Researchers have found an association between regular use of proton pump inhibitors and type 2 diabetes. However, given that this was an observational study, they could not prove that the drugs cause the condition.
Proton pump inhibitors (PPIs), which treat acid reflux, peptic ulcers, and indigestion, are among the world’s most widely prescribed drugs.
The drugs, including omeprazole and lansoprazole, reduce the amount of acid produced by specialized cells in the stomach lining.
Most medical professionals believe that short-term use of PPIs is safe, but many have concerns about long-term use. Some studies have linked the drugs to an increased risk of fractures, chronic kidney disease, pneumonia, gut infections, and dementia.
However, most of the evidence to date has only established associations rather than causal links, so the issue of the long-term safety of PPIs remains controversial.
In the latest contribution to this debate, an observational study suggests that PPIs may increase the risk of type 2 diabetes and that the risk increases the longer a person takes the drugs.
The researchers behind the study recommend that doctors regularly test for diabetes in people who have been taking the drugs for 2 or more years, especially those at high risk of the condition.
The study, led by researchers at Sun Yat-sen University in Shenzhen, China, has been published in the journal Gut.
Health and lifestyle surveys
The scientists analyzed data on 204,689 individuals (176,050 females and 28,639 males) who were part of the Nurses’ Health Study (NHS), NHS II, and the Health Professionals Follow-up Study (HPFS).
Participants provided information about their medical history, health, and lifestyle at enrollment and every 2 years after that. They also reported whether they used PPIs two or more times a week.
The participants included in this study did not have diabetes at baseline. However, after a median follow-up period of 9.8 years in HPFS and 12 years in NHS and NHS II, 10,105 participants had received a diabetes diagnosis.
The absolute risk of diabetes diagnoses per year was 7.44 for every 1,000 people taking PPIs regularly, compared with 4.32 for every 1,000 people who did not take the drugs.
To calculate the risk associated with taking PPIs, the researchers accounted for other variables potentially linked to diabetes, such as demographic factors, high blood pressure, high cholesterol, physical inactivity, and other medications the participants were taking.
After making these adjustments, they found that people who took PPIs regularly were 24% more likely to develop diabetes than those who did not.
The risk appeared to be cumulative. Those who had been taking the drugs for up to 2 years had a 5% increased risk, whereas those taking them for more than 2 years had a 26% increased risk.
The study found that those who had stopped taking PPIs had a reduced risk of developing diabetes, and this risk continued to decline as the time since they stopped taking the drugs elapsed.
Stomach acidity
The study also found that regular use of another class of drugs called H2 blockers — a less potent suppressor of stomach acid — had associations with a 14% increased risk of diabetes.
The authors argue that this supports the idea that reducing acidity in the gut is responsible for increasing the risk of diabetes, through its effect on the community of bacteria living there.
They cite evidence that PPI use has associations with reduced diversity of gut bacteria. In addition, they say both PPI use and diabetes have links to increases in the abundance of some bacterial species and decreases in others.
Observational studies suggest that other medicines that have a significant impact on gut bacteria, such as antibiotics, may also increase the risk of diabetes.
“Owing to its wide usage, the overall number of diabetes cases associated with PPI use could be considerable,” the authors write. “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.”
The authors call for more research, including randomized controlled trials, to establish whether a causal link exists. They also recommend basic scientific research to investigate the underlying mechanisms.
‘Simply not convinced’
Naveed Sattar, a professor of metabolic medicine at the University of Glasgow in the United Kingdom, who researchers the causes of diabetes, was skeptical about the findings.
Prof. Sattar told the Science Media Centre in London:
“I am simply not convinced that PPI use actually increases diabetes risk. There could be a number of other reasons, what we call ‘residual confounding’ — for example, people who take PPIs may also be more likely to have unhealthy lifestyles in other ways, and the authors have not fully adjusted for all the other things that could cause diabetes and lead people to take more PPI.”
A recent review of research found no evidence that taking PPIs significantly affects glucose or insulin levels in people who already have diabetes.
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