Patient Considerations for Use of Guanylate Cyclase-C Agonists in the Treatment of IBS-C and Chronic Idiopathic Constipation

By Clinical Content Hub

Satish S. C. Rao MD, PhD, FRCP, FACG, AGAF
Medical College of Georgia, Augusta University

Key Takeaways

  • Linaclotide and plecanatide deliver similar symptom relief to patients with irritable bowel syndrome with constipation (IBS-C). Plecanatide is pH independent, making it a better option for patients taking medications such as proton pump inhibitors (PPIs) that influence gut pH levels.
  • Polyethylene glycol (PEG) and lubiprostone can be effective for patients with chronic idiopathic constipation (CIC) but do not work well for patients with IBS-C because they do not address abdominal pain.
  • Patients will eventually become refractory to both guanylate cyclase-C agonists and chloride channel activators. This can be overcome by cycling patients through the available prescription medications.

Satish SC Rao, MD, PhD, is a professor of medicine at the Medical College of Georgia at Augusta University. His clinical areas of focus include motility, anorectal disorders, colonic and anorectal manometry, biofeedback therapy, and digestive health disorders. His research focuses on the pathophysiology and treatment of IBS as well as constipation and fecal incontinence. He has pioneered new techniques to evaluate esophageal, gastric, colonic, and anorectal function (gut-brain axis) as well as the technique of biofeedback therapy for dyssynergic defecation. He is currently investigating the neurobiological mechanisms of biofeedback therapy and pioneering new treatments for fructose intolerance.

Given that linaclotide and plecanatide offer similar results for patients with IBS-C, similar dosing regimens, and comparable adverse effects, how might a clinician choose between the 2 in a difficult-to-treat patient who has failed over-the-counter medications? 

Both linaclotide and plecanatide deliver similar results and both work on the guanylate cyclase-C receptors, but their mechanism of action differs.

Plecanatide is pH independent, whereas linaclotide works in only a fairly narrow range of pH.1 If the gut pH is lower or higher than the target range, linaclotide may not work as efficiently. As such, if patients are taking PPIs, which can change the pH of the stomach or small bowel, they may not respond to linaclotide. In these patients, plecanatide is recommended.

The 2 medications are also formulated differently. Linaclotide comes as a small gel capsule in doses of 72, 145, and 290 µg. Plecanatide comes as a tablet and is clinically approved in a 3 mg dose only.
 
Both medications can cause diarrhea, but this adverse effect is less common with plecanatide than with linaclotide. If a patient taking plecanatide is experiencing diarrhea, I advise them to break the tablet in half, or even in quarters, to see if that improves the adverse effects. With linaclotide, this is impossible because it is a gel capsule. If the lowest dose of linaclotide is still causing negative effects, there are no opportunities for dosing titration.
 
Linaclotide also has more dosing conditions. It should be taken 30 minutes before a meal, whereas plecanatide has no such restrictions.2 When choosing between the 2 for my patients who are taking PPIs, I recommend linaclotide in the evening because their PPI will have worn off by then, or I recommend plecanatide because it is pH independent.

The most commonly prescribed medication in the treatment of IBS-C is PEG (52.0%), followed by linaclotide (43.1%) and lubiprostone (32.1%).3 How accurately do you believe that these statistics reflect physician selection of treatments and why?

Only one study has assessed the safety and efficacy of PEG in patients with IBS-C. Although PEG seemed to offer relief from constipation, it did not improve pain or discomfort.4 This is a problem because IBS-C has 2 symptoms: abdominal pain and constipation. Since PEG improves only constipation and not pain, I do not routinely use PEG in patients with IBS-C.

I believe physicians keep prescribing PEG because they are not distinguishing IBS-C from CIC. They may think that if they can help to improve constipation and pain, the discomfort will also improve eventually. Because PEG is widely available over the counter, physicians usually prescribe PEG to a patient who has difficulties with bowel movements. Also, PEG has been used for almost 25 years. Linaclotide and lubiprostone are fairly newer and have been in use for only 10 and 15 years, respectively. The sheer confidence in a product that has been available for over 20 years could explain why some physicians often prescribe PEG.

“Although there is significant overlap in symptoms between IBS-C and CIC, they should be treated as being distinct.”

Given that linaclotide appears to offer the best results in terms of complete bowel movements and plecanatide appears to have the best safety profile, when and why would a clinician consider switching to or from a guanylate cyclase-C agonist to another drug class such as a chloride channel activator? What key patient factors might a health care provider want to consider when determining the most appropriate therapy?

Actually, linaclotide and plecanatide have almost exactly the same effects on complete bowel movements. The complete rates are considered clinically identical because the 2 drugs have never been compared head-to-head. Plecanatide has a better safety profile with fewer adverse effects but it is also less efficacious for the full spectrum of symptoms associated with IBS-C. Linaclotide is more efficacious but causes more diarrhea.
 
For the management of IBS-C, I prefer a guanylate cyclase-C agonist because a chloride channel activator will not address the pain of IBS-C; chloride channel activators only relieve constipation.
 
For patients with CIC, I would consider lubiprostone after looking closer at the scope of their constipation. If the patient’s constipation is associated with upper gastrointestinal (GI) symptoms such as gastroparesis, which is seen in about 30% of patients with constipation, lubiprostone would be a terrible choice because it causes nausea, and 25% of patients with upper GI symptoms already experience nausea.4,5 However, if patients have constipation that is primarily a colonic disorder, or if they are older individuals, lubiprostone is best.

So choose lubiprostone for colonic-limited disease or for older patients and plecanatide or linaclotide for younger patients, people with more diffuse GI symptoms, or for those with IBS-C.

Linaclotide adverse effects
Flip
The adverse effects of linaclotide include diarrhea, abdominal distension, flatulence, and abdominal pain.

Patient satisfaction scores for over-the-counter options such as stool softeners or fiber supplements are quite low (<15%), whereas only 18.7% of patients with IBS-C reported even trying a prescription medication.3 Is there a clear relationship between patient satisfaction and initiation of prescription medication?

I believe patient satisfaction has more to do with the patient’s initial experience of care with a physician or practice. I have noticed that most primary care providers (PCPs) prefer not to treat patients with IBS and instead refer these patients to a gastroenterologist. But some gastroenterologists no longer see patients and only do procedures. When a patient with IBS sees such a specialist, they may be subjected to unwanted procedures or may eventually be sent back to their PCP. These patients will not get better, they will only get frustrated.
 
Gastroenterologists with more traditional practices may take the time to recognize the problem. They may try to treat a patient’s symptoms and titrate the drugs and may even take the next step of prescribing neuromodulators or antidepressants if the initial drugs do not work. In my experience, patient satisfaction with a PCP or with a procedure-based practice is very low, whereas the traditional practice model accrues a higher level of satisfaction with care. Also, I believe that ultimately what matters to a patient is not just the medication they are given but everything else in addition to that prescription.

Should clinicians follow the same considerations when prescribing medication for IBS-C vs CIC? Why or why not?

No. Although there is significant overlap in symptoms between IBS-C and CIC, they should be treated as being distinct. Pain is an important component of IBS-C, because patients with IBS may still have pain even with daily bowel movements. Patients with CIC may experience discomfort or occasional pain while being backed up, but that is not the predominant feature of their illness. Instead, CIC is characterized by harder stools, straining, and having stools at fixed times of day. In my opinion, IBS-C and CIC are very different illnesses with some overlap, so the medications prescribed should differ. Although some drugs are approved for both conditions, PEG and lubiprostone work only in CIC.

What are the adverse events, outcomes, or endpoints clinicians should monitor when following up with patients with IBS-C or CIC who are receiving guanylate cyclase-C agonists?

Diarrhea is a primary concern. Other adverse events are bloating and rarely headache or edema. Nausea may be a concern to some extent, but it is not as common as with lubiprostone. Nausea seems to appear when there is a lot of active secretion in the gut and the gut is distended. If patients experience severe symptoms even at a low dose of a drug, then that is not the drug for them and we will move on to the next option. If any drug is working, I strongly recommend that a patient continue to use it until it stops working, which is prone to happen at some point. Typically, we will then switch the patient to another medication.
 
Patients in whom the working window for any given drug is very small — sometimes even as short as a month — can be switched between 3 different medications on a monthly basis. In some cases, I have been surprised at how patients respond as if they have never received the drug before. It is still unclear why some patients’ disease becomes so refractory. Usually there is some sensitivity at a receptor level. But if the patient takes a drug holiday, they should respond well again afterward.

This Q&A was edited for clarity and length.

Disclosures

Satish S. C. Rao, MD, PhD, reported affiliations with In Control Medical LLC; Ironwood Pharmaceuticals, Inc.; Laborie Medical Technologies, Inc; Neurogut, Inc.; Progenity, Inc.; QuinTron Instrument Company, Inc.; Sanofi Genzyme; Takeda Pharmaceuticals U.S.A., Inc.; Valeant Pharmaceuticals International, Inc. and Vibrant Pharma Inc

References

1. Leelasinjaroen P, Yu S, Bhagatwala A, et al. Investigation of small intestinal luminal pH and intestinal transit in constipated patients with or without clinical response to linaclotide. Neurogastroenterol Motil. 2016;28(suppl 1):106. 2nd Federation of Neurogastroenterology and Motility Meeting abstract 341. doi:10.1111/nmo.12881

2. Rey E, Mearin F, Alcedo J, et al. Optimizing the use of linaclotide in patients with constipation-predominant irritable bowel syndrome: an expert consensus reportAdv Ther. 2017;34(3):587-598. doi:10.1007/s12325-016-0473-8

3. Rangan V, Ballou S, Shin A, Camilleri M, Lembo A. Use of treatments for irritable bowel syndrome and patient satisfaction, based on IBS in America survey. Gastroenterology. 2020;158(3):786-788. doi:10.1053/j.gastro.2019.10.036

4. Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol. 2013;108(9):1508-1515. doi:10.1038/ajg.2013.197

5. Cryer B, Drossman DA, Chey WD, Webster L, Habibi S, Wang M. Analysis of nausea in clinical studies of lubiprostone for the treatment of constipation disorders. Dig Dis Sci. 2017;62(12):3568-3578. doi:10.1007/s10620-017-4680-1

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                                                                                                            Reviewed June 2022