Dual-mechanism oral small molecule MBX-2982 acts as GPR119 agonist. [© Celso Pupo - Fotolia.com]
Diabetes equipment, used by patients. [Celso Pupo-Fotolia.com]

The results of research by an international team of scientists suggest that regular use of proton pump inhibitors, or PPIs, which are commonly used to treat acid reflux, is linked to a heightened risk of developing type 2 diabetes. The results, published in Gut, also indicated that this risk of type 2 diabetes increases with duration of PPI use, prompting the investigators to advise that people taking these drugs for 2 or more years should have regular blood glucose check-ups to screen for diabetes.

“Physicians should therefore exercise caution when prescribing PPIs, particularly for long-term use,” concluded the researchers, including Changhua Zhang, PhD, at The Seventh Affiliated Hospital, Sun Yat-sen University, China, and colleagues in China, the Chinese University of Hong Kong, and at Massachusetts General Hospital in the U.S. “Screening for abnormal blood glucose and type 2 diabetes may be required for regular PPI users, particularly for high-risk populations.”

Zhang is co-corresponding author of the team’s published paper, which is titled, “Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies.”

PPIs are used to treat acid reflux, peptic ulcers, and indigestion. They are among the top 10 most commonly used drugs worldwide, the authors noted. And while it is generally accepted that short-term use of PPIs is safe, long-term use has been linked to an increased risk of bone fractures, chronic kidney disease, gut infections and stomach cancer. Recent studies have also indicated that PPIs can affect gut microbial communities, they continued. “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.”

In 2014, the global prevalence of type 2 diabetes was 8.5%, and the researchers wanted to find out if the widespread use of PPIs and the high prevalence of diabetes might be linked. “Given the widespread use of PPIs and the high prevalence of diabetes, investigation of their association could have a major impact on clinical and public health practice,” they wrote. Their observational study drew on data for 204,689 participants (176,050 women and 28,639 men) aged 25–75 years, in the U.S. Nurses’ Health Study, which started in 1976 (NHS), the NHS II, which started in 1989, and the Health Professionals Follow-up Study (HPFS), which started in 1986. At enrollment and every 2 years after that, participants updated information on their health behaviors, medical history, and newly diagnosed conditions. Starting in 2000 for the NHS, 2001 for NHS II, and 2004 for the HPFS, participants were also asked whether they had used PPIs regularly in the preceding 2 years: regular use was defined as 2 or more times a week.

The data analysis showed that during the average tracking period of around 9–12 years across all three groups, 10,105 participants were diagnosed with type 2 diabetes. The annual absolute risk of a diagnosis among regular PPI users was 7.44/1000, compared with 4.32/1000 among those who didn’t take these drugs.

After taking account of potentially influential factors, including high blood pressure, high cholesterol, physical inactivity and use of other medication, the analysis found that individuals who regularly used PPIs were 24% more likely to develop type 2 diabetes than those who didn’t. The risk of developing also increased with increasing duration of PPI use. Taking these drugs for up to 2 years was associated with a 5% increased risk, while taking them for more than 2 years was associated with a 26% increased risk of developing type 2 diabetes. The risk fell the more time had elapsed since stopping. “The risk of diabetes was likely to increase with the duration of PPI use and to decrease with the time stopping PPIs,” the investigators stated.

Further analysis showed that diabetes risk among PPI users wasn’t affected by sex, age, family history of diabetes, smoking, alcohol intake, diet, physical activity, high cholesterol, or regular use of anti-inflammatory drugs. But it was higher among participants who weren’t overweight or who had normal blood pressure. “Our results suggested that participants with lower BMI or normal blood pressure seemed to be at a greater risk for diabetes in association with PPI use,” the team noted.

For comparison, the researchers also looked at the potential impact of H2 blockers, another type of drug that is used to curb excess stomach acid production. They found that regular use of these drugs was associated with a 14% increased risk of type 2 diabetes. Similarly, longer term use was associated with a higher risk, while longer time since stopping was associated with a lower risk. “Additional analyses showed that H2RAs, a less potent acid suppressor, was also associated with diabetes but the association was less marked, lending further biological plausibility to the interplay between acid suppression and the aetiopathogenesis of type 2 diabetes,” the investigators noted. “These associations were independent of traditional diabetes risk factors as well as major clinical indications for PPI use.”

While the observational study was not designed to establish cause, it did involve a large cohort of participants, whose health was tracked over a relatively long period, the researchers pointed out. “One of the strengths of our study is that it was based on three well-established prospective cohorts with large sample sizes, a sufficient number of events and over 12 years of follow-up,” they pointed out, noting that future research, including cohort studies, randomized controlled trials, and meta-analyses, would be required to confirm their conclusions.

A mounting body of evidence suggests that changes in the type and volume of bacteria in the gut (the microbiome) may help explain the associations found between PPI use and an increased risk of developing diabetes, the scientists added. “The mechanism underlying the association between PPI use and diabetes is still unclear. Increasing evidence suggests that gut microbiota may mediate this association … we also recommend additional basic scientific research to investigate the underlying mechanisms.”

Given the range of side effects and the heightened risk of diabetes associated with prescribing PPI drugs, doctors should carefully weigh up the pros and cons of prescribing such medication, the scientists cautioned. “Owing to wide usage, the overall number of diabetes cases associated with PPI use could be considerable,” they warned. “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 type 2 diabetes is recommended.”

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