Linaclotide and Irritable Bowel Syndrome: Implications from a Study

Both men and women can suffer from irritable bowel syndrome (IBS) with blended symptoms like diarrhea, constipation, abdominal pain and alike. Nearly 3% to 20% of the American population has experienced IBS now and then. For long, linaclotide has been used to treat this disease. Recently, a study is carried out to test the efficacy of linaclotide on IBS treatment.

Linaclotide was developed by the American company of Ironwood and approved by the US FDA in August 30, 2012. It is the first drug with this mechanism to treat constipation. It is a capsule used to treat irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC).

Linaclotide is a guanylate cyclase C agonist, which binds to intestinal GC-C and increases intracellular and extracellular guanylate (cGMP) concentrations. Elevated intracellular cGMP can stimulate intestinal fluid secretion, accelerate gastrointestinal tract migration, thereby increasing the frequency of defecation; elevated extracellular cGMP concentration can reduce the sensitivity of pain nerves, reduce bowel pain.

In two randomized studies, 1,604 participants confirmed the safety and efficacy of linaclotide therapy in patients with IBS-C. In the trial, the patients were randomly divided into treatment group and placebo group, with a total dose of 290 micron g for 12 weeks. The results showed that linaclotide was more effective than placebo in terms of abdominal pain and increased spontaneous defecation (CSBMS). The two studies were published in the 2012 issue of the American Journal of Gastroenterology. Two other tests, in a multicenter clinical trial, confirmed the safety and efficacy of linaclotide in patients with chronic idiopathic constipation, including 1 272 patients with chronic constipation. The two studies were published in the New England Journal of Medicine in 2011 and reported in Medscape Medical News. In both studies, patients were randomly divided into placebo group, linaclotide 145 ug/d group, or linaclotide 290 ug/d group. After 12 weeks of treatment, total spontaneous defecation (CSBM) was more than three times a week, and CSBM increased or exceeded the baseline for at least 9 weeks within 12 weeks. The patients who reached the end point in the 145 mg group were significantly higher than those in the placebo group.

Results: a total of 800 patients (mean age 43.5 years, 90.5% female, 76.9% white) were assessed. Of the 405 patients treated with linaclotide, 136 (33.6%) met the termination criteria set by the FDA. A total of 83 (21%) patients in the placebo group met the experimental termination condition, and the difference was statistically significant (P <0.0001). The number of cases requiring treatment (NNT) was 8.0, 95%CI: 5.4–15.5.

At 12 weeks, the proportion of the linaclotide treatment group that met the following criteria within 6 weeks was significantly higher than that of the placebo group: compared with baseline data, the amount of fully autonomous bowel elimination was greater than or equal to 1 (48.6 and 29.6%, P < 0.0001). Compared with the placebo group, the proportion of the remaining three experimental termination conditions in the linaclotide treatment group was significantly higher than that in the control group, and the difference was statistically significant (P < 0.05). The degree of ease in peptide treatment group was obviously higher than that of the placebo group and secondary terminal includes: compared with the baseline data, in the 12 weeks of treatment of abdominal pain, abdominal discomfort, abdominal distension, defecate frequency (weekly completely autonomous and independent stool defecation frequency) and fecal consistency, etc., (P < 0.001). The random withdrawal period continued to accept linaclotide treatment, and symptoms relief was observed. In the original linaclotide treatment group, patients were randomly divided into the placebo group, once again the symptoms of constipation type of irritable bowel syndrome were found. However, the severity was significantly lower than baseline symptoms. Diarrhea is one of the most common side effects of medication. 5.7% of patients in the linaclotide group were discontinued due to adverse reactions, compared with 0.3% in the placebo group.

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