Proton Pump Inhibition: Pros and Cons of Extended Use in Type 2 Diabetes

Given the influences of the gut microbiome, researchers explored the potential benefits and adverse effects of long-term use of PPIs on the pancreas and liver in people with type 2 diabetes.

With Arthur Swislocki, MD, and Mathew Weir, MD

Proton pump inhibitors (PPIs) have become one of the most widely used medications both in the United States and globally.1 Over-the-counter PPIs are intended for short-term use to achieve relief of mild heartburn but these medications are often taken for prolonged durations for prophylaxis and management of a variety of acid-related disorders.1   

While generally considered to be safe, recent studies have identified an increased risk of adverse effects associated with long-term use of PPIs, including osteoporotic-related fractures, Clostridium difficile infection, community-acquired pneumonia, vitamin B12 deficiency, kidney disease, and dementia.2   

Exploring possible problems in relying on proton pump inhibition to reduce heartburn in people with diabetes.

In addition, data from  a postmarketing safety analysis of PPI use introduced concerns of a rise in kidney injury and electrolyte imbalances among patients taking proton pump inhibitors.3 Recent studies have also identified associations between PPI use and acute kidney injury, chronic kidney disease (CKD), and end-stage renal disease (ESRD).3

Exploring Possible Adverse Effects of Extended Proton Pump Inhibition 

With the growing prevalence of diabetes, whether clinicians should be concerned about the overreliance of PPIs in these patients was explored by a team of researchers at the University of California School of Medicine at Davis (UC-Davis).3 Their findings were published in the journal, Metabolic Syndrome and Related Disorders.

“In addition to the growing global epidemic of diabetes, there is increasing awareness of the contribution of medications, both prescription and OTC, to glucose intolerance,” said Arthur Swislocki, MD, FACP, professor of medicine at UC-Davis, and consultant endocrinologist for Veteran’s Administration of Northern California Health Care System in Martinez, California, in an interview with EndocrineWeb.

Commenting on the impetus behind this recently published study, “The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes”,3 Dr. Swislocki said “we wished to address the possible impact of proton pump inhibitor use on glucose tolerance, given the wide use of these agents, and we were pleased to find no significant deleterious effect and no impact on renal function.”

The researchers wanted to explore the premise that if prolonged use of PPIs reduces gastric acid in the gut, the result may be a suppression of gastrin levels— a hormone involved in beta cell production.

Since individuals with type 2 diabetes (T2D) experience reduced beta cell function, a decline in gastrin secretion may precipitate a cascade having a negative effect on beta cell proliferation and function, thereby improving glycemic control.

Suppression of Gastric Hormone Activity Does Not Change HbA1c

In seeking the support of their research, Dr. Swislocki and his team identified a small study in which that patients with T2D who were taking PPIs exhibited a slightly lower hemoglobin A1c (HbA1c) than subjects not taking PPIs.4

This prompted the initiation of the retrospective, multicenter electronic database analysis of files drawn from the Veterans Integrated Service Network.3 Patients who were receiving their medical care from this healthcare network were eligible for participation in the study if they met the following criteria:

  • Under treatment for type 2 diabetes
  • Had a HbA1c > 6.5%
  • Taking a proton pump inhibitor concurrently with metformin or sulfonylurea monotherapy

In comparing the intervention group who were taking a PPI to a control group with T2D but not taking medication for heartburn, the researchers reported a statistically significant decrease in HbA1c.

However, there was no statistically significant difference between the two groups on the post-A1c.

“I am not at all surprised by these results,” said Mathew Weir, MD, professor of medicine and director of nephrology at the University of Maryland School of Medicine in Baltimore. He told EndocrineWeb that there is no pathophysiological reason why PPIs would substantially improve glycemic control in patients with T2D

“In our view, patients with diabetes may be prescribed PPIs if those agents are warranted, as our data, based on a large Veteran population, offered no significant benefit in terms of glycemic control or deleterious effect on renal function,” said Dr. Swislocki.

Chronic Kidney Disease and PPI Use in Patients with Diabetes 

Findings from another recent study—a trial of 5,994 patients using proton pump inhibitors, and 23,976 matched patient controls offered an indication that PPI exposure was associated with 1.52-fold increased risk of chronic kidney disease in Taiwanese patients with diabetes when the daily dosage was > 180 mg taken for one year.5    

However, Dr. Swislocki said: “the study authors noted that the patients receiving PPIs had issues with blood pressure which might have predisposed them to a higher rate of renal problems.” Dr. Weir concurred, saying this outcome was likely due to potential bias of a confounding variable by indication.

Dr. Swislocki recommended the following: “clinicians should be alert to the possibility of diabetic gastroparesis being misinterpreted as gastroesophageal reflex disease (GERD) and in these cases consider whether proton pump inhibition therapy is appropriate in those individuals.” However, “our data do not allow us to identify individuals who might be adversely affected by extended use of PPIs.”

Consequently, the American Gastroenterological Association (AGA) recommends that individuals intending to remain on protein pump inhibitors for long-term use take the lowest effective dose to manage their condition; and, the AGA guideline provides indications under which long-duration PPI use is warranted.6  

Continue Reading:
Is Metformin Obsolete? Debating its Future in Managing Type 2 Diabetes
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