Durability of Response of Linaclotide in the Management of Chronic Idiopathic Constipation

Abstract

Introduction: Linaclotide is approved for the treatment of chronic idiopathic constipation (CIC) and IBS-C. It activates guanylate-cyclase C (GC-C) receptors on the luminal surface of enterocytes resulting in increased intestinal secretion and decreased transit time. Two phase 3 studies demonstrated that 21 days of linaclotide therapy resulted in as least 3 complete and spontaneous bowel movements (CSBM) per week and an increase of 1 CSBM per week. Since recurrence of constipation is common, the purpose of this study was to describe durability of response to linaclotide in patients with an initial response. Methods: Electronic medical records of 167 patients who began linaclotide for the management of CIC were reviewed retrospectively. To be eligible for inclusion, patients must have responded to standard dosing (145 mcg daily) for at least 4 months with appropriate follow up and documentation. Response was defined as ≥3 CSBM/week and 1 additional BM/week and a Bristol stool score (BSS) of 3-4. Patients who required dose adjustment within the first 4 months or experienced an adverse effect (AE) of treatment during initial therapy were excluded. Variables including age, gender, duration of therapy, time to follow up, response to therapy, BSS, dose and frequency of linaclotide, and AE were all recorded. Data were summarized with Microsoft excel 14.6. Paired t-test was used to compare initial and final BSS. Results: 32 of 167 patients met criteria for review. 5 were men and 27 were women. Mean age was 57 ± 18 (range 19-93). 28 patients (87.5%) exhibited sustained response with a mean follow up time of 15.3 months (range 4-36 months). BSS at the time of inclusion was 3.5 ± 0.6. BSS at the last follow up time was unchanged at 3.4 ± 0.8 (range 2-5, p = 0.55). AE were observed in 6 patients (18.7%). Three had diarrhea and 3 had discomfort or bloating. The mean time to first reported AE was 12 months (range 6-36 months). In all cases, minimal alterations in dose or frequency resulted in improvement of AE. Conclusion: CONCLUSIONS 1. 87.5% of patients in this cohort of initial responders to standard dose linaclotide demonstrated durable reponse with a mean duration of 15.3 months. 2. BSS was stable over an extended period of therapy. 3. AE occurred in 18.7% of patients, on average 12 months after starting therapy. 4. Most patients with AE responded well to changes in dose and/ or frequency of administration of linaclotide or minimal adjunctive therapy.