Do GLP-1 (Glucagon-like peptide-1) receptor agonist medications decrease the absorption and delay the onset of action of other medications due to their effect on gastric emptying?

GLP-1 Receptor Agonists and Drug Absorption

GLP-1 receptor agonists do delay gastric emptying and can reduce peak concentrations (Cmax) and delay time to peak concentration (tmax) of co-administered oral medications, but these changes do not result in clinically significant alterations in overall drug exposure (AUC) or clinical outcomes for most medications. 1, 2

Mechanism of Gastric Emptying Delay

• GLP-1 receptor agonists delay gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone through vagal nerve-mediated pathways, specifically by activating nitrergic and cyclic adenosine monophosphate pathways on the myenteric plexus. 1, 3

• This mechanism leads to reduced phasic gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased fasting and postprandial gastric volumes. 1, 3

• The delay in gastric emptying measured by scintigraphy (the gold standard) is approximately 36 minutes compared to placebo—a modest delay relative to standard fasting periods. 4

Impact on Oral Medication Absorption

The AGA guideline explicitly states that GLP-1 receptor agonists may impact the absorption of some oral medications that require rapid onset of action due to delayed gastric emptying. 1

Pharmacokinetic Changes Observed:

• Treatment with GLP-1 receptor agonists results in reduced Cmax and delayed tmax across multiple drug classes including: 2

  • High solubility/high permeability drugs (warfarin, contraceptive pills, acetaminophen)
  • High solubility/low permeability drugs (ACE inhibitors)
  • Low solubility/high permeability drugs (statins)
  • Low solubility/low permeability drugs (digoxin)

• However, the area under the curve (AUC)—representing total drug exposure—remains clinically unchanged. 2

• No clinically significant differences in therapeutic endpoints have been documented with co-administration. 2

Differences Between Formulations

• Short-acting GLP-1 receptor agonists (like exenatide) have more pronounced effects on delaying gastric emptying than long-acting formulations. 3, 5

• Tachyphylaxis develops with continuous exposure, meaning the gastric emptying delay diminishes over time with long-acting preparations or chronic use of short-acting preparations. 1, 5

• Acute and intermittent infusions produce more pronounced gastric emptying delays than continuous infusions. 1

Clinical Recommendations

Dose adjustments are probably not required for simultaneous use of GLP-1 receptor agonists with most oral medications. 2

Specific Cautions:

• Exercise caution when using GLP-1 receptor agonists with medications requiring rapid onset of action (though specific examples are not well-defined in the literature). 1

• When combining with insulin or insulin secretagogues (sulfonylureas), adjust doses as clinically indicated and monitor for hypoglycemia, as this represents a true drug interaction risk rather than an absorption issue. 1

• Use particular caution in patients with kidney dysfunction or when prescribing drugs with narrow therapeutic indices (such as digoxin, warfarin), as pharmacokinetic studies primarily enrolled healthy subjects and may not reflect these populations. 2

Important Caveats

• The gastric emptying effects are not present in patients who have had a vagotomy, confirming the vagal-dependent mechanism. 1, 3

• Effects are more pronounced in individuals with normal or rapid baseline gastric emptying compared to those with already delayed emptying. 1, 3

• Avoid using GLP-1 receptor agonists with other GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors. 1

• For liquid medications specifically, acetaminophen absorption testing shows no substantial differences at time points relevant to clinical care, suggesting liquid formulations may be less affected. 4