From the Journals

PPIs associated with diabetes risk, but questions remain



Regular use of proton pump inhibitors (PPIs) is associated with an increased risk of type 2 diabetes, according to a large prospective analysis of the Nurses’ Health Study. The results follow on other studies suggesting other potential adverse effects of PPIs such as dementia, kidney damage, and micronutrient deficiencies.

The authors, led by Jinqiu Yuan and Changhua Zhang of Sun Yat-sen University (Guangdong, China), call for regular blood glucose testing and diabetes screening for patients on long-term PPIs. But not all are convinced. “I think that’s a strong recommendation from the available data and it’s unclear how that would be put into practice. I think instead practitioners should adhere to best practices, which emphasize using the lowest effective dose of PPIs for patients with appropriate indications,” David Leiman, MD, MSHP, assistant professor of medicine at Duke University, Durham, N.C. said in an interview.

“Overall, the data from the study can be classified as provocative results that I think may warrant further study,” he added. Randomized, controlled trials or many more observational studies would be required to establish causality between PPI use and diabetes risk, and in any case the findings of the current study don’t warrant a change in practice, Dr. Leiman said, noting that the study’s design makes it likely that much or all of the observed associations were due to confounding.

The study appeared online Sept. 28 in Gut.

The researchers analyzed data from 80,500 women from the Nurses’ Health Study, 95,550 women from the Nurses’ Health Study II, and 28,639 men from the Health Professionals Follow-up Study (HPFS), with a median follow-up time of 12 years in NHS and NHS2 and 9.8 years in HPFS.

The absolute risk of diabetes was 7.44 per 1,000 person-years in PPI users versus 4.32 among nonusers. After adjustment for lagging PPI use for 2 years and stratification by age and study period, PPI use was associated with a 74% increased risk of diabetes (hazard ratio , 1.74; 95% confidence interval, 1.37-2.20). Multivariable adjustment for demographic factors, lifestyle habits, comorbidities, and use of other medications and clinical indications for PPI use attenuated the association but did not eliminate it (HR, 1.24; 95% CI, 1.17-1.31).

There was no statistically significant association in the HPFS group (HR, 1.12; 95% CI, 0.91-1.38), possibly because of the smaller sample size.

At 1 year, the number needed to harm with PPIs was 318.9 (95% CI, 285.2-385.0). At 2 years it was 170.8 (95% CI, 150.8-209.7) and at 3 years it was 77.3 (95% CI, 66.8-97.0).

At 0-2 years, PPI use was associated with a 5% increase in diabetes risk (HR, 1.05; 95% CI, 0.93-1.19). More than 2 years of use was associated with higher risk (HR, 1.26; 95% CI, 1.18-1.35).

There was also an association between stopping PPI use and a decreased risk of diabetes: Compared with current PPI users, those who had stopped within the past 2 years had a 17% reduction in risk (HR, 0.83; 95% CI, 0.70-0.98), and those who had stopped more than 2 years previously had a 19% reduction (HR, 0.81; 95% CI, 0.76-0.86).

The researchers also examined diabetes risk associated with use of H2 receptor agonists (H2RAs), since the drugs share clinical indications with PPIs. H2RA use was also associated with a higher risk of diabetes (adjusted HR, 1.14; 95% CI, 1.07-1.23).

The researchers suggested that the fact that the less potent H2RA inhibitors had a less pronounced association with diabetes risk supports the idea that acid suppression may be related to diabetes pathogenesis.

The authors also suggest that changes to the gut microbiota may underlie increased risk. PPI use has been shown to reduce gut microbiome diversity and alter its phenotype. Such changes could lead to weight gain, metabolic syndrome, and chronic liver disease, which could in turn heighten risk.

The study is limited by its observational nature, and lacked detailed information on dosage, frequency, and indications for PPI use.

SOURCE: Yuan J et al. Gut. 2020 Sep 28. doi: 10.1136/gutjnl-2020-322557.

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