Evidence Grade A — Regulatory approved. 121 published studies. 14 registered clinical trials.
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Plecanatide (sold as Trulance) is a daily tablet for irritable bowel syndrome with constipation (IBS-C) and chronic constipation. It targets the same gut pathway as linaclotide (Linzess) but was designed to more closely resemble the body's own natural gut hormone, potentially offering better tolerability. Notably, it can be taken with or without food — unlike linaclotide which requires an empty stomach.
Plecanatide is also known by these brand and alternate names:
121 published studies: 80 human, 0 animal, 0 in-vitro, 58 reviews
Plecanatide is marketed as Trulance (approved January 2017 for chronic constipation; January 2018 for IBS-C). It is taken as a 3 mg tablet once daily, and unlike linaclotide, it can be taken with or without food.
The main clinical differentiator from linaclotide is tolerability: the diarrhoea rate in IBS-C trials was 4.3% for plecanatide compared to approximately 20% for linaclotide. Post-marketing diarrhoea rates have been even lower. Efficacy on constipation symptoms is broadly comparable between the two agents. Plecanatide carries the same boxed warning against use in children under 6 years. The choice between linaclotide and plecanatide often comes down to tolerability profile and individual response.
Plecanatide activates the same GC-C receptors in the intestinal lining as linaclotide, stimulating fluid secretion and reducing visceral pain sensitivity. The key design difference is that plecanatide has pH-dependent binding — it works most strongly in the slightly acidic environment of the upper small intestine (where GC-C receptors are most concentrated), rather than throughout the entire gut. This more targeted action may explain its lower rate of diarrhoea compared to linaclotide.
The key differentiator from linaclotide is the diarrhoea rate — 4.3% for plecanatide versus approximately 20% for linaclotide in IBS-C trials. Since diarrhoea is the main reason patients stop taking these medications, this lower rate may translate to better long-term adherence. Effectiveness for constipation symptoms appears broadly comparable between the two drugs. No head-to-head efficacy trials exist, so definitive superiority claims cannot be made. With linaclotide now available as a generic, plecanatide faces significant pricing pressure. It carries the same boxed warning against use in children under 6 years. Market uptake has been modest, and no major ongoing research programmes are expanding its indications.
PeptideTrace tracks 14 registered clinical trials for Plecanatide sourced from ClinicalTrials.gov.
GCC Agonist Signal in the Small Intestine
Efficacy and Safety of Plecanatide Comparing With Placebo in the Treatment of Functional Constipation
Efficacy and Safety of Plecanatide in Children 6 to <18 Years With Irritable Bowel Syndrome With Constipation (IBS-C)
A Postmarketing Study of Plecanatide in Breast Milk of Lactating Women Treated With TRULANCE®
An Efficacy and Safety Study of Plecanatide in Adolescents 12 to <18 Years of Age With Chronic Idiopathic Constipation
FDA ORIG 1
FDA SUPPL 1
FDA SUPPL 2
FDA SUPPL 10
FDA SUPPL 7
FDA SUPPL 11
Health Canada Market Authorisation
Plecanatide is a 16-amino-acid synthetic analogue of human uroguanylin with a single amino acid substitution (Leu→Asp at position 3). It has 2 disulfide bonds and was designed to mimic the endogenous ligand for GC-C more closely than linaclotide.
Plecanatide activates the same GC-C/cGMP/CFTR pathway as linaclotide, producing intestinal fluid secretion and potentially reducing visceral pain. The key pharmacological distinction is pH-dependent binding: plecanatide has higher affinity for GC-C at pH 5.0 (the acidic environment of the proximal small intestine/duodenum) compared to neutral pH. This pH-activation profile mimics endogenous uroguanylin, which is most active in the proximal gut. This may theoretically produce more targeted proximal activation and less distal colonic fluid secretion.
Plecanatide is marketed as Trulance (Salix/Bausch, approved January 19, 2017 for CIC; January 25, 2018 for IBS-C). Dose: 3 mg daily for both indications. Diarrhea rate in IBS-C trials: 4.3% (versus ~20% for linaclotide). Post-marketing diarrhea rate: <0.5%. Can be taken with or without food (versus linaclotide's fasting requirement). No head-to-head trials versus linaclotide exist.
Linaclotide is marketed as Linzess (approved August 2012). It is taken as a daily oral capsule on an empty stomach, at least 30 minutes before the first meal. The recommended dose is 290 mcg for IBS-C and 72 or 145 mcg for chronic constipation. In clinical trials, approximately 34% of IBS-C patients met the composite improvement endpoint compared to 17% on placebo. Diarrhoea is the most common side effect (approximately 20%) and the leading reason for discontinuation. Linaclotide has a boxed warning against use in children under 6 years due to deaths in young mice, though no such events have been reported in humans. It competes with plecanatide (which targets the same pathway) and other IBS-C treatments.
Elamipretide (Forzinity) was approved by the FDA for Barth syndrome based on the TAZPOWER trial. The randomised crossover phase (12 patients) did not meet its primary endpoints, but the open-label extension (168 weeks) demonstrated durable improvements in walking distance and muscle strength that formed the basis for approval. Barth syndrome affects approximately 1 in 300,000–400,000 births. A larger Phase III trial in primary mitochondrial myopathy (218 patients, MMPOWER-3) did not meet its primary endpoint, and the drug was not approved for that broader indication. Elamipretide remains approved exclusively for Barth syndrome. See also SS-31 (#158) for the research compound context.
Glucagon has been available as an emergency injection since the 1960s and remains the standard rescue treatment for severe hypoglycaemia. Recent innovation has focused on making it easier to administer in emergencies. Baqsimi, approved in 2019, was the first needle-free option as a nasal powder. Gvoke, also approved in 2019, eliminated the need to mix and reconstitute the medication before injection — a significant advance since severe hypoglycaemia often impairs the ability to follow complex preparation steps. Dasiglucagon (Zegalogue), a next-generation stable liquid glucagon approved in 2021, further improved on the convenience of rescue administration. Beyond emergency rescue, glucagon's receptor is now a major research target — dual and triple agonists combining glucagon receptor activity with GLP-1 (such as survodutide and retatrutide) are in advanced clinical trials for obesity and metabolic disease.
Evidence Reviews
Timelines
Regulatory Status
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