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Results of a prospective cohort study published in the International Journal of Cardiology add to the evidence suggesting that acid suppression via proton pump inhibition is associated with an increase in the risk for cardiovascular disease. This was a well-known cohort, part of the UK Biobank Study, and included nearly 460,000 participants without cardiovascular disease at the study’s onset (2006-2010) who were followed through 2018. After multivariate adjustment, use of proton pump inhibitors (PPIs) was associated with a 44% greater risk for incident of cardiovascular disease (CVD), including a 65% higher risk for coronary heart disease, a 21% higher risk for stroke, a 17% higher risk for atrial fibrillation, a 61% higher risk for heart failure, and a 36% higher risk for venous thromboembolism.
This is not the first study to suggest cardiovascular harm related to this class of medication. A meta-analysis of 17 randomized and controlled trials concluded that the use of PPIs increased cardiovascular risk 70% among people using them to control GERD (gastroesophageal reflux disease), with a greater risk found among long-term users and for omeprazole specifically. A systematic review of 37 studies published in Heart, Lung & Circulation found a 68% higher mortality risk and a 54% higher rate of major cardiovascular events associated with PPI use.
Given that PPIs are one of the most commonly and increasingly prescribed medications (in 2009, they were used in an estimated 9.2% of outpatient visits) and that the majority of studies that examine this association find evidence of harm, this should be of concern, even if causality cannot be determined. Globally, an estimated 25% of the adult population are estimated to be taking a PPI, most on a high dosage, and approximately one-third taking them for more than 3 years. Although often recommended for short-term use (4 to 8 weeks), many people take PPIs for a much longer than recommended (or even an indefinite) period of time. For example, in an analysis of over 3,000 people admitted into critical care started on stress ulcer prophylaxis, nearly half continued to take acid-suppressive medications past the recommended period. A 2013 analysis of 22 skilled long-term facilities found that nearly 80% of admitted patients were taking PPIs, and that 65% of these patients did not have an appropriate diagnosis for PPI use. A number of conditions may require long-term PPI use, such as for patients with Barrett’s esophagus, severe erosive esophagitis, etc., and de-prescribing may not be an option (and it can be quite difficult to do in those for whom it is appropriate). However, there is also evidence that, at least in some populations, PPI usage is poorly monitored. Overuse has also been attributed to inappropriate prescriptions for ulcer prevention in low-risk patients or for stress ulcer prophylaxis, among other conditions, as well as over-the-counter use.
While there are many concerns associated with long-term PPI use, among them dementia, renal damage, bone fractures, infections, etc., there is also some evidence that short-term use may increase the risk for cardiovascular disease, though causality is difficult to determine. For instance, in a very large retrospective nationwide study in Taiwan, which included nearly 200,000 treatment courses, PPI use was linked to an overall 36% higher risk for ischemic stroke. In a nested case-control subset of this study, which included over 15,000 hospitalized patients (due to ischemic stroke) and over 15,000 matched controls, short-term PPI use (<30 days) was associated with a 77% greater risk for stroke, versus a 28% higher risk with longer-term use (91-180 days before stroke onset).
While one possibility for this association is “channeling bias,” i.e., clinicians are more likely to prescribe medications to patients they believe have more severe disease (thus overrepresenting CVD among patients receiving PPIs), a number of mechanisms have been proposed that plausibly explain this heightened risk. For example, PPIs are known to impair magnesium absorption, roughly doubling the likelihood of hypomagnesemia in the general population, and increasing the risk 7-fold among people also taking loop diuretics. Higher circulating magnesium levels have previously been associated with a 30% lower risk (per 0.2-mmol/L increment) of CVD, a significant and clinically meaningful protective effect. Data from The Atherosclerosis Risk in Communities (ARIC) Study found that PPI users had a 24% higher likelihood of having hypomagnesemia, as well as a 31% greater risk for incident cardiovascular disease. Although they concluded that hypomagnesemia did not explain the association between PPI use and CVD, the difference in the serum magnesium levels between PPI users and non-users was quite small (0.02 mmol/L), an order of magnitude lower than previously found to be associated with CVD risk in the above study. Additionally, the analysis only assessed whether hypomagnesemia modified the associated risk; serum magnesium as a biomarker has been criticized as a poor measure of total body magnesium status (because it is tightly controlled), and it may be possible that serum magnesium does not reflect the link between magnesium loss and cardiovascular risk. What is clear is that PPI use should be monitored closely, with clear justifications for their continued use, given the associated cardiovascular (and other) risks.
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