Stratifying Patients With IBS-C to the Appropriate Agent

Following their discussion of available agents for irritable bowel syndrome with constipation (IBS-C), the panel considers how to optimally stratify patients.

Mark Pimentel, MD: I told you we were going to argue about diarrhea with these products. The data are the data. How they collect the data is 1 thing, but we’ve all used all these products. Do you have a feeling on the stratification of intensity? So Amitiza [lubiprostone]. The strength of that diarrhea effect versus plecanatide, versus linaclotide. How would you sort of stack them? Ali, do you want to take a shot at that? There are patients who have extreme constipation who need the extreme. There are patients who have mild constipation for whom maybe a milder agent would be the right choice. We’re really putting the patient in the center and are saying, “OK, which of these 3 products fits the severity of your case?” That’s really what the framework of my question is. Can you rank these? And then perhaps compartmentalize them to patients?

Ali Rezaie, MD: It’s hard to rank them based on evidence, but I can tell you based on anecdote. In real life, what happens is that multiple factors are there. Patient symptoms. Let’s face it: what drug is covered by what insurance, and how much they have to pay. And also how many times you take that medication. And also, what is the adverse effect profile of that drug? Based on that, in my practice I go after GC-C [guanylate cyclase-C] agonists first. If the patient is on the mild-to-moderate side in terms of constipation, I’ll try plecanatide first, and then linaclotide. Interestingly enough, I have seen patients who don’t respond to 1 GC-C agonist but respond to another. It’s a bit confusing as to how that happens, but again, the sites of action of these 2 drugs are different. Plecanatide works mostly on proximal small bowel, as opposed to linaclotide, which is more distal.

And then, in my practice, if GC-C agonists or secretagogues are not working, then I switch to Amitiza, mostly because it’s a twice-daily medication. And also, the adverse effect of nausea can be significant with some of the patients.

Mark Pimentel, MD: What do you do? Do you do it that way?

Anthony J. Lembo, MD: Pretty similar. As Ali said, it kind of varies from patient to patient. I actually use all 3 pretty liberally. If they have more pain, I’ll choose 1 of the GC-Cs. If it’s constipation and is more mild, I will give lubiprostone. I like linaclotide and I like lubiprostone because they’re different doses. We talked about 8 and 24 for lubiprostone, but in fact, there’s no reason you can’t do 16, which is how I have patients take it. I start once, and then go twice, 3. They can find that right dose. And the same thing with linaclotide. With plecanatide, you don’t have that kind of leeway. But I use all 3. And I think for efficacy of linaclotide and plecanatide, they’re pretty similar. I’m not sure about the adverse effects. I occasionally see diarrhea, which oftentimes isn’t a big problem for patients with both products.

Mark Pimentel, MD: A new product just came on the market, really for chronic constipation, so not really IBS-C [irritable bowel syndrome with constipation]. I guess that’s why we sort of skimmed over it. But perhaps there is a crossover benefit? And that is prucalopride. Why don’t you take that one, Tony?

Anthony J. Lembo, MD: Prucalopride was approved by the FDA in December 2018. But in fact, it’s been out in Europe for probably a decade or so. The initial studies were done here over 15-plus years ago. It seems to be effective for chronic idiopathic constipation. It has not been studied in IBS with constipation, just to be clear. But there are lots of studies that have been done, mainly in Europe now, showing that it’s effective. It appears to be safe, devoid of any cardiovascular adverse effects. There was another product called tegaserod, which was like prucalopride; but prucalopride is a full 5-HT4 agonist, and tegaserod is a partial agonist. There was some question as to whether there were cardiovascular concerns with tegaserod, which we don’t think have really panned out.

Brennan Spiegel, MD: Which is also back now.

Anthony J. Lembo, MD: Which also got approved, exactly. I’ve not been able to get it at the pharmacy yet. I don’t think it’s out, but prucalopride is. We now have 2 5-HT4 [5-hydroxytrypamine 4] agonists.

Tegaserod was studied in IBS with constipation and was shown to be effective. We were using it quite extensively before it was removed from the market. I think that with prucalopride, there’s probably some good reason to use it. We don’t know the effect of abdominal pain, but I suspect it will probably be effective.

Mark Pimentel, MD: Yeah. There might be limitations on whom to use tegaserod in because of some of the narrow discussions with the FDA. We have to see what that all looks like.

William D. Chey, MD: Actually, the indication is for women with IBS-C under the age of 65. It’s important for people to realize that is the FDA approved indication. One other thing to know about tegaserod, which is interesting, is that it’s the only drug that we’ve talked about that actually has an RCT [randomized controlled trial] in IBS-M, or IBS with a mixed bowel pattern, and did show benefits. You’re right, we’ll see how this sorts out in the marketplace. But there are no studies with prucalopride in IBS-C at the current time.

Brennan Spiegel, MD: I do think this is an important advance for the toolbox for those of us who are managing these patients. It does seem like prucalopride works across the GI [gastrointestinal] tract, including in the foregut. We haven’t talked a lot about this, because we’ve been focused on IBS, but we know there’s overlap with other conditions. Particularly dyspepsia, functional dyspepsia, GERD [gastroesophageal reflux disease] to some degree overlaps with IBS. I’m not saying 5-HT4 agonists necessarily cure those conditions, but there is evidence that tegaserod, for example, can, to some degree, reduce the foregut symptoms of dyspepsia. So for me, when I think of a patient as lower-GI symptoms but also foregut symptoms, I start thinking that maybe these 5-HT4s, particularly the highly selective 5-HT4 agonists, are useful.

Mark Pimentel, MD: Prokinetics. They’re back.

Ali Rezaie, MD: A point that Bill mentioned is very important. You were talking about IBS with diarrhea, not IBS-C. And IBS-M… I feel like it’s left out sometimes. There are very few studies on IBS-M, with tegaserod being 1. TARGET 1 and TARGET 2 on rifaximin also included IBS-M patients and some data with peppermint. That’s essentially it. So that’s another group that we need to pay attention to.

Mark Pimentel, MD: This is why I have a deep bench, because you remind me of this category of drugs that just recently came out. So thank you for that.