NHE3 Inhibitors for IBS-C: A Georgia Gastroenterologist’s Perspective

Physician’s Weekly recently spoke with Satish SC Rao, MD, PhD, FRCP, FACG, AGAF—an American Gastroenterological Association (AGA) Distinguished Clinician Award, AGA Distinguished Educator Award, and AGA Masters Award for Outstanding Clinical Research recipient whose research interests include constipation and the pathophysiology and treatment of IBS—about NHE3 inhibitors and their unique method of action (MOA) in treating patients with IBS-C.

PW: How do NHE3 inhibitors work?  

Dr. Rao: The goal of sodium hydrogen exchange 3 (NHE3) inhibition is to block sodium absorption in the intestinal lumen. Whenever sodium is retained inside the gut lumen, it draws water into the lumen, leading to fluid accumulation inside the gut. This fluid accumulation distends the gut, induces peristalsis, and consequently, contraction and movement of gut contents, such as stool, leading to laxation. 

How does that MOA differ from that of other treatments for IBS-C? 

Current drugs act primarily on chloride channels increasing active secretion of chloride ions into the gut lumen. Lubiprostone is a type-2 chloride channel activator that opens up chloride channels located on the intestinal brush border, leading to active chloride secretion into the lumen. Linaclotide and plecanatide act on guanylate cyclase-C receptors on the brush border, releasing cyclic GMP, an active compound inside the intestinal cell. The cyclic GMP, in turn, activates another chloride channel on the intestinal brush border (CFTR), leading to active chloride secretion into the gut lumen. Thus, these are secretagogues for chloride ions, whereas tenapanor (an NHE3 inhibitor) is a sodium channel blocker. 

What makes NHE3s particularly useful in treating IBS-C, considering the condition’s multifactorial pathophysiology? 

Animal models have shown that NHE3 blocking improves constipation, reduces visceral hypersensitivity (pain), and improves leaky gut (ie, tighter sealing of the gut epithelium). 

What evidence is there to support the use of NHE3 inhibitors in treating IBS-C? 

Two large randomized controlled trials—T3MPO-1 and T3MPO-2—were conducted in ~1,300 total patients with IBS-C for 12 weeks or 26 weeks, respectively. Both studies showed a significantly higher responder rate for tenapanor compared with placebo for the primary end point (a composite of pain and constipation improvement with 6 or 12 weeks of treatment), as well as for secondary outcomes (pain alone or constipation alone). This led to FDA approval.