Prolonged Use of Proton Pump Inhibitors and Risk of Type 2 Diabetes: Results From a Large Population-Based Nested Case-Control Study

CONTEXT: It is still debated whether prolonged use of proton pump inhibitors (PPIs) might affect metabolic health. OBJECTIVE: To investigate the relationship between prolonged use of PPIs and the risk of developing diabetes. METHODS: We performed a case-control study nested into a cohort of 777 420 patients newly treated with PPIs between 2010 and 2015 in Lombardy, Italy. A total of 50 535 people diagnosed with diabetes until 2020 were matched with an equal number of controls that were randomly selected from the cohort members according to age, sex, and clinical status. Exposure to treatment with PPIs was assessed in case-control pairs based on time of therapy. A conditional logistic regression model was fitted to estimate the odds ratios and 95% CIs for the exposure-outcome association, after adjusting for several covariates. Sensitivity analyses were performed to evaluate the robustness of our findings. RESULTS: Compared with patients who used PPIs for < 8 weeks, higher odds of diabetes of 19% (95% CI, 15-24), 43% (38-49), and 56% (49-64) were observed among those who used PPIs for between 8 weeks and 6 months, 6 months and 2 years, and > 2 years, respectively. The results were consistent when analyses were stratified according to age, sex, and clinical profile, with higher odds ratios being found in younger patients and those with worse clinical complexity. Sensitivity analyses revealed that the association was consistent and robust. CONCLUSIONS: Regular and prolonged use of PPIs is associated with a higher risk of diabetes. Physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use.