Guanylate Cyclase-C Agonists for IBS-C

Mark Pimentel, MD: Let’s transition to the GC-C [guanylate cyclase-C] agonists. Tony, let’s start with linaclotide, and then we’ll move on to plecanatide. And then we’ll argue about which has less diarrhea, because that’s always the argument. But start with linaclotide.

Anthony J. Lembo, MD: Sure. It was the first of the 2 GC-C agonists. These are receptors that are on the lining of the GI [gastrointestinal] tract—so from the antrum right down to the distal colon. Most of the effect is probably, like lubiprostone, in the small bowel. By stimulating the GCC, it has a second messenger, cyclic-GMP [guanosine monophosphate], which turns out to be important because it does 2 different things, as far as we know, at least from animal models. It opens the chloride channel, and it also may affect the afferent nerves in the submucosa or other linings of the GI tract, thereby reducing abdominal pain.

Linaclotide is a product that is taken once a day, and it comes now in 3 different doses—72, 145, and 290 micrograms. The lower doses are for constipation, and the higher dose is for IBS [irritable bowel syndrome] with constipation. Those are at least the FDA-approved doses, but in clinical practice we’ll use a variety of different doses with it. And in clinical trials, it shows that it improves abdominal pain, which is key, and bloating, as well as stool frequency and consistency. One of the issues with linaclotide is that it can cause diarrhea, and sometimes it can be severe.

Mark Pimentel, MD: I think that’s part of the reason they went to lower doses, right? To try to get under the diarrhea? Am I wrong in that?

Anthony J. Lembo, MD: No, that’s correct. The data with the lower doses—of course 72 micrograms was studied in chronic idiopathic constipation—didn’t actually show less. But in clinical practice, I see less. Importantly, I tell patients that this could happen. I think if you prepare the patient for it and let them know that the first couple of times they take it to be aware that that could happen—don’t plan it when they’re about to take a long trip or anything—that it’s less of an issue with patients.

Mark Pimentel, MD: Bill, plecanatide. This is the contrasting agent. It’s not really contrasting because it’s the same category.

William D. Chey, MD: Yeah, absolutely. It’s a very similar agent. This is also a GC-C agonist. It works by a similar mechanism to what Tony talked about. Like linaclotide, there are large phase 3 studies showing benefits for chronic idiopathic constipation and IBS-C [IBS with constipation], and it’s approved for both indications in the United States. The main adverse effect with linaclotide is diarrhea, and that is seen, as Tony mentioned, in around 20% of patients in clinical trials. Lower rates of diarrhea were reported in the plecanatide trials, but there’s a lot of—as you alluded to, Mark—controversy as to how that data were collected. I’m not sure I’m the best person to comment on that particular issue. What I would say, just from a practical standpoint, is that I think they’re both very effective drugs. I also, by the way, think they’re both very safe. We’ve done some work, which I think is quite interesting, showing that regardless of whether you’re talking about a GC-C agonist or other forms of treatment for constipation, most patients who are constipated actually don’t mind having some loose stool. They don’t view it as an adverse event.

Mark Pimentel, MD: Well, this goes back to quality of life a little. There are studies that show that regarding the quality of life of the IBS-D [IBS with diarrhea] patient versus IBS-C, doctors are threatened or enthusiastic about working up diarrhea, and they want to do, do, do. And when they see a constipated patient, they’re like, “Uh, constipation!” But the patients are more miserable in the constipation category than they are in the diarrhea category because they never get relief. Brennan, should we not worry? Diarrhea doesn’t matter? Let’s get them relief because they’re quite miserable?

Brennan Spiegel, MD: I think you’re on to something with this. Literally, urgency requires sort of an urgent work-up in the mind of the physician. Whereas constipation is slow, and we could take our time. It’s sort of facetious but not. And you’re right: I think doctors are maybe a little more laissez-faire about taking a laxative. I think it’s important, again, to distinguish. We’re talking about IBS-C here. We’re talking about not just moving bowels but also reducing the bloating and the discomfort. That’s all part of why quality of life is so affected in IBS-C and in IBS-D for slightly different reasons. I think we need to be just as aggressive at improving quality of life in these patients as we would in IBS-D patients.

Transcript edited for clarity.