How can I treat constipation caused by a GLP‑1 receptor agonist (e.g., exenatide, liraglutide, semaglutide, dulaglutide) that I am taking for type‑2 diabetes or obesity?

Managing Constipation Caused by GLP-1 Receptor Agonists

Constipation from GLP-1 medications should be treated with a stepwise approach starting with osmotic laxatives (polyethylene glycol 17 g daily), combined with increased fluid intake (≥2 liters daily) and dietary fiber (25-30 g daily), while maintaining the GLP-1 therapy unless severe complications develop. 1

Understanding the Mechanism

GLP-1 receptor agonists cause constipation through their fundamental mechanism of action on the gastrointestinal tract:

• These medications delay gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone via vagal pathways, which slows the entire digestive process 2
• The effect extends beyond the stomach to reduce overall gut motility, decreasing phasic contractions throughout the intestinal tract 2
• Constipation represents a significant adverse effect, with semaglutide showing a risk ratio of 6.17 compared to placebo 1
• This is a dose-dependent effect that occurs more frequently with higher doses and may persist throughout treatment 1

First-Line Management Strategy

Start with osmotic laxatives as the primary intervention:

• Polyethylene glycol (MiraLAX) 17 g (one capful) dissolved in 8 oz of liquid once daily is the preferred first-line agent because it is non-stimulating, well-tolerated, and can be used long-term 1
• Increase fluid intake to at least 2 liters daily, as GLP-1 medications can cause relative dehydration from reduced oral intake and potential gastrointestinal losses 1
• Add dietary fiber gradually to 25-30 g daily through food sources or supplementation (psyllium, methylcellulose), though fiber alone is often insufficient 1

Escalation Protocol When First-Line Measures Fail

If constipation persists after 1-2 weeks of osmotic laxatives:

• Add a stimulant laxative such as bisacodyl 5-10 mg daily or senna 2 tablets at bedtime for short-term relief 1
• Consider magnesium citrate 150-300 mL as a single dose for acute severe constipation (use cautiously in patients with renal impairment) 1
• Increase the polyethylene glycol dose to 17 g twice daily if tolerated 1

Medication Adjustments and Timing Considerations

Do not discontinue the GLP-1 receptor agonist for mild-to-moderate constipation, as the metabolic and cardiovascular benefits typically outweigh this manageable side effect:

• The gastrointestinal adverse effects, including constipation, are most prominent during dose titration and often improve with continued exposure due to partial tachyphylaxis 2, 1
• Most GI adverse events occur within the first month of therapy and may diminish over time 1
• Slow titration with gradual dose escalation every 4 weeks minimizes all gastrointestinal symptoms, including constipation 2

When to Consider Dose Reduction or Discontinuation

Reduce the GLP-1 dose or discontinue therapy only in these specific scenarios:

• Severe constipation unresponsive to maximal laxative therapy for >2 weeks that significantly impairs quality of life 1
• Development of persistent severe abdominal pain, which may indicate bowel obstruction, pancreatitis, or gallbladder disease requiring immediate evaluation 1, 3
• Patients with preexisting severe gastroparesis or GI motility disorders who develop worsening symptoms, as GLP-1 agents can exacerbate these conditions 2, 3
• Evidence of functional small bowel obstruction, which has been reported as a rare but serious complication in patients with prior GI motility problems 2, 3

Critical Safety Warnings

Watch for red-flag symptoms that require immediate discontinuation:

• Persistent severe abdominal pain with distension may represent bowel obstruction rather than simple constipation 1, 3
• Right upper quadrant pain with fever suggests cholecystitis, a known risk with GLP-1 therapy 2
• Complete inability to pass stool or flatus for >3 days despite laxatives warrants urgent evaluation 3

Special Population Considerations

Patients with prior bowel obstruction or significant GI surgery:

• These individuals are at higher risk for GLP-1-induced bowel complications and require closer monitoring 3
• Consider starting at the lowest possible dose with very slow titration (extending the 4-week intervals to 6-8 weeks between increases) 2
• Maintain a lower threshold for imaging studies (abdominal X-ray or CT) if symptoms worsen 3

Elderly patients:

• More vigilant monitoring is needed for dehydration from combined reduced oral intake and constipation 2
• Ensure adequate hydration and consider more aggressive laxative therapy earlier in the course 2

Practical Implementation Algorithm

1. Week 0-2: Start polyethylene glycol 17 g daily + increase water to 2 L daily + add dietary fiber 1
2. Week 2-4: If no improvement, increase polyethylene glycol to twice daily OR add stimulant laxative (bisacodyl or senna) 1
3. Week 4-6: If still constipated, consider temporary dose reduction of GLP-1 agent by one step while maintaining laxative regimen 2, 1
4. Beyond 6 weeks: If severe constipation persists despite maximal therapy, discontinue GLP-1 agent and consider alternative diabetes/obesity medications 1, 3

Common Pitfalls to Avoid

• Do not assume "gassiness" or bloating is benign intestinal gas—it may represent significant gastric distension with retained contents or early bowel obstruction 1
• Do not wait for spontaneous resolution of moderate-to-severe constipation, as GLP-1 effects on gut motility persist throughout treatment 2, 1
• Do not use bulk-forming laxatives alone (psyllium, methylcellulose) as first-line therapy, as they require adequate fluid intake and gut motility to work effectively 1
• Do not overlook medication interactions—opioids, anticholinergics, and calcium channel blockers can worsen GLP-1-induced constipation 1

Long-Term Management Perspective

• Constipation management typically requires ongoing laxative therapy for the duration of GLP-1 treatment, as the gut-slowing effects are part of the therapeutic mechanism 2, 1
• Most patients can successfully continue GLP-1 therapy with appropriate laxative management, preserving the substantial cardiovascular (20-26% MACE reduction) and metabolic benefits 2
• The decision to discontinue should balance the severity of constipation against the proven mortality and morbidity benefits, particularly in patients with established cardiovascular disease 2