AGA/ACG Guideline on Chronic Constipation

The 2 leading gastrointestinal societies in United States—the American Gastroenterological Association and the American College of Gastroenterology—collaborated to produce guidance on pharmacological agents available for the treatment of chronic idiopathic constipation.

Brian Lacy, MD, is a professor of medicine at Mayo Clinic in Jacksonville, Florida. Lin Chang, MD, is a professor of medicine in the division of digestive disease at the David Geffen School of Medicine at UCLA in Los Angeles. William Chey, MD, is the section chief and professor of medicine in the division of gastronomy and hepatology at the University of Michigan in Ann Arbor.

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TRANSCRIPT:

Brian Lacy:

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida, and I am absolutely delighted to be speaking today with Dr. Lin Chang, professor of medicine in the Division of Digestive Diseases at the David Geffen School of Medicine at UCLA in Los Angeles, and also to Dr. William Chey, section chief and professor of Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan in Ann Arbor.

Now both doctors Chang and Chey are international experts in disorders of gut-brain interaction, but more pertinent to our discussion today they have recently coauthored a joint AGA and ACG, and that means, of course, the American Gastroenterological Association and the American College of Gastroenterology guideline on the pharmacologic management of chronic constipation published both in the American Journal of Gastroenterology and in the AGA Journal as well.

Doctors Chang and Chey, welcome. What an absolute delight to have you both here together. Let's begin simply, why a joint AGA and ACG guideline on chronic constipation? Dr. Chey?

William Chey:

Thanks, Brian. Maybe a better question is why not? You think about it, the societies always do guidelines, and for actually many years, we really tried carefully to orchestrate who is doing what, but in more recent years, we seem to have more and more overlap. And Lin and I are good friends and colleagues, worked together a long time, as we have with you, actually, for many years as well, and bottom line is we felt that a joint guideline would be much more powerful, much more impactful, than a guideline by either organization alone, or even worse, two separate guidelines by each organization on the same topic. We decided that it would make a lot of sense to join forces, and fortunately, we were able to help persuade the boards of the AGA and the ACG to collaborate on this first ever joint, AGA-ACG guideline.

Lin Chang:

Yeah. This would give us the two leading societies, GI societies, in our country, a unified voice and also would be better for patients, clinicians, membership, payers, and also that we wouldn't have conflicting views because we were together and agreeing on the recommendations. And that was, as Bill said, much more impactful and powerful.

Brian Lacy:

Yeah. What a wonderful collaboration. I think it also is very reassuring to clinicians that they're hearing this unified voice when they're thinking about patient care. Thank you for doing this. I know how much hard work this really is. So Dr. Chang, how actually was the guideline put together?

Lin Chang:

Well, I had always been thinking that the ACG and the AGA should do a guideline together, and I thought about that about the IBS treatment because both societies did it around the same time, but with the chronic idiopathic constipation, or CIC, they were both starting it at the same time. And I was asked to be on the AGA guideline for CIC, and Bill was leading the ACG effort. And so I had talked to Shahnaz Sultan, or Shahzi, who is the chair of the AGA guideline committee, and talked to Bill about why don't we do it jointly, and we agreed. We came up with a proposal, because it had never been done before, and we also worked with David Juan, who was the chair of the ACG Practice Parameters Committee, oversees the guideline, and we came with agreement on the process and the methodology.

And Bill presented to the ACG Board of Trustees, and I did that with the AGA Governing Board, and we all agreed on this process. And what we decided to use, and Bill has always brought this up, is that we tried to use the strengths of both societies on the way they did the guidelines, and both guidelines use the grade methodology. And so we did it together, taking the strengths of both, and we had equal membership from both societies. We structured it with an executive committee with two members of the ACG, that's Bill and Tony Lembo and Shahzi and me on the AGA side, and then we had three subcommittees. We divided up, we all agreed on the different treatments we were going to review as a group, and then we had decide on the PICOs for each of the treatments. And then we assigned committee members to the subcommittee where there was no conflict with that treatment.

And we had a methodologist, a senior methodologist, overseeing, one methodologist per committee, came up with a certainty of evidence, looked at the evidence, and then we came together as an entire committee, including guideline committee members that were not involved in the evidence review committees, looked at the evidence, and then decided on the recommendations. But, if a member had a conflict with the treatment, they were not involved in that discussion of the guideline recommendation, and I think that's important to remember. And then we published it, the same document, in the Red Journal and in Gastro.

Brian Lacy:

Wonderful. Lots of moving parts there and really a lot of effort to make this as clean and transparent as possible, which, again, should reassure clinicians. Bill, there were 10 recommendations made by the panel, and let's start really simply, a conditional recommendation was made for fiber. Why was that?

William Chey:

Well, largely because, despite the fact that we all think of fiber first and we all use fiber first, there isn't an incredibly robust set of data to support the use of fiber. It's not to say that the data's negative, it's only to say that, let me give an example, is that the three types of fiber that were evaluated in the guideline were bran, inulin, and psyllium. And for bran, there was actually only one placebo-controlled, randomized-controlled trial that qualified for inclusion in the analysis. For inulin, there were two, and for psyllium, there was only three randomized placebo-controlled trials that evaluated psyllium for chronic constipation. The best evidence was for cilium.

And the general recommendations are to always think about total fiber intake as opposed to just what you're supplementing. For example, when we say that it's recommended that people consume 20 to 30 grams of fiber per day, it's important for clinicians to realize that isn't necessarily what you're trying to shoot for in terms of the amount of supplementation. It's total fiber, 20 to 30 grams of total fiber per day. A person may be very well eating 10, 15, even 20 grams of fiber per day. You have to supplement according to the amount of fiber that they're taking on a daily basis. That's why it's so important to actually work with a dietician, for example, who can help you to determine what the appropriate level of supplementation might be, or at least take a dietary history so you have some feel for that.

Brian Lacy:

Great, great teaching point. Fiber, simple, cheap, safe, that said, there's just not the amount of evidence, as we're going to hear later about some pharmaceutical agents. Lin, a strong recommendation was made for the use of polyethylene glycol, an osmotic laxative. What was the data to support this strong recommendation?

Lin Chang:

There were three randomized clinical trials comparing polyethylene glycol, a osmotic laxative, with placebo, and the certainty of evidence for complete spontaneous bowel movements, spontaneous bowel movements, and global relief was moderate, but there was a low certainty of evidence for the side effects that cause someone to discontinue a trial. But, overall, the evidence was supportive that PEG would improve bowel habits in patients, and so was given a strong recommendation. I should say that we looked at different endpoints, like complete spontaneous bowel movement frequency, spontaneous bowel movement frequency, global relief, treatment discontinuation, quality of life, but the critical outcomes were improvement in CSBMs SBMs, and treatment discontinuation. You'll look at those particular critical outcomes a little bit more when you're making your recommendation. But, in general, it's thought that polyethylene glycol, it's available over the counter, that it was effective in patients with chronic idiopathic constipation.

Brian Lacy:

Wonderful.

William Chey:

One other thing, too, just to mention is PEG is one of the only agents that we use for constipation that actually has six-month RCT, six-month randomized-controlled trial data, which is, I think, also reassuring to listeners that there is, if you want to call it that, longer term data to support the safety and efficacy of PEG.

Brian Lacy:

Bill, thank you. Great teaching point there. Bill, shifting gears a little bit, thinking about another osmotic agent, in this case, magnesium oxide, the group gave a conditional recommendation to magnesium oxide. Why a little bit of a less enthusiastic recommendation?

William Chey:

Yeah. Brian, the first thing to say about this is, which is a really important point, is this is the first constipation guideline that's ever recommended magnesium. I actually, I'll take credit for this, I pushed really hard to get magnesium included amongst the different therapies, primarily because, for me, magnesium oxide has been one of my go-to laxatives for constipated patients for decades. It's valuable to just understand there is data to support magnesium oxide, but there are issues with the data, there's issues with all data, but in particular, with this, realize the recommendation is based upon two small studies that ended up enrolling fewer than 50 patients in total to magnesium oxide. That's the first thing.

Second thing is all the studies, the two studies that were done, were conducted in Japan. We have no studies from the United States or from Europe. The third thing is that the dose used in the studies was 1.5 grams per day, which for those of us who use magnesium, that's a lot of magnesium. Given all of those caveats around the data, small dataset from one country with a higher dose than we typically use, we felt like we had to qualify it a bit in terms of the recommendation.

Brian Lacy:

Wonderful, and maybe that will stimulate researchers here or in Europe to perform similar but larger studies. Lin, lactulose has been around a long time. It was given a conditional recommendation. I actually rarely recommend this, mostly because of the side effects of bloating. What was the panel's view?

Lin Chang:

There was randomized-control data looking at lactulose for chronic constipation, so it definitely was worth us investigating, but there were only two trials, and one was in the Netherlands, both about 100 patients. It was only a three-week course, so we should remember that. Chronic constipation is a long-term condition, and I think it's the indirectness that is rated in grade methodology. If it's a very short duration of time, you really think about how applicable it is using it for long term.

But lactulose was studied in one country, Netherlands, 103 patients for three weeks with variable dose, and then there was another study with 55 patients with one single dose, 30 milliliters, for 12 weeks. I think it was 12 weeks. And so you're starting with two studies, they're different. One study didn't show any effect on spontaneous bowel movements frequency, while the other one did, and there was some evidence of global relief. But, overall, the evidence for these outcomes was very low because there was a risk of bias based on the methodology of randomization and blinding, so that it just had a very low certainty of evidence, and that's why it was given a conditional recommendation.

The other point I want to make with this guideline is that the committee did put together implementation remarks, and there are statements under each treatment, and that is based on the committee, the experts, getting together and making recommendations that they thought were important for clinical practice use of each of these treatments. And it's not necessarily based on rigorous scientific data, it's our collective experience. For lactulose, it was important to know, and I think we all know this and this limits our use, is that it does cause bloating and gas, and the higher dose you use, you're going to have more of that. We did make that recommendation that you may not want to use it so early in the regimen because of those side effects, because those symptoms are patient are what patients report anyways, even without treatment, with chronic constipation.

William Chey:

Brian, can I make one additional comment too?

Brian Lacy:

Of course.

William Chey:

And one of the other implementation comments, I think, is important for people in clinical practice regarding lactulose, and that lactulose is the only laxative therapy for which there has been conducted an RCT in pregnant women. Actually, if you're looking for an evidence-based and safe treatment for pregnant women, lactulose would be your option.

Brian Lacy:

Great point there because, really, nothing else has been studied, so we have data to support that. Bill, thinking about bisacodyl, this is used a lot. This stimulant laxative is used a lot to treat symptoms of occasional constipation, but this wonderful guideline is on chronic constipation. What was the recommendation from the joint AGA and ACG committee?

William Chey:

Following on the heels of Lin's comments, so first thing to say is that, for both bisacodyl and another compound that's available in other parts of the world that's structurally related, pharmacologically related is probably a better way to say it, and that is sodium picosulfate, both of these have been evaluated in randomized-controlled trials and found to be effective for constipation-related outcomes, increasing spontaneous bowel movements, increasing complete spontaneous bowel movements, improving other things like straining, stool consistency, those types of endpoints. The thing that's similar to what Lin talked about, though, is that both of those RCTs were four-week RCTs, so relatively short duration. And the reality is that I think, if you were to ask 100 gastroenterologists about whether they had concerns about stimulant laxatives like bisacodyl or sodium picosulfate, you'd hear probably a substantial minority of folks with concerns about the safety of those laxative therapies when used over long periods of time.

And here's the reality, the reality is we don't have any long-term safety data. We don't know whether there are issues or not. Right now, there don't appear to be, but in fairness, we don't have long-term safety data. By the way, we don't have long-term safety data for virtually any of these treatments. I don't want to make it sound like this is only relevant to bisacodyl and sodium picosulfate. The same issue actually should be considered for all these. We really have, with the exception of the prescription medications where there's an FDA requirement to have at least one year's safety data, for all the OTC remedies, we have no long-term data.

Brian Lacy:

No, that's a great point, Bill, to just, again, put things in perspective to make sure we're not calling out one OTC agent versus another. And, Lin, before we shift gears and start talking about some prescription medications, what about senna and another stimulant laxative? A lot of patients like it. Many providers recommend it. Is there long-term data, speaking to Bill's point, supporting the use of senna for chronic constipation?

Lin Chang:

The data on senna, which is so widely used, is even less than what Bill mentioned. There's actually only one randomized-controlled trial, placebo-controlled trial, with senna with only 30 patients in each arm, and it's four weeks, just like the other stimulant laxatives. And it did show benefit in spontaneous bowel movements and complete spontaneous bowel movements, but the certainty of evidence was rated down because of indirectness and imprecision, and imprecision meaning that there's a wider confidence interval when you look at these outcome measures. That's why it was given a low certainty of evidence conditional recommendation. But, just thinking about what Bill said, I don't know who is going to conduct those long-term studies of over-the-counter stimulant laxatives. It probably won't be done. That's the issue.

William Chey:

The other thing, Lin, too, that you just have to say in fairness is that a lot of these things people have been using for not just decades, for literally centuries. You think about things like senna, the ancient Egyptians used senna all the time as a laxative therapy. Magnesium oxide has been used as a remedy in the Far East and other countries for many, many ... People have been using these things for long periods of time, and it doesn't seem that there have been significant safety signals that have been reported in association with their use for many, many years.

Brian Lacy:

Absolutely. The history of these agents is important to recall. Bill, it's a little hard to believe, as we start thinking about pharmaceutical agents, that the FDA gave approval to lubiprostone over 17 years ago, January 2006, and lubiprostone, this type two chloride channel activator, is used routinely for the treatment of chronic constipation. What strength of recommendation was provided by the joint panel for

William Chey:

Lubiprostone has, like you said, been around a very, very long time, and it works by acting at the CLC2 channel to increase chloride secretion. And there are several, actually, I think three randomized-controlled trials which have evaluated lubiprostone for patients with chronic idiopathic constipation, showing benefits in a lot of those key clinical endpoints that Lin alluded to, spontaneous bowel movements, complete spontaneous bowel movements, constipation response. The guideline actually gave a conditional recommendation and a low certainty of evidence, primarily because, relatively speaking, by industry standards, the studies were small, and again, of only four weeks duration. I think, as we get into this discussion, Lin will talk about the data for some of the other prescription medications, which tends to be longer term, and also use uses standardized FDA criterion, which, in fairness to lubiprostone, weren't necessarily available at the time these studies were done.

Brian Lacy:

Yeah. That's a great point, Bill. Certainly routinely used and considered very safe, and the guidelines were different 20 years ago when these studies were done and only four-week studies were required, and now longer studies are required. And so linaclotide is a guanylate cyclase-C agonist, also called a GCC agonist for most of our listeners who are here today on Apple or Spotify. And this was approved 11 years ago, in 2012. It was given a strong recommendation by the panel. And what was the data supporting the strong recommendation for linaclotide?

Lin Chang:

Yeah. These were well-conducted studies that had to use an endpoint that was accepted by regulatory agencies that we were just mentioning. There's three 12-week randomized-controlled trials, and actually, all three doses were studied in CIC, which sometimes I forget about the highest dose being studied, but really settled on the 145 microgram dose daily. And also, later on, the 72 microgram dose daily was studied as well. But it did show a significant benefit of an increase in complete spontaneous bowel movements per week, including responder rate, and spontaneous bowel movement frequency, improvement in stool consistency and in global relief. Overall, the evidence was supportive that linaclotide was efficacious for chronic idiopathic constipation, but the certainty of evidence was rated down because of imprecision, not only just for the efficacy endpoints, but also for diarrhea as a cause for treatment withdrawal. The overall evidence was moderate, but a strong recommendation.

Brian Lacy:

Wonderful. Bill, plecanatide is another GCC agonist, and this was also given a strong recommendation, and it was approved by the FDA in in January of 2017 for CIC. Did the panel comment on choosing one GCC agonist over another? Is there direct comparison data to help clinicians?

William Chey:

There's, of course, no direct comparison data, and we actually didn't talk about this a lot. I think there are a number of practical things to think about that might help you to choose one or the other. One of the things that people like about linaclotide is the dosing flexibility, to have three different doses available that you can titrate, if you will, to an individual patient's needs. On the other hand, I think, particularly for primary care doctors, that makes it really confusing. And so one thing that's nice about plecanatide is there's one dose, there's one FDA- approved dose, three milligrams, and that's by the way, the same dose that's available for chronic idiopathic constipation and IBSC. Some people just like that, the fact that it's very simple.

The other thing is that, linaclotide, you really should dose it on an empty stomach before a meal. With plecanatide, it's recommended that it doesn't matter whether you take it with or without food. And then the most common side effect for both the drugs is diarrhea. It's important to just recognize that that is an issue for both the drugs. The diarrhea, there's been a lot of debate about which drug causes more or less diarrhea. I think, in the absence of direct comparative studies, it's really hard to make a judgment regarding that particular point.

Brian Lacy:

Wonderful. And I think we all know, and many of our listeners know, I think the definitions used to classify diarrhea was a little bit different in the different studies, so it makes it tricky to tell. Lin as we wind down here, prucalopride is a 5-HT4 agonist, a serotonin type four agonist, and this was approved in Europe several years ago before receiving FDA approval here, which occurred in 2018, for the treatment of CIC. What was the strength of the recommendation from the panel for the use of prucalopride for CIC, and let us know a little bit about the data?

Lin Chang:

This agent had the highest number of clinical trials. There were five randomized-controlled trials that studied the efficacy of prucalopride compared to placebo in CIC, and mainly studying the two milligram daily dose. There was a study that also looked at the four milligram daily dose. United States, it's FDA-approved for both one milligram and two milligrams daily. But the studies support that prucalopride had significant improvement in complete spontaneous bowel movements, spontaneous bowel movements, and also the responder definition. There were very small number of serious adverse events, or the adverse diarrhea, that caused patients to withdraw treatment. There was some difficulty understanding the estimates of those events when you look at the trials. But, overall, it was given a moderate rating for certainty of evidence and a strong recommendation.

Brian Lacy:

Wonderful. Lin and Bill, this has been an absolutely wonderful conversation. I've learned a lot. I know our listeners have learned an awful lot. Any last thoughts for our listeners?

Lin Chang:

I would say that our committee spent a lot of time on this clinical decision support tool, because I know everybody likes algorithms, and there's not always one way to treat chronic idiopathic constipation. We definitely realized, in our group of experts, that we may all go down a different type of path, but in general, we did try to make a summary. But one comment that I want to make is that we didn't evaluate dyssynergic defecation or defecatory disorders that can contribute to chronic idiopathic constipation. But, if you look at the clinical decision support tool, we do bring that in to assess that in patients if they fail fiber or over-the-counter laxatives, that you should really be thinking about dyssynergic defecation because the treatment's different. It would be anorectal biofeedback or pelvic floor physical therapy. I did want to bring in that comment.

And then the other comment we made as a group, and Bill can weigh in on this, on the stimulant laxatives, we considered using it more short-term or as rescue medicine. We do have a lot of different options for more long-term use. That's some of the discussion that we had. I know, Bill, you want to comment more.

William Chey:

Just one comment. I'm glad you made the comment about dyssynergic defecation and evacuation disorders, which people should definitely think about in patients who don't respond to OTC or prescription medications. The only other comment is we actually had a fairly robust debate about whether to discuss or include natural laxatives as part of the treatment algorithm because, while everybody agreed that thinking about fiber and natural laxatives first is what they do in real life. Since we didn't talk about natural laxatives as part of the guideline, we didn't really include it as an important part of the treatment algorithm. But I just wanted to say that there is evolving evidence to suggest that a number of agents, natural agents, possess laxative properties.

I think everybody's aware of prunes, people are increasingly thinking about kiwi fruit, but there are lots of other things too. Watermelon and mango contain lots of fructose, which, for some people, exerts a laxative effect, papaya the same way. And then there are other natural substances, plants, that contain stimulant laxative properties, like aloe vera, for example, or rhubarb. There are lots of ways to skin the constipation cat, and there are many, many options, natural options, fiber, OTC, prescription medications. And so I think it's a really exciting time for patients and providers because we have so many tools at our disposal. The key is to understand what the tools are and when to use which one.

Lin Chang:

Yeah, I think that's an important point, to personalize the management approach. And that could be based on multiple factors, what the patient's been on, what they're interested in, their insurance coverage, and what their most bothersome symptoms are. I think that is an important point.

Brian Lacy:

Wonderful. For our listeners, you've been listening in to two international experts on chronic idiopathic constipation, Dr. Lin Chang at the Geffen School of Medicine at UCLA in Los Angeles, and Dr. William Chey, professor of medicine at the University of Michigan in Ann Arbor.

This is Gut Check. Whether you're listening in on Apple or Spotify or some other platform, we're delighted to have you here today. We hope you learned a lot, I certainly did, and we're looking forward to having you tune in for another podcast in the future. Again, Bill and Lin, thank you so very much.

Lin Chang:

Thank you.

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