Efficacy of Linaclotide in Type II Diabetics With Chronic Constipation: A Randomized, Double-Blind, Placebo-Controlled, and Cross-Over Trial: 119

Introduction: Chronic constipation (CC) is the most common GI symptom in patients with diabetes mellitus (DM) which occurs secondary to diabetic autonomic neuropathy (DAN). Conventional treatment of CC in DM has been suboptimal, thus creating a need for better therapies. Linaclotide, a peripherally-acting agent that activates guanylate cyclase- C (GC-C) increasing secretions into the gut lumen, has been shown to relieve symptoms of chronic idiopathic constipation. However, the effects of linaclotide on diabetics with symptoms of CC (DM-CC) has not been investigated. Methods: Type II diabetics with DAN who met Rome III criteria for CC were enrolled. After randomization, all participants received 4 weeks of linaclotide (145 μg QD) and 4 weeks of placebo in a cross-over design with 2 weeks wash-out between treatment arms. Patients were requested to keep a stool diary to record: (a) the frequency of complete spontaneous bowel movements (CSBM), and (b) stool consistency based on a 7-point Bristol Scale (1:separate hard lumps to 7: atery, no solid pieces) while completing both arms of the study. Rescue medication was permitted. Continuous variables with normal distribution were presented as mean±SD and comparison made by t-test. The Bristol scale, which is an ordinal variable, was presented as median (95%CI) and compared using Wilcoxon signed-rank test. Adverse events (AEs)/Serious (S)-AEs were assessed at each clinic visit. Results: The study population consisted of 20 DM-CC patients with mean age 54.4 (28-67yrs), 15 women, mean BMI (32 ±7). The average CSBM in the linaclotide group increased from 3.9±2.6/week to 9.8±4.9 (P<0.0001), while treatment with placebo did not change CSBM (4.2±3.1/ week at baseline vs. 5.3±3.9 after placebo). Linaclotide significantly increased median Bristol scale from 2.1 (1.2-3) at baseline to 3 (2.3-4.4) (P=0.03) while median Bristol scale was not significantly changed by placebo: 2 (1-3) before and 3 (1-4.5) after. Patients' glucose levels were stable and HbA1C was <8.2% during the study. No SAEs were observed; 3 patients, recorded diarrhea while being on the study drug, not requiring discontinuation of the drug. Conclusion: This study indicates that linaclotide 145 μg QD is a safe and effective treatment for DM-CC significantly increasing CSBMs (approx. 2.5 fold) and improving stool consistency compared to placebo. Studies on long-term efficacy of linaclotide in DM-CC patients are recommended.