Proton pump inhibitors (PPIs) are among the most commonly prescribed classes of drugs and their use is increasing, particularly for long-term treatment. Moreover, they are often being over-prescribed and used for inappropriate conditions. In recent years, considerable attention has been directed towards their wide range of adverse effects. Even when a potential underlying biological mechanism for an adverse effect is plausible, the clinical evidence is often weak.
PPIs are generally considered to be effective and well tolerated with rare and mild side effects in short-term use. Concern for and evidence on the potential long-term complications of PPI therapy are increasingly emerging.
- To review the most recent literature reporting possible associations between long-term PPI treatment and adverse effects
- To discuss the mechanisms through which these complications might develop
PPIs are used to treat patients with acid related disorders. Several long-term side effects have been investigated ranging from interaction with other drugs, increased risk of infection, reduced intestinal absorption of vitamins and minerals, and more recently, kidney damage and dementia.
On Vitamin and Mineral Absorption
Gastric acid environment plays a major role in the physiologic pathways. Changes related to long-term gastric acid inhibition may interfere, in particular, with the absorption of several vitamins and minerals.
Dietary iron is mostly constituted by non-heme iron in ferric form (Fe3+). Ferric iron needs to be oxidized to more soluble forms (ferrous, Fe2+) for better absorption in the duodenum. PPIs lower gastric acid levels thus iron absorption may be decreased. There is a significant association between the chronic use of PPI and the presence of anemia. Reduction in absorption of non-heme iron associated with the use of PPIs has been reported also in patients affected by hemochromatosis. However, the evidence of a correlation between PPI and development of iron deficit anemia remains poor. Routine investigation of anemia in long-term PPI treatment is not recommended in clinical practice.
Vitamin B12 Binds to R factors forming a non-absorbable complex present in saliva and gastric juice. In the duodenum, the alkaline pancreatic juice that contains proteases breaks up the binding between B12 and R factor. Cobalaminbinds with the intrinsic factor. Decrease of gastric acid production induced by PPI could potentially lead to Vitamin B12 malabsorption.
Results of a recent systematic review and of a meta-analysis of nine observational studies suggest that in case of low serum magnesium levels, PPI treatment should be discontinued. There could be a prompt resolution of hypomagnesaemia after 1 to 2 weeks from PPI withdrawal but there could also be a recurrence after PPI re-challenge. Underlying mechanisms for magnesium metabolism remain poorly defined. It could be affected by gastrointestinaI malabsorption and renal wasting
Absorption of calcium compounds can be significantly reduced in the presence of achlorrhydia.
A randomized controlled trial (RCT) on women older than 65 years of age showed a significant reduction of calcium carbonate absorption in omeprazole users. A study performed on young male patients did not find any significant difference between the absorption of dietary calcium among patients taking full dose of omeprazole compared with controls.
Higher Incidence of Bone Fractures
Vitamin B12 malabsorption increaseshomocysteine levels and reduces the osteoblastic (bone forming) activity with subsequent effects on bone formation and strength. Hypergastrinemia secondary to prolonged acid suppression, together with a diminished calcium absorption, triggers the production of parathormone stimulating bone resorption
PPI treatments enhance the production of amyloid-β and modulate its degradation by lysosomes in microglia. Higher levels of amyloid-β were found in brains of micesimilar to the extracellular deposition of amyloid-β peptides seen in the pathogenesis of Alzheimer disease.Low vitamin B12 status has been associated with cognitive dysfunction. Only limited number of studies have investigated this association in humans.
Haenisch and colleagues, using data from a longitudinal multicenter cohort study, assessed the association between PPI use and risk of dementia in elderly subjects. Patients receiving PPIs had a significantly increased risk of any dementia and of Alzheimer disease compared with subjects not receiving PPI medication.More studies, randomized clinical trials (RCTs) in particular, are needed to confirm this association
Alteration of Clopidogrel Pharmacodynamics and Cardiovascular Risk
Potential interaction between PPIs and clopidogrel, leading to an attenuated antiplatelet effect have been raised. Competitive metabolism effect has been suggested. PPIs are metabolized by the cytochrome P450 involved in the biotransformation of clopidogrel to an active form.
Shah and colleagues found a small but significant 1.16-fold increased association between myocardial infarction and use of PPIs among patients with gastroesophageal reflux as well as a twofold increase in association with cardiovascular mortality. The association was present regardless of clopidogrel use.
Two recent meta-analyses have confirmed that patients using PPIs with clopidogrelhad increased risk of cardiovascular events including higher overall mortality, myocardial infarction, and acute coronary syndromes Conflicting results were found when only RCTs were included. There were no significant differences in ischemic events or mortality observed in RCTs, while the use of PPIs in patients taking clopidogrel was significantly associated with a reduced risk of GI bleeding.
PPIs are a marker of increased risk rather than a direct cause of worse outcome. To reduce competitive metabolism with clopidogrel, PPIs with a reduced interaction with CYP2C19 enzyme (e.g. Esomeprazole or Pantoprazole) should be chosen. Other alternatives include Histamine-2 (H2) receptor antagonists to suppress gastric acid production. Next-generation antiplatelet agents not dependent on the CYP2C19 enzyme(ticagrelor or prasugrel)can also be used to substitute clopidogrel.
Specific mechanism by which PPIs lead to acute interstitial nephritis (AIN) is still unknown. PPIs or their metabolites might deposit in the kidney’s tubulo-interstitium compartment and directly stimulate an immune response leading to AIN. Long-standing lower glomerular filtration rate due to PPI induced AIN may transition to chronic interstitial nephritis leading to higher chronic kidney disease(CKD) risk on a longer-term follow-up.
In the study by Lazarus and colleagues, the risk of CKD was 50% higher in PPI users compared with nonusers. There exists a dose–response effect (higher risk among patients taking PPIs twice daily compared with once a day). There is also a higher risk compared with patients taking H2 antagonists
A second study by Arora and coworkers evaluated in 71,516 veterans the association between PPI use and chronic kidney disease from 2001 to 2008. 34% veterans who developed CKD during the study, those using PPIs had a significantly higher risk of CKD development. A similar study by Xie and colleagues used national veterans database to identify 173,321 new users of PPI and followed them for 5 years to evaluate the risk of renal disease. Patients treated with PPIs also had a significantly increased risk of CKD and a doubling of serum creatinine level
On Enteric Infections
PPIs are assumed to increase the proliferation of spores by decreasing the intraluminal gastric acidity, allowing spores to survive in the modified gastric environment and better spread of Clostridium difficileinfections (CDI). Kwok and colleagues analyzed data from 39 studies. They found out a significant association between PPI use and the risk of CDI compared with non-PPI users. The risk of CDI was increased further in cases of concomitant use of PPIs and antibiotics.
Tleyjeh and coworkers found among the 47 eligible studies, an association between PPI use and the risk of CDI. The high heterogeneity among studies and publication bias weakened the results. The study advocated for the careful use of PPIs in patients with higher risk for CDI development, advanced age, undergoing chemotherapy, has immunodeficiency, and those who were exposed to infected subjects.
In addition toC. difficile-associated disease, strong suppression of acid could also increase the risk of other enteric infections. There is an increased risk for both Salmonella and Campylobacter infections. There is a predisposition to small intestinal bacterial overgrowth (SIBO) through reduced bacterial clearance, intestinal bacterial overgrowth, altered GI motility, and increased intestinal permeability.
PPIs lead to a significant change in the overall microbiota composition also in patients with cirrhosis. Recent studies have shown possible PPI-related complications in cirrhotic patients. A meta-analysis by Deshpande and colleagues from eight observational studies found a threefold higher risk of developing spontaneous bacterial peritonitis among patients taking PPIs.
A prospective study investigated the relationship between PPI treatment and the overall survival in cirrhotic patients. I revealed that PPI treatment was associated with higher Model for End- Stage Liver Disease (MELD) scores and presence of ascites. Furthermore, PPI treatment was significantly associated with increased mortality and was considered the second cause of death in cirrhotic patients, after presence of hepatocarcinoma. PPIs should be used with caution in patients with advanced liver disease.
There is a risk of community-acquired pneumonia (CAP) among subjects treated with PPIs. Upper GI bacterial overgrowth, may lead to an increased susceptibility to respiratory infections by potential micro-aspiration or translocation into the lungs.
Proton Pump Inhibitors and Gastrointestinal Neoplasia
The risk of sporadic fundic gland polyposis (FGPs) seems to increase with long-term use of PPIs and it continues to increase with a prolonged use. Short-term treatment does not seem to be related with an increased risk of FGPs development.
A meta-analysis of 11 observational studies reported that the use of acid suppressive drugs was associated with an increased risk of gastric cancer although the lack of information on H. pylori infection limits the results.
Brunner and coworkers studied the effects of daily pantoprazole therapy for up to 15 years and showed no evidence that, hypergastrinaemia leads to dysplastic or neoplastic enterochromaffin-like (ECL) cell changes in humans
Long-term PPI therapy at a regular dose was not associated with a significantly increased risk of colorectal carcinoma (CRC)
Proton pump inhibitors are among the safest and most effective class of drugs. In recent years, however, considerable attention has been pointed towards a wide range of adverse effects. The majority of the associations are mainly based on observational studies. Confounding factors and alternative possible explanations need to be taken in account when evaluating these studies. In most cases, RCTs would be useful to further confirm these associations.
For most side effects, a clear underlying biological mechanism is plausible. However, the clinical evidence of the adverse effect is often weak and cannot be clearly associated to PPI use. While short-term PPI treatment rarely represents any harm, concern for the complications regarding long-term prescriptions exists.
Special attention should be given to elderly patients with significant comorbidity and on multidrug treatment when starting PPI therapy. Finally, in most cases and based on the available evidence, PPI benefits seem to outweigh potential adverse effects. The clinical indication for PPI use should always be reviewed to determine whether the treatment is still necessary and to avoid over prescription.
Leonardo H. et al. Proton Pump Inhibitors: Risks of Long-Term Use. Journal of Gastroenterology and Hepatology 32 (2017) 1295–1302 1295. 2017