patients receiving GAI demonstrated increased numbers of bacteria including Streptococcus, a known cause of community acquired pneumonia[34]. It is possible that the risk of pneumonia is increased as result of reflux aspiration of gastrointestinal contents into the lungs. PPIs may also directly inhibit the H+-K+-ATPase present in the respiratory tract, altering the pH of its seromucinous secretions[35].”
“The few paediatric studies available have made similar conclusions. Notably, a prospective study of 93 paediatric patients (4-36 mo) with endoscopically diagnosed GORD, showed that children treated with either ranitidine or omeprazole for 8 wk were 3.58 and 6.39 times more likely to develop acute gastroenteritis and community-acquired pneumonia respectively, compared with healthy children during the 4 mo follow-up[17]. Comparing 4 mo before and after enrolment, a significant increase in the incidence of acute gastroenteritis and pneumonia was found only in the treatment group, demonstrating that infection susceptibility could continue even after therapy cessation[17].”
“The results of safety studies on the use of gastric acid inhibiting drugs in infants, particularly in intensive care, where hospital-acquired pathogens are responsible for significant morbidity and mortality are concerning[38].”
Elevation of gastric pH also interferes with protein digestion, and it is hypothesised that normally digestible dietary peptides are preserved and recognised by the immune system as allergens[19].”
“Increasing gastric pH leads to hypergastrinemia, which has growth-promoting effects on several epithelial types[46]. Consequently, long-term PPI therapy is associated with parietal and enterochromaffin-like cell hyperplasia, as demonstrated by a RCT between esomeprazole treatment for 5 years compared with laparoscopic antireflux procedures for GORD[47].”
“By reducing gastric acidity, PPIs may interfere with the absorption of dietary protein-bound vitamin B12 and ionised calcium from dietary salts[22].”
“PPIs have also been associated with an increased risk of fracture, as impaired calcium absorption is thought to cause a compensatory state of hyperparathyroidism to stimulate osteoclasts and bone resorption[51]”
“During 2006-2012, there were 26 reported cases of hypomagnesaemia associated with PPIs in literature, with symptoms including electrocardiogram abnormalities and neuroexcitability, including tetanus and seizures, which resolved following withdrawal of PPI[52].”
“The safety of PPIs in infants also requires more prospective RCTs to remove the effect of confounders and bias. Irritable infants with uncomplicated GORD are hence recommended to continue lifestyle modifications, such as changing feeding techniques or formula composition, and avoid acid suppression. If PPIs are to be prescribed, only the minimal effective dose should be used, and should be weaned as soon as possible. There is no direct evidence to suggest increased safety of H2RA medication compared with PPI and in situations where acid suppression is indicated (e.g., esophagitis) they have decreased potency. Attention should be paid to the substantial epidemiological evidence of increased infection risk with PPIs, especially in the vulnerable population group of preterm infants.”

PPI Side Effects News, What PPI Companies Hide From Doctors
New studies show that intake of these drugs for prolonged period are linked to chronic kidney disease, myocardial infarction, bone loss, dementia, and many more complications.
“Researchers found that patients who took PPI’s had a 96% increase risk of developing kidney failure and a 28% increased risk of chronic kidney disease.
“These acid reducing drugs may increase the risk for chronic kidney disease by 20 to 50%.”

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease (JAMA Intern Med)
” Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk [of chronic kidney disease] than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21).”
“Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.”

Proton pump inhibitors are associated with increased risk of development of chronic kidney disease. (BMC Nephrology)
“Use of proton pump inhibitors is associated with increased risk of development of CKD [chronic kidney disease] and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications.”

Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. (J Am Soc Nephrol)
“Our results suggest that PPI exposure associates with increased risk of incident CKD [chronic kidney disease], CKD progression, and ESRD [end-stage renal disease).”

Association of Proton Pump Inhibitors With Risk of Dementia (JAMA Neurology)
“The avoidance of PPI medication may prevent the development of dementia.”

Proton Pump Inhibitors (PPIs) accelerate endothelial senescence (endothelial aging)
“Our data may provide a unifying mechanism for the association of PPI use with increased risk of cardiovascular, renal and neurological morbidity and mortality.”

Proton Pump Inhibitors Accelerate Endothelial Senescence (Circulation Research)
” To conclude, we found that chronic exposure of human ECs to the PPIs, esomeprazole or SCH-28080, accelerates endothelial aging. This adverse effect seems to be because of an inhibition of lysosomal acidification and subsequent impairment of proteostasis. The accumulation of protein aggregates is associated with an increase in oxidative stress, endothelial dysfunction, and senescence. Vascular senescence would provide a mechanistic explanation1113 for the accumulating evidence that PPIs increase the risk of cardiovascular morbidity and mortality, renal failure, and dementia.25 In the presence of consistent epidemiological evidence of harm and a unifying mechanism for the disparate disorders linked to PPI use and with the knowledge that PPIs are being used by millions of people for indications and durations that were never tested or approved, it is time for the pharmaceutical industry and regulatory agencies to revisit the specificity and the safety of these agents.”