Is the long-term use of PPIs problematic?

A long-term study of 20,000 people with type 2 diabetes reported that long-term use of PPIs is associated with increased cardiovascular and mortality risks.

Intestinal flora disturbance is the suspected cause of the association

According to study authors, this link is due to alterations of the intestinal flora: a less acidic pH value in the stomach favours an intestinal overgrowth of oral microbiota bacteria, while microbial diversity in the intestine decreases at the same time. The resulting dysbiosis also means changes in the metabolites released by the intestinal flora. The gut microbiome contains about 1015 microbial cell types and more than 22 million microbial genes, which exceeds the cells and genes of humans. With these genes, the gut microbiome can synthesise a variety of enzymes with versatile capabilities and ferment numerous compounds that would escape digestion by human enzymes.2

Disruption of these intestinal metabolites can promote inflammation, alter the composition of lipoprotein subclasses, and also impact the metabolism of macro- and micronutrients, as the authors explain. In addition, PPIs appear to directly worsen glycaemic control: higher HbA1c levels have been documented in diabetics on PPIs, which in turn influence the risk of macrovascular damage.3

Data from other studies also highlight the problem that PPIs inhibit proton pumps non-specifically, that is, not just those of the stomach's parietal cells. Blocked acid production in our cells (more specifically, reduced acidification in lysosomes), interferes with the elimination of toxins or metabolic end products that are no longer needed, and is associated with increased oxidative stress, endothelial dysfunction, telomere shortening, and accelerated senescence in human endothelial cells.4-6

Limiting the use and duration of PPIs

The benefits and risks of PPI use need to be carefully weighed in type 2 diabetics, and cardiovascular health needs to be monitored more intensively if they are used, the authors suggest.1

But this is not the first time this has been seen outside of the diabetic population. When proton pump inhibitors were approved, they were originally designed to be taken for up to a maximum of 6 weeks.6 Unfortunately, what we see again and again today - especially as patients age - is a widespread, long-term use, although the indication or benefits are insufficiently questioned as a treatment progresses.

In a long-term cohort of 350,000 adults (not limited to diabetics) who received acid-inhibiting medications for the first time, the risk of mortality was also increased by 23%, with the risk of death increasing with PPI exposure duration. Tthe increase particularly affected patients without a documented medical indication for PPIs.4 "The adverse effects associated with PPI use are serious, and all of them are independently associated with a higher risk of death," concluded the US Department of Veterans Affairs study at the time.

Dietary optimisation makes sense in many ways

Diabetics are more affected by these risks than the general population: they are three times more likely to be prescribed PPIs, and they are two to four times more likely to experience cardiovascular complications and premature death.3 These patients would benefit from dietary optimisation and support for gut flora diversity in several ways: the same highly processed foods that promote diabetes also predispose them to reflux.

At the same time, a large number of studies and practice-based audits have consistently concluded that even a few simple but targeted dietary modifications result in significant improvements in weight, HbA1c, lipid profiles, and blood pressure, as well as leading to high rates of remission in type 2 diabetes and prediabetes.

PPIs should only be used when clearly indicated, and for short periods of time, and discontinuation effects should be taken into account and discussed with those receiving treatment. Treating chronic and complex gastrointestinal problems with PPIs can mask undetected physiological problems and lead to further complications.6


  1. Geng, T. et al. Proton Pump Inhibitor Use and Risks of Cardiovascular Disease and Mortality in Patients With Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism dgac750 (2022) doi:10.1210/clinem/dgac750.
  2. Liu, J. et al. Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives. Aging and Disease 13, 1106 (2022).
  3. In German only: Langzeiteinnahme von PPI kann kardiovaskuläres Risiko und Mortalität erhöhen. (2023).
  4. Xie, Y. et al. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open 7, (2017).
  5. Yepuri Gautham et al. Proton Pump Inhibitors Accelerate Endothelial Senescence. Circulation Research 118, e36–e42 (2016).
  6. In German only: Christoph Dr., S. Die tödliche Seite der PPIs. DocCheck.