What is Linaclotide (Linzess)?

Linaclotide (Linzess): A Guanylate Cyclase-C Agonist for IBS-C and CIC

Linaclotide (Linzess) is a guanylate cyclase-C (GC-C) agonist that is strongly recommended for treating irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) due to its high efficacy in improving bowel movements and reducing abdominal pain. 1

Mechanism of Action

Linaclotide is a minimally absorbed 14-amino acid peptide that works locally in the intestinal lumen by:

• Binding to GC-C receptors on intestinal epithelial cells
• Increasing intracellular and extracellular cyclic guanosine monophosphate (cGMP)
• Stimulating chloride and bicarbonate secretion into the intestinal lumen
• Increasing intestinal fluid secretion and accelerating gastrointestinal transit
• Reducing visceral pain sensitivity through cGMP-mediated effects on pain-sensing nerves 1, 2

FDA-Approved Indications and Dosing

• IBS-C in adults: 290 mcg once daily
• CIC in adults: 72 mcg or 145 mcg once daily
• Functional constipation in children 6-17 years: 72 mcg once daily 1, 2

Clinical Efficacy

For IBS-C:

• Across 4 randomized controlled trials (RCTs) with 1307 patients receiving linaclotide:
  • 34% of linaclotide patients met the FDA responder endpoint vs. 18.8% with placebo
  • Significantly improved abdominal pain (RR 0.83; 95% CI 0.78-0.88)
  • Increased complete spontaneous bowel movements (CSBMs) (RR 0.86; 95% CI 0.83-0.89)
  • Improved global assessment of IBS-C symptoms 1

For CIC:

• Significantly increased CSBMs per week (MD 1.37; 95% CI 1.07-1.95)
• Improved spontaneous bowel movements (SBMs) per week (MD 1.97; 95% CI 1.59-2.36)
• Enhanced stool consistency (MD 1.25; 95% CI 1.1-1.39)
• Increased global relief rates (RR 1.96; 95% CI 1.63-2.35) 1

Administration Guidelines

• Take on an empty stomach, at least 30 minutes before the first meal of the day
• Administer at approximately the same time each day
• Swallow capsules whole; do not crush or chew
• For patients unable to swallow capsules, can open and sprinkle beads on applesauce or mix with water 2

Adverse Effects

The most common adverse effect is diarrhea:

• Occurs in 16.3% of patients taking linaclotide vs. 2.3% with placebo
• Led to treatment discontinuation in 3.4% of patients vs. 0.2% with placebo
• No serious adverse events due to diarrhea were reported in clinical trials 1

Special Populations

• Contraindicated in children less than 2 years due to risk of severe dehydration
• Contraindicated in patients with known or suspected mechanical gastrointestinal obstruction
• Not recommended in IBS-C patients under 18 years (except for functional constipation in ages 6-17)
• Elderly patients: Limited data in patients >65 years; use caution due to potential for decreased hepatic, renal, or cardiac function 2

Clinical Pearls

• Linaclotide ranked first in efficacy among secretagogues for IBS-C in network meta-analyses
• May be particularly useful in patients with concurrent abdominal discomfort, pain, and bloating
• Diarrhea typically occurs early in treatment and is generally mild to moderate in severity
• No dosage adjustment needed for renal or hepatic impairment
• Minimal systemic absorption means negligible drug interactions 1, 2

Monitoring

• Assess for improvement in bowel movements and abdominal symptoms
• Monitor for diarrhea, especially during the first weeks of treatment
• Evaluate for adequate hydration if diarrhea occurs
• Consider dose reduction if diarrhea is severe or persistent 1

Linaclotide represents an important therapeutic option for patients with IBS-C and CIC, with strong evidence supporting its efficacy and a favorable safety profile when used appropriately.