It’s been a while since scientists first started to question whether proton pump inhibitors (PPIs), a popular group of anti-heartburn medications, cause stroke or not. To unravel this mystery, a multitude of studies have been trying to reach a consensus to no avail. But the last study to address this offered valuable insight into the topic thanks to its large sample size and strong methodology. This rigorous, international study, published in the peer-reviewed journal, BMC Medicine, revealed that regular use of PPIs increases the risk of stroke by 16% (1).
From the nineties onwards, PPIs revolutionized the treatment of many stomach conditions because they offered an effective solution alternative to stomach and esophagus surgeries—the only game in town back then. Due to popular demand, PPIs became a lucrative business for many pharmaceutical companies before long. Nexium, Protonix, and Prilosec, popular brand names of PPIs, may sound familiar to many people who commonly use them throughout the world for relieving symptoms of heartburn, indigestion, and stomach pain even without the need for a prescription.
PPIs work by reducing acid production in the stomach. They are usually used to treat stomach ulcers and heartburn, in addition to other conditions of the esophagus. Shortly after the discovery of PPIs, doctors began to have nagging doubts that long-term use of these drugs may lead to stroke. These doubts, however, are not easily resolvable. Most patients who are prescribed PPIs for a long time are diagnosed with chronic conditions, such as hypertension and diabetes. Those patients take PPIs because they use a load of medications to treat their chronic conditions, and these medications often cause stomach discomfort and heartburn. The confusion arises because these chronic diseases might also play a role in stroke development, to begin with, making it difficult for researchers to untangle the mystery of what exactly caused a stroke—the drug or the chronic disease.
But a group of researchers from various universities across the world decided to study a big sample to solve this scientific riddle. So, they chose the UK Biobank, a large, ongoing study that started in the UK in 2006, originally to study the association between certain environmental and genetic factors on the one hand, and various health conditions on the other. In this study, researchers surveyed almost half a million participants from England, Wales, and Scotland about their long-term use of PPIs, and followed them for stroke up until 2017. Ultimately, the study revealed that patients who had been using PPIs had a 16% higher risk of developing a stroke. The study also looked into previous clinical trials exploring PPIs and stroke, which were found to be in line with the new study findings.
Unlike previous studies, this study was special in that it surveyed a very large sample of participants (about half a million), and for a long period. Plus, it employed robust statistical methods to avoid confusion and precisely attribute strokes to either PPI or other factors, such as chronic conditions.
The reason why PPIs might cause stroke remains unknown, but one explanation pins the blame on a chemical compound called nitric oxide (NO) (2,3). This compound is instrumental in regulating platelet function, ensuring a smooth and steady blood flow to the brain. PPIs decrease the amount of NO in the bloodstream through a complex mechanism, causing disturbance to the blood flow heading toward the brain. This disturbance is the main culprit behind stroke, which simply means that “little-to-no blood” is reaching the brain. Another explanation ascribes stroke in PPI users to the fact that PPIs may play a role in developing diabetes and chronic kidney disease, which both are risk factors for stroke (4).
Fortunately, many who use PPIs to treat occasional heartburn will breathe a sigh of relief when knowing that taking PPIs for a short period is not expected to lead to stroke. However, long-term use seems to affect, or at least contribute to, stroke development. Given the mounting evidence for the PPI-stroke link, doctors should rethink the rush for prescribing PPIs, especially to patients with chronic conditions who are more prone to stroke from the get-go. This is to say nothing of the chronic consequences of PPIs, including diabetes, rheumatoid arthritis, fractures, and dementia (5).
References:
- Yang M, He Q, Gao F, Nirantharakumar K, Veenith T, Qin X, et al. Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials. BMC Medicine. 2021 Dec 3;19(1):316.
- How May Proton Pump Inhibitors Impair Cardiovascular Health? | SpringerLink [Internet]. [cited 2022 Jan 9]. Available from: https://link.springer.com/article/10.1007%2Fs40256-016-0160-9
- Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, et al. Unexpected Effect of Proton Pump Inhibitors. Circulation. 2013 Aug 20;128(8):845–53.
- Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies | Gut [Internet]. [cited 2022 Jan 9]. Available from: https://gut.bmj.com/content/70/6/1070
- Side Effects of Long‐Term Proton Pump Inhibitor Use: A Review – Haastrup – 2018 – Basic & Clinical Pharmacology & Toxicology – Wiley Online Library [Internet]. [cited 2022 Jan 9]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/bcpt.13023
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Sari is a medical doctor, health writer, and specialist in global health, who has been involved in skincare research and studies for a long time.
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