Home / Resources / Articles / Prolonged Use of Proton Pump Inhibitors Linked to Increased Risk of T2DM

Prolonged Use of Proton Pump Inhibitors Linked to Increased Risk of T2DM

Oct 27, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Arjay Mendoza, PharmD Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences

Long-term users of the acid reflux drugs known as Proton Pump Inhibitors (PPIs) have a 24% higher risk of developing type 2 diabetes than non-PPI users. 

Proton Pump Inhibitors (PPIs) are medications used to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), stress ulcer, and indigestion. They are among the most commonly used drugs in the United States, as well as worldwide, due to their proven safety and efficacy. However, recent studies have shown that long-term use of PPIs has been associated with an increased risk of bone fractures, chronic kidney disease, gut infections such as C. difficile, vitamin B12 deficiency, and stomach cancer. 


According to Gut, British Medical Journal (BMJ), regular use of PPIs was linked to modest-duration dependent risk for developing type 2 diabetes mellitus (T2DM). This was based on a prospective study of three large cohorts in the United States with over 2,127,471 person-years (PYs) of follow-up and 10,105 incident cases of diabetes; the researchers found that regular PPI users have a hazard ratio of 1.24 (95% CI: 1.117 to 1.31) vs. non-PPI users. This means that long-term PPI users (>2 years) have a 24% higher risk of developing diabetes compared to non-PPI users. Aside from this, according to a team of researchers at the University of California Davis School of Medicine, they found out that there is an increasing awareness of the contribution of PPIs to glucose tolerance. This is with regard to the premise that if prolonged use of PPIs reduces gastric acid secretion in the digestive tract, the result might be gastrin level suppression, which can further affect beta cell production.   

After the data has been analyzed in 204,689 patients in the prospective study (28,639 men and 176,050 women, aged 25-75 years old) with the average tracking period of around 9 to 12 years, 10,105 participants were diagnosed with T2DM. The annual absolute risk (AR) of diabetes diagnosis among PPI users was 7.44 out of 1000, compared to 4.32 out of 1000 for non-PPI users. Further analysis showed that diabetes was not affected by gender, age, family history, smoking, alcohol intake, and diet, etc. However, participants with lower BMI or normal blood pressure seemed to be at a greater risk of acquiring diabetes with prolonged PPI use. 

Because of this increased risk of T2DM after taking into consideration all confounding factors such as high blood pressure, high cholesterol, sedentary lifestyle, physical inactivity, and use of other medications, physicians are advised to exercise caution when prescribing PPIs to adult patients, especially for long-term use. Hence, the general recommendation is that regular blood glucose check-up is needed to screen for diabetes, as well as screening for type 2 diabetes mellitus according to the American Diabetes Association (ADA) diagnostic criteria.  

In comparison, the researchers also looked into the potential effects of H2-blockers in diabetes risk, such as omeprazole, etc., due to their reduction in stomach acid production. They found out that the regular use of acid-suppressing medications was associated with 14% increased risk of T2DM, with long-term use even more associated with a higher risk. However, since it is just an observational study, the results cannot establish causation, but can pave the more for further research in the future. 

Although the mechanism is still unclear on how PPIs are associated with increased risk of diabetes, a growing number of scientific evidences points out that changes in the type and volume of bacteria in the gut may be responsible for the association between the two. Indeed, given the potential risk of diabetes and other adverse effects with long-term use of PPI, extreme caution should be used in prescribing the medication especially for adult patients, especially if they are going to take it daily and for over 2 years. 

Practice Pearls: 

  • Chronic use of proton pump inhibitors (PPIs) has been linked to increased risk of type 2 diabetes mellitus (T2DM) in adult patients.
  • Long-term users of PPIs have a 24% higher risk of developing diabetes compared to non-PPI users. 
  • Physicians should exercise caution when prescribing PPIs, especially for long-term use (>2 years).


Villegas, Kelly et al. “The effect of proton pump inhibitors on glycemic control in patients with type 2 diabetes.” Metabolic syndrome and related disorders vol. 17,4 (2019): 192-196. doi:10.1089/met.2018.0138 

Yuan J, He Q, Nguyen LH, et al. “Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies.” Gut. BMJ. 28 September 2020. doi: 10.1136/gutjnl-2020-322557 


Arjay Mendoza, PharmD Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences 



See more about proton pump inhibitors and diabetes.