Regular use of proton-pump inhibitors (PPIs) increases patients’ risk of developing type 2 diabetes mellitus (T2DM) by 24%, an observational study published in Gut has suggested.
Researchers conducted a prospective analysis using data from 204,689 participants, who did not have diabetes, from three ongoing US cohorts: the Nurses’ Health Study, the Nurses’ Health Study II and Health Professionals Follow-up Study.
Participants were asked at the start of the study, and then for every subsequent two-year period thereafter, whether they had used PPIs regularly in the previous two years.
PPIs are used to treat acid-related disorders such as gastro-oesophageal reflux disease, peptic ulcer disease and non-ulcer dyspepsia.
The researchers defined regular use as taking PPIs two or more times per week. They also collected information on age, ethnicity, lifestyle and family history, with cases of diabetes confirmed using the American Diabetes Association diagnostic criteria.
After a median of 10 to 12 years — depending on the cohort — a total of 10,105 cases of diabetes were documented among participants.
“Regular PPI users had a 24% higher risk of diabetes than non-users (HR [hazard ratio] 1.24, 95% CI 1.17 to 1.31),” the study concluded.
It added that the risk of developing diabetes “increased with duration of PPI use”. For participants who used PPIs for up to 2 years, the risk increased by 5%, while those who used PPIs for more than 2 years saw their risk increase by 26%, compared with non-users.
In addition, it said stopping PPI use was likely to be associated with a lower risk of diabetes.
According to the study, the possible mechanism for the association could be related to gut microbiota, as previous studies have shown that PPI use is associated with reduced diversity of gut microbiome and consistent changes in the microbiota phenotype.
Anja St. Clair Jones, a consultant gastroenterology pharmacist at Brighton & Sussex University Hospitals NHS Trust, described the study as “interesting” but said that, in view of limited understanding of the human gastrointestinal microbiota and its impact on gut integrity and host health, further research into PPIs as a risk for developing diabetes was needed to properly understand the implications for clinical practice.
“The result signposts a possible association between PPI usage and diabetes but is not able to explain the mechanism of this association,” she said. “PPIs are also implicated in weight gain, metabolic syndrome and chronic liver disease, which are all risk factors for diabetes.”
“The complexity of the metabolic processes, the gut biome-host interactions — which are affected by a multitude of factors such as diet, travel, infections — [and] exposure to bacteria and environment, as well as the self-reporting, pose a considerable challenge to the investigators despite statistical mitigation.”
St. Clair Jones also pointed out that the study population was “98% white” so did not investigate ethnicity, which can also affect diabetes risk. “It cannot be translated into the Asian or African population,” she said.
The authors of the study said that the results suggested that the association between PPI user and T2DM was “likely to be stronger” among participants with a lower body mass index (BMI) or normal blood pressure.
“This is in divergence to the traditionally expected risk factors for developing metabolic diseases, such as high BMI, high blood pressure, inactivity, age, dietary factors etc.,” St. Clair Jones added.
The researchers concluded that, given the potential risk of diabetes and other adverse effects such as enteric infections, clinicians should “carefully balance” the benefits and harms in prescribing PPIs, particularly for long-term continuous use.
“For patients who have to receive long-term PPI treatment, screening for abnormal blood glucose and [T2DM] is recommended,” they said.