By Seema Gupta, MD, MSPH
Synopsis: In a large study, long-term use of proton pump inhibitors in menopausal women was associated with an increased risk of developing hypertension.
Source: Soliman AI, Wactawski-Wende J, Millen AE, et al. Proton pump inhibitor use and incident hypertension in menopausal women. J Am Heart Assoc. 2025;14(13):e040009.
Proton pump inhibitors (PPIs) are among the most widely prescribed medications globally. They commonly are used to manage acid-related gastrointestinal disorders, such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. Their widespread, often long-term use has raised growing concern about systemic effects beyond the gastrointestinal tract. These include increased risks of pneumonia, chronic kidney disease, bone fractures, micronutrient deficiencies, and even dementia.1
More recently, concerns have emerged about the potential cardiovascular consequences of PPI use, particularly their effect on nitric oxide (NO) bioavailability.2 NO is a critical vasodilator produced by endothelial cells, playing a central role in blood pressure regulation and vascular homeostasis. PPIs may impair NO production by disrupting the gastric reduction of dietary nitrate to nitrite, a key step in the enterosalivary nitrate-nitrite-NO pathway. Additionally, PPIs have been shown to reduce the activity of endothelial NO synthase (eNOS), further decreasing NO availability. These mechanisms may contribute to endothelial dysfunction and elevated blood pressure, underscoring the importance of evaluating cardiovascular risks associated with prolonged PPI use. However, whether prolonged PPI use is associated with clinical hypertension remains unclear, and current studies have been insufficient to establish a causal relationship.
In their study, Soliman et al analyzed data from 64,720 postmenopausal women enrolled in the Women’s Health Initiative Observational Study between 1993 and 1998, all of whom were free of hypertension and cardiovascular disease at baseline. PPI use and duration were recorded through detailed medication inventories at enrollment. Incident hypertension, defined as physician-diagnosed and/or treated high blood pressure, was self-reported through annual follow-up questionnaires. Linear regression was used to examine changes in measured systolic blood pressure over a three-year period.
Researchers found that over an average follow-up period of 8.7 years, 28,951 participants developed hypertension. Compared to non-users, those taking PPIs had a 17% increased risk of developing hypertension after adjusting for relevant confounders (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.08-1.27). Risk rose with longer duration of use, showing a dose-response relationship (HRs of 1.13, 1.17, and 1.28 across increasing categories; trend P < 0.001). Additionally, systolic blood pressure rose by an average of 3.39 mmHg over three years in new PPI users relative to never-users (P = 0.049).
Commentary
The study by Soliman et al adds a critical dimension to our understanding of the systemic consequences of chronic PPI use. While PPIs are widely prescribed and often viewed as benign agents for gastrointestinal acid suppression, this large, prospective analysis in more than 64,000 postmenopausal women highlights a statistically and clinically meaningful association between long-term PPI use and incident hypertension. With a 17% increased risk overall — and even greater risk with longer duration — these findings challenge the traditional compartmentalization of PPIs as agents confined to gastroinstestinal safety considerations.
This study has several practice-changing implications. First, clinicians should approach long-term PPI use with greater scrutiny, particularly in patients with additional cardiovascular risk factors. The default practice of indefinite PPI renewal — often without reassessing indication — needs to be reevaluated.3 Second, when PPI therapy is clinically justified, it should be prescribed at the lowest effective dose and for the shortest necessary duration.4 Third, there may be value to blood pressure monitoring in long-term users, especially as part of a broader cardiovascular risk assessment.
Importantly, these findings also raise questions for further investigation. Does hypertension risk reverse upon discontinuation of PPIs? Are certain patient populations more vulnerable — such as those with existing endothelial dysfunction or impaired NO metabolism? And could co-administration of dietary nitrate or nitrate-preserving strategies mitigate this risk?
In an era increasingly focused on deprescribing and precision medicine, this study adds urgency to a growing body of literature calling for a reexamination of the systemic effects of PPIs. It underscores the need for a more integrated approach to risk assessment — one that recognizes the subtle but meaningful ripple effects of chronic medication use beyond their primary targets.
Seema Gupta, MD, MSPH, is Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
References
1. Maes ML, Fixen DR, Linnebur SA. Adverse effects of proton-pump inhibitor use in older adults: A review of the evidence. Ther Adv Drug Saf. 2017;8(9):273-297.
2. Tayal R, Yasmin S, Chauhan S, et al. Are proton pump inhibitors contributing in emerging new hypertensive population? Pharmaceuticals (Basel). 2023;16(10):1387.
3. Metaxas ES, Bain KT. Review of proton pump inhibitor overuse in the U.S. veteran population. J Pharm Technol. 2015;31(4):167-176.
4. Farrell B, Pottie K, Thompson W, et al. Deprescribing proton pump inhibitors: Evidence-based clinical practice guideline. Can Fam Physician. 2017;63(5):354-364.
