Which guanylate cyclase-c (GUCY2C) agonist has a lower risk of causing diarrhea?

Plecanatide Has Lower Diarrhea Rates Than Linaclotide

Plecanatide causes significantly less diarrhea (4.3%) compared to linaclotide (16.3%), with lower discontinuation rates due to diarrhea (1.2% vs 3.4%), making it the preferred guanylate cyclase-C agonist when minimizing diarrhea risk is the priority. 1

Direct Comparison of Diarrhea Rates

The 2022 AGA guidelines provide head-to-head data on both GC-C agonists:

Plecanatide:

• Diarrhea incidence: 4.3% vs 1.0% placebo 1
• Discontinuation due to diarrhea: 1.2% vs 0% placebo 1
• No diarrhea-related serious adverse events 1

Linaclotide:

• Diarrhea incidence: 16.3% vs 2.3% placebo 1
• Discontinuation due to diarrhea: 3.4% vs 0.2% placebo 1
• No diarrhea-related serious adverse events 1

This represents a nearly 4-fold higher diarrhea rate with linaclotide compared to plecanatide (16.3% vs 4.3%). 1

Important Caveat About Meta-Regression Analysis

The AGA guidelines note that a meta-regression analysis controlling for differences in placebo arm diarrhea rates found similar rates between the two agents. 1 However, the raw clinical trial data consistently shows plecanatide with lower absolute diarrhea rates, which is what matters most for patient counseling and drug selection when diarrhea avoidance is the goal. 1

Dose-Related Considerations for Linaclotide

If linaclotide must be used, lower doses reduce diarrhea risk:

• 72 μg dose: 2.4% discontinuation due to diarrhea 2
• 145 μg dose: 3.2% discontinuation due to diarrhea 2
• 290 μg dose (IBS-C indication): 3.4-4.5% discontinuation due to diarrhea 1, 3

The 72 μg dose for chronic constipation has a diarrhea profile approaching that of plecanatide, though still higher than plecanatide's 1.2% discontinuation rate. 2, 1

Clinical Algorithm for GC-C Agonist Selection

When diarrhea avoidance is the priority:

• Choose plecanatide 3 mg once daily (4.3% diarrhea rate) 1

When maximizing efficacy is the priority:

• Choose linaclotide 290 μg once daily for IBS-C (ranked first in efficacy among secretagogues, but 16.3% diarrhea rate) 1

For patients with high diarrhea concern but needing linaclotide:

• Consider starting with 72 μg dose for chronic constipation (2.4% discontinuation rate) 2

Quality of Evidence

Both recommendations are based on high-quality evidence from the 2022 AGA guidelines:

• Plecanatide: MODERATE certainty evidence 1
• Linaclotide: HIGH certainty evidence 1

The linaclotide evidence base is more robust (4 phase 3 RCTs with 2,612 patients) compared to plecanatide (2 phase 3 RCTs), but plecanatide's lower diarrhea profile is consistent across trials. 1