Longer Use of Proton Pump Inhibitors Tied to Diabetes Risk

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that "physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use," say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

"Nonetheless, epidemiologic evidence on the topic remains conflicting," they acknowledge, adding that "future studies are still needed to validate our findings."

If the results are confirmed, these "may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications," Ciardullo and colleagues conclude.

Not Enough Data to Support a Change in Practice

The current findings align with a recent analysis of three prospective cohort studies of US healthcare workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told Medscape Medical News in an email. "But the effect size remains relatively small and may be explained by residual or unmeasured confounding," he cautioned.

"Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs," said Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina.

"Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users," and recommends that the decision to discontinue PPIs "should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events," he noted.

"Clinicians should be prepared to discuss the described risks associated with PPIs," said Leiman, but they should "also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication."

First-Choice Therapy for Acid-Related Disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio [OR], 1.19; 95% CI, 1.15 - 1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38 - 1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49 - 1.64).

The researchers acknowledge limitations including the study was not a randomized controlled trial and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index (BMI) or family history of diabetes that may have affected the outcomes.

Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Ciardullo and Leiman have reported no relevant financial relationships. Disclosures for the other authors are listed in the article

J Clin Endocrinol Metab. Published online April 16, 2022. Article

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