Linaclotide

Gastrointestinal manifestations of type 2 diabetes are prevalent and cause morbidity. These can present as nausea, vomiting, bloating, diarrhoea and/or constipation. Constipation is common in the general population; however, even more so in those with diabetes. It is reported that anywhere between 20–60% of people with diabetes are affected which in some cases will be a consequence of autonomic dysfunction. Linaclotide has been licensed in the treatment of moderate to severe constipation and associated gastrointestinal symptoms, and may have potential for use in those who have this and diabetes. The clinical pharmacological action of linaclotide is illustrated in Figure 1. Linaclotide is a highly selective guanylate cyclase-C (GC-C) agonist with a dual action. Firstly, it binds to transmembrane enzyme GC-C which when activated amplifies the concentration of both intracellular and extracellular cyclic guanosine monophosphate (cGMP). Intracellular cGMP via protein kinase GII (PKG-II) leads to the phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channels on cell membranes. These inhibit sodium absorption while increasing chloride and bicarbonate secretion leading to an increase in intestinal secretions and an acceleration in gastrointestinal transit time. The second action of linaclotide is in inhibition of colonic nociceptors resulting in the easing of gastrointestinal symptoms including pain. It is minimally absorbed and metabolised in the small intestine. Three to five percent is eliminated unchanged in faecal matter. Two phase 3 studies underpin the licensed indication for linaclotide both designed to meet regulatory requirements of the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for irritable bowel syndrome constipation (IBS-C). The FDA recommended combined responder endpoints that capture abdominal pain and constipation, whereas the EMA recommended co-primary responder endpoints that capture abdominal pain/discomfort along with an assessment of change in overall symptoms. The first trial was a 26-week randomised double-blind, placebo- controlled trial to assess the efficacy and safety of the use of 290μg linaclotide in IBS-C.1 The primary endpoints were determined in the first 12 weeks, assessed according to the FDA requirements for IBS-C. These equated to: (i) 30% or more improvement in baseline daily worse abdominal pain score; and (ii) an increase of one or more complete spontaneous bowel movements (CSBM) for more than six of 12 weeks and three other primary endpoints (improvements in abdominal pain and CSBM) for nine of 12 weeks. A total of 804 patients completed the study; 33.7% of linaclotide patients met the FDA endpoint compared to 13.9% of placebo patients (p<0.0001, 95% Cl 3.9, 7.1). Pain and CSBM were better in the treatment group (48.9% responders in linaclotide-treated patients vs 34.5% of placebo-treated patients, and 47.6% of linaclotide- treated patients vs 22.6% of placebo patients, respectively). The remaining primary endpoints (p<0.0001) and all secondary endpoints (p<0.001) were better for the treatment group. The second trial was a 12-week randomised double-blind, placebo- controlled trial in 800 patients.2 The FDA endpoint was met by 33.6% of linaclotide-treated patients, compared with 21% of placebo-treated patients (p<0.0001). More linaclotide patients, compared with placebo patients, reported for at least six of 12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs 37.5%, p=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs 29.6%, p<0.0001). A greater percentage of linaclotide patients vs placebo patients were also responders for the other three primary endpoints (p<0.05). Significantly greater improvements were seen in linaclotide vs placebo patients for all secondary endpoints (p<0.001). Both trials were evaluated further based on efficacy parameters prespecified for EMA submission and concluded that linaclotide significantly improved abdominal pain/discomfort and relief of IBS-C symptoms compared with placebo over 12 and 26 weeks.3 Adverse events in both trials were minimal. A randomised double-blind, placebo- controlled, cross-over trial was designed to test the efficacy of linaclotide in people with type 2 diabetes and chronic constipation. A 28-day randomisation to linaclotide or placebo with a two-week break in between where treatment is withdrawn but patients are still monitored was followed by a 28-day period of the opposite treatment administered.4 Only 20 were recruited. The average CSBM increased from 3.9±2.6 per week to 9.8±4.9 (p<0.0001) with linaclotide. The placebo group did not see a significant change in CSBM, from 4.2±3.1 per week to 5.3±3.9 after. Stool consistency also improved ranging from 2.3–4.4 on the Bristol stool chart on linaclotide, 1–4.5 on the placebo. Managing chronic constipation is challenging and many with diabetes have it. Most guidelines including those of NICE encourage lifestyle changes, including increasing fluid intake and dietary modification, another dietary challenge for those with diabetes. First-line pharmacological management is ispaghula, a bulk forming laxative, then an osmotic laxative such as macrogol or lactulose, then a stimulant. Linaclotide could be useful adjunctive treatment as it may provide symptom control, stool softening and increased CSBM, although not specifically licensed when it is due to autonomic dysfunction. There has been recent interest in testing its efficacy using novel constipation outcome scores and the development of a modified release preparation which may improve symptom control with effects manifest further down the small intestine.5, 6 Further studies including use specifically in diabetes-related constipation would be helpful.