Regular use of proton pump inhibitors (PPIs) was linked with modest duration-dependent risk for developing type 2 diabetes, researchers reported.
In a prospective study of three large U.S. cohorts, and in over 2,127,471 person-years of follow-up, 10,105 incident cases of diabetes occurred, with regular PPI users having a hazard ratio of 1.24 (95% CI 1.117-1.31) versus non-users, according to Shanghai Zhang, MD, PhD, Yulong He, MD, both of Sun Yat-sen University in Shenzhen, China, and colleagues.
As PPI duration of use increased, fully adjusted HRs rose to 1.05 (95% CI 0.93-1.19) for >0 to 2 years of use and 1.26 (95% CI 1.18-1.35) for >2 years compared with no PPI use, they stated in Gut.
"Physicians should therefore exercise caution when prescribing PPIs, particularly for long-term use," according to the authors.
The study followed a total of 204,689 participants free of diabetes in the Nurses' Health Study (NHS), NHS II, and the Health Professionals Follow-up Study (HPFS). Participants were 121,700 and 116,430 female nurses from two different time periods (ages 30-55 and ages 25-42, respectively), as well as 51,529 male healthcare professionals of various specialties (ages 40-75).
The authors noted that at baseline, regular PPI users tended to be less physically active, and had higher rates of hypertension and hypercholesterolemia. They also were more likely to use non-steroidal anti-inflammatory drugs and steroids versus non-PPI users.
"As expected, PPI users had considerably higher rates of gastric or duodenal ulcer, gastroesophageal reflux disease and upper gastrointestinal tract bleeding," the authors stated.
Diabetes was confirmed by American Diabetes Association diagnostic criteria. The study assessed HR after adjusting for demographic factors, lifestyle habits, comorbidities, other medication use, and clinical indications.
The authors pointed out that, despite the irreplaceable role of these suppressants in acid-related disease, using them over the long term has been linked with various adverse effects such as bone fractures, chronic kidney disease, enteric infections, and gastric cancer. Additionally, a recent randomized controlled trial found that PPI users seemed to have a modest, but not statistically significant, increased risk of diabetes compared with placebo.
As to mechanisms of action, mounting evidence has suggested that alterations in the gut microbiota may mediate this association, with previous research linking PPIs with reduced diversity in the intestinal microbiome and consistent changes in the microbiota phenotype.
For example, both PPI use and diabetes have been associated with an increase in the gut abundance of Blautia and Lactobacillus and a decrease in the genus Bifidobacterium.
PPI use could also result in weight gain, metabolic syndrome, and chronic liver disease, which in turn may increase type 2 diabetes risk.
The investigators called for research to elucidate the underlying mechanisms.
The study had several limitations, including its observational nature and inability to exclude residual confounding effects. In addition, detailed data on PPI dosage, frequency, timing of exposure, brand, and indications were not collected in the cohorts, and the association between PPI use and diabetes may have been confounded by indications.
In terms of the findings' generalizability, all participants were healthcare professionals, who may have different characteristics from the general population. Moreover, misclassification of participants was possible owing to the lack of data on treatment timing. The results may also have been limited by left truncation, interval data, and reliance on self-report.
"At a population level, PPIs may have an even more pronounced effect on gut microbiome than other commonly used drugs such as antibiotics, leading to warnings of overuse of PPIs and calls for further investigation into the sequelae of long-term PPI consumption," the authors warned.
But Daniel E. Freedberg, MD, of Columbia University in New York City, urged caution when interpreting the results, despite the study's good design.
"The association between PPIs and diabetes was very weak. PPI users differ from non-users and it is not possible to account for all of these differences in this type of study," he told MedPage Today. "These baseline differences, rather than PPIs themselves, are the most likely explanation for the study findings."
Freedberg, who was not involved in the study, pointed out that the American Gastroenterological Association does not recommend special monitoring for adverse effects among long-term PPI users so "This study is unlikely to change that recommendation."
However, he recommended careful consideration as to why people use long-term PPIs. "The best reasons are to prevent certain causes of gastrointestinal bleeding, such as Barrett's esophagus and erosive esophagitis, especially among patients with serious bleeding in the past. Patients who take long-term PPIs but don't have any of these reasons should speak to their doctors."
Disclosures
The study was supported by the Startup Fund for the 100 Top Talents Program, Sun Yat-sen University, the National Heart, Lung, and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases.
Zhang, He, and co-authors, as well as Freedberg, disclosed no relevant relationships with industry.
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