Metformin and PPIs: Concurrent Use Seems Acceptable

Metformin has become the cornerstone of oral therapy for American’s epidemic type 2 diabetes mellitus (T2DM). Proton pump inhibitors (PPIs) have similarly become the cornerstone of treatment for our pervasive acid reflux problem. Metformin, a drug that is not metabolized but rather excreted unchanged in the urine, has few interactions.

Recently, however, researchers have been debating a potential drug interaction between metformin and the PPIs. The basis of the debate is this: metformin requires hepatocyte uptake using the organic cation transporter (OCT) system to be effective. In vitro research found that PPIs inhibit OCT1, OCT2, and OCT3, creating a concern that PPIs might reduce metformin’s effectiveness.

A study published in the September issue of The British Journal of Clinical Pharmacology found no evidence of such an interaction.

This observational cohort study drew data from the UK’s Health Improvement Network (THIN) Database that contains data from more than 9 million patients. They used data from 2003 and later because HgA1c testing only became widely available in that year.

In the THIN population, they examined 4 groups:

• Patients who started metformin monotherapy without PPI exposure (n=30,954)
• Patients who started metformin after having taken PPIs for at least 6 months (n=3,618)
• Patients who started a PPI without being on any diabetes drug (n=1,396)
• Patients who started a PPI after at least 180 days of continuous metformin monotherapy (n=801)

PPIs did not reduce the effectiveness of metformin. Instead, starting a PPI improved glycemic response by -0.06 HbA1c percentage points. The researchers suggest that PPIs may increase adherence to metformin by ameliorating its gastrointestinal side effects.

Patients often started other drugs when they started metformin—drugs like statins or ACE inhibitors. This made the researchers question their findings’ sensitivity. They recalculated, controlled for baseline medication use, and found the same results.

Despite a mechanistic basis for a potential drug-drug interaction, these researchers could not confirm a clinical drug-drug interaction between PPIs and metformin.