Cardiovascular and non-cardiovascular concerns with proton pump inhibitors: Are they safe?

The introduction of proton pump inhibitors (PPIs) has been a cornerstone in the treatment of acid-related disorders, such as gastroesophageal reflux and peptic ulcer, and their use has increased rapidly during the last decades. Being highly lipophilic drugs, they may potentially affect several pathophysiological pathways involved in cardiovascular and kidney morbidity, immune response and infections, absorption of selected nutrients, bone metabolism and cognitive function. Clinical epidemiology evidence coming from well-designed analyses of observational data consistently reported that long-term use of PPIs may increase the risk of cardiovascular events among patients treated with thienopyridines, tubular-interstitial nephritis and chronic kidney disease, hypomagnesemia, and fractures. Conversely, currently available evidence about the impact of PPIs on cardiovascular risk among patients not treated with thienopyridines, infections, nutritional disorders, cognitive impairment and dementia is limited by confounding. Given that randomized controlled trials investigating these issues are unlikely to be realized, the application of modern pharmacoepidemiology principles is expected to mitigate limitations of observational studies while addressing these relevant knowledge gaps. Meanwhile, physicians should be aware of potential issues related to long-term use of PPIs and weigh benefits of PPI therapy for appropriate indications along with the likelihood of the potential risks. A deprescription trial should be considered for all PPI users who do not have definite indications for long-term therapy.