Lin Chang, MD, AGAF, lead author of the 2022 American Gastroenterological Association (AGA) Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation (IBS-C)— “intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS-C” and “an update of a prior technical review and guideline” published in 2014—spoke with Physician’s Weekly about the guideline and the overall topic of pharmacological management of IBS-C.
PW: What does the 2022 AGA Guideline on the Pharmacological Management of IBS-C add to prior guidance on this topic?
Dr. Chang: The prior AGA guideline on pharmacotherapy for IBS was published in 2014. At that time, we evaluated pharmacologic treatments for IBS with diarrhea (IBS-D) and IBS-C, as well as treatments that were not specific for an IBS bowel habit subtype. Since that was published, for both IBS-D and IBS-C, there have been new studies on treatment. A couple were updates or additional studies on treatments we already reviewed in the 2014 guideline. But there have also been developments and approvals of new agents for IBS-D and IBS-C. For IBS-C, there were three new treatments that were included in the 2022 guideline. So, essentially, we felt we needed to update the guideline because of the new treatments and additional information on treatments we had already reviewed in the 2014 guideline.
What do you feel are the most important recommendations made in the guideline for gastroenterologists to know?
There were a number of important recommendations. I think gastroenterologists should pay attention to the newer agents, where they may not have seen the Grade methodology approach applied to their studies, which assesses the certainty of evidence based on these studies, and also the recommendations based on the certainty of evidence by a guideline committee. This is one of the first guidelines clinicians will see this information, as it relates to IBS-C, on tenapanor (which is new), plecanatide, and the reintroduction of tegaserod. This additional information in the 2022 guideline wasn’t included in 2014, which I think is important, along with updated information from a large study on linaclotide, which didn’t change the recommendation.
More recent guidelines from the AGA include a clinical decision support tool, which is also important to know about. Guidelines assess the available evidence from randomized controlled trials, and the guideline committee that has expertise in that disease will give recommendations based on the evidence. This information is meant to provide the scientific evidence of the treatments, but in clinical practice (the real world), you have to take a lot of other factors into consideration when deciding on the best treatment, such as the patients’ preferences and values, risks, and benefits. We just provide the evidence; you take the evidence and determine in clinical practice if that should be utilized in a given patient. The clinical decision support tool was created to provide a treatment algorithm, based on the evidence, that can help guide clinical practice. To me, that’s the most important aspect. The guideline provides information for the clinician, patient, and policymakers, but the clinician and the patient in a shared decision model will decide what’s best for that patient. The guideline shows which treatments are suggested or recommended by the AGA for use in patients with IBS-C. But the algorithm in the clinical decision support tool is also based on severity of symptoms and recommends what to use for first, second, and third line.
What standout research influenced the recommendations?
The additional studies for a new therapy that we had not reviewed in the past or for linaclotide, for which there was a new study. We assessed randomized controlled trials, so a drug versus placebo, not comparative studies, like tegaserod versus linaclotide, for example. We didn’t look at pathophysiologic or microbiome data.
Trying to understand how peripherally acting agents can reduce and relieve abdominal pain is a novel concept in IBS research. It has traditionally been thought that treatments that affect the brain and the gut are needed to relieve abdominal pain because pain in IBS can be centrally mediated. But many of these agents are peripherally acting agents. But there have been some data, for example with Linaclotide, that show a novel peripherally mediated mechanism by which it can reduce abdominal pain. I thought that was interesting because it explains why this agent could be effective for relieving abdominal pain, and plecanatide, which is a very similar agent, may reduce pain via a similar mechanism.
And there has been a lot of attention to “leaky gut,” which is a lay term for increased intestinal permeability or reduced mucosal barrier function. Increased intestinal permeability has been linked to symptoms in IBS, such as abdominal pain. There have been some studies examining whether certain IBS treatments can normalize intestinal barrier function, and mediate symptom relief.
I should mention tenapanor’s unique mechanism of action. Lubiprostone, linaclotide, and plecanatide are all considered secretagogues, as they increase chloride secretion into the lumen of the bowel, where sodium and water follow, and that helps constipation and IBS symptoms. I feel like tenapanor has a similar net effect, but it specifically blocks the reabsorption of sodium. Instead of increasing electrolyte secretion into the lumen of the intestine, tenapanor blocks the bowel from reabsorbing the electrolytes. It’s a novel mechanism for treating IBS-C. Tenapanor is also thought to improve or normalize the intestinal permeability, or the altered mucosal barrier function, and this may be another reason why it reduces symptoms of IBS-C.
Can you explain the conditional strength for most of the recommendations?
A strong recommendation means that a clinician would recommend the treatment in most patients with IBS-C. “Recommend” was only used when there was a high certainty of evidence and “suggest” was otherwise used. A conditional recommendation means that clinicians use the treatment in a majority of patients, but not use it many patients, making that decision based on risks, benefits, and patient preferences. It’s a shared decision-making process as opposed to recommending something for most patients.
Are there any developments in the field since the guideline was published that you feel would/should change the recommendations?
A major change is that tegaserod was taken off the market for “business reasons.” Tegaserod was a treatment developed years ago and was more recently reintroduced, but the FDA only approved it in a select group of individuals, which were women younger than 65 without a history of cardiovascular ischemic events. Perhaps it wasn’t utilized that much because it was considered more of a third-line treatment. Even though the guideline suggested its use, it’s not currently available.
I do want to point out that this guideline is only for pharmacotherapy. We didn’t review fiber or diet or brain-gut behavior therapy. We did cover that in the clinical decision support tool, but our aim was just to evaluate pharmacotherapy. But those other treatments are important and effective in IBS too.
Do you feel pharmacological management is often considered too late in the management of patients with IBS-C?
I have a few thoughts about that. I think patients are sometimes not correctly diagnosed with IBS-C, so they’re not placed on the appropriate pharmacotherapy. Often in patients with IBS-C, the focus is treating constipation, so sometimes they’re diagnosed with constipation, not IBS with constipation. These patients are often treated with over-the-counter remedies. Many people will try these or increase fiber in their diet, but they may be doing it intermittently. And some people need routine, consistent use of treatments. In some individuals with moderate-severe IBS-C symptoms, even though you improve the constipation and they’re having daily BMs, they can still have abdominal pain, discomfort, and bloating. And that’s really due to visceral hypersensitivity. Even though bowel habits and abdominal pain are mildly associated, there can be patients who still have pain, bloating, and discomfort but have regular bowel movements.
With IBS-C, as opposed to chronic constipation, you have to think about using agents that reduce abdominal pain and constipation, or you will have to add another treatment on top of the constipation treatment, to relieve abdominal symptoms.