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Primarily used to help control Gastroesophageal Reflux Disease (GERD), proton pump inhibitors (PPIs) are some of the most commonly used medications among American patients. They’re available by prescription and over-the-counter but are intended for short-term use. For long-term relief from GERD, patients ideally start with a PPI before transitioning to an H2 blocker.

In select cases, patients may use them longer than a few weeks to manage prophylaxis or an acid-related issue. Yet, multiple studies have shown that a visible percentage of patients take PPIs long term to lessen heartburn or another less-severe condition.

Due to this trend, researchers at the Seventh Affiliated Hospital, Sun Yat-sen University in Shenzhen, China wanted to examine the relationship between long-term PPI usage and the development of type 2 diabetes. Their recently published study determined that patients who use PPIs long term have a greater risk of developing type 2 diabetes. Risks increase the longer a patient remains on the PPI.

Background

stomach painResearchers wanted to examine the “why” behind 2014 statistics. At that point in time, 8.5 percent of the world’s population had been diagnosed with type 2 diabetes and PPI usage had significantly increased over the past two decades.

To assess this relationship further, researchers examined data on 204,689 subjects (176,050 women and 28,639 men) between the ages of 25 and 75 from the U.S. Nurses’ Health Study (NHS), the NHS II and the Health Professionals Follow-up Study (HPFS). None of the subjects initially had diabetes.

Assessing NHS patients from 2000 onwards, NHS II from 2001 and HPFS from 2004, researchers asked participants about their PPI usage every two years and counted “regular use” as at least two times per week. Subjects were further asked about a diabetes diagnosis. Among all three groups, 13,528 subjects were regular PPI users.

Results

Examining each group for nine to 12 years, researchers found that 10,105 subjects were eventually diagnosed with diabetes. The greatest percentage came from the regular PPI group, at 7.44 cases out of 1,000. By contrast, non-users had a type 2 diabetes diagnosis rate of 4.32 out of 1,000.

Once researchers controlled for comorbid factors like blood pressure, high cholesterol and physical inactivity, the regular group had a 24-percent greater rate of developing diabetes than non-users. Factors like age, sex and family history of diabetes did not appear to influence a subject’s risk. However, patients with overweight BMIs or high blood pressure saw elevated risks among the PPI group.

Researchers also assessed risks for subjects using H2 blockers. While not as extreme, patients taking this group of drugs long term saw a 14-percent higher risk for type 2 diabetes compared to users taking neither a PPI or H2 blocker.

Researchers postulated that patients using these drugs experience increased type 2 diabetes risk because PPIs and H2 blockers have potential to transform the gut microbiome over time.

Other Risks of Using PPIs

A greater risk for type 2 diabetes is only one concern for patients using PPIs long term. A 2019 study found that risk for dying from kidney failure, heart disease and stomach cancer also increase with time.

Researchers examined over 200,000 U.S. veterans taking over-the-counter or prescription PPIs and found that, within 10 years, 13 percent of the subjects died from a cardiovascular condition. Long term, fatality risks related to a cardiovascular condition jumped to 18 percent.

Researchers also examined patients using an H2 blocker. While they also were at risk, the likelihood of dying from a cardiovascular condition decreased to 11 percent.

The longer patients remained on the medications, risk increased. For individuals who took a PPI for at least one year, risk ranged from 63 to 71 percent, compared to subjects who had only used the medication for a few months.

Since 2010, the FDA has released multiple safety warnings and required label changes for adverse side effects resulting from long-term usage. These include:

  • Pneumonia
  • Adverse drug interactions
  • Elevated dementia risks
  • Fractures (arm, wrist and hip)
  • Hypomagnesemia
  • Diarrhea from clostridium difficile
  • Vitamin B12 deficiency
  • Acute interstitial nephritis (AIN)
  • Lupus erythematosus
 

Hypergastrinemia is another possibility from long-term suppression of gastric acid. Patients experience elevated levels of stomach acid and more intense GERD symptoms once discontinuing a PPI, even if they only used the drug for a couple of months.
 
Did you develop type 2 diabetes after using a PPI long term? In spite of their popularity, PPIs come with serious side effects that patients should be educated on to help make informed decisions.