Irritable bowel syndrome (IBS) is a chronic, relapsing gastrointestinal (GI) condition characterized by abdominal pain related to defecation, bloating, and changes in the frequency or shape of stool.
IBS is the most commonly recognized disorder of gut-brain interaction (GBID) (previously called functional gastrointestinal disorder) and is reported by patients in all age groups, although it most commonly develops in patients before the age of 50. Women are generally diagnosed with IBS more often than men.
IBS can be classified according to the Rome IV criteria into four subtypes, depending on the shape of the stool, such as IBS predominantly with diarrhea (IBS-D), IBS predominantly with constipation (IBS-C), IBS with mixed bowel habits (IBS-M) and unsubtyped IBS (IBS-U). IBS-U is used only when there is an abnormality in stool consistency insufficient to meet the criteria for any of the other subtypes above. It is not uncommon for patients to transition from one subgroup to another, and IBS often overlaps with other DGBIs. The estimated prevalence of IBS-C is 1.3%.
Traditionally, treatment for IBS includes lifestyle modifications, including dietary changes, psychological interventions, and symptomatic treatments (e.g., laxatives, antidiarrheal agents, and antispasmodics). The American College of Gastroenterology (ACG) recommends the use of guanylate cyclase and chloride channel activators to treat the overall symptoms of IBS-C. A systematic and network literature review of therapies for IBS-C that included linaclotide, plecanatide, tenapanor, and tegaserod found that all treatments were significantly more effective compared to placebo, but linaclotide 290 μg once daily was ranked as the most effective.
Linaclotide, a guanylate cyclase C receptor agonist with secretory and visceral analgesic activities, is approved for the symptomatic treatment of moderate to severe IBS-C in adults in the European Union (EU) and the United States (US). ). Linaclotide is classified as a secretagogue. These agents stimulate intestinal transit by increasing intestinal secretion towards the gastrointestinal tract. Evaluating the use of linaclotide in routine clinical care is important because of the potential for off-label use and misuse and to evaluate outcomes in specific groups of patients who were not included in the clinical development program.
The aim of this study was to describe the use of linaclotide in three European countries with a focus on two specific subgroups of interest: those not sufficiently documented in the clinical program [elderly population, pregnant or lactating women, men, patients with hepatic impairment or kidney disease, cardiovascular disease (CVD), hypertension or diabetes] and those with the potential for off-label use [patients with obesity, eating disorders (ED), low body mass index (BMI)] or misuse, [patients with mechanical intestinal obstruction (MBO) or inflammatory bowel disease (IBD)]. Furthermore, this study also investigated the time to discontinuation of linaclotide treatment in a real-world setting.
| Materials and methods |
Post-authorization safety study conducted in three databases from the launch date of linaclotide in three countries to 2017: Clinical Practice Research Datalink in the United Kingdom (UK), the Research Information System in the database of Primary Care in Spain and the Patient, Prescription and Causes of Death Records in Sweden. Cohorts of IBS patients were identified using diagnosis and treatment codes; IBS subtypes were identified using symptoms and treatment codes; patients with obesity, ED, OBM, and IBD were identified using diagnosis codes or body mass index.
| Results |
There were 1319, 1981 and 5081 linaclotide users from the United Kingdom, Spain and Sweden with a median age of 45, 57 and 51 years, respectively; the majority were women. In the United Kingdom, Spain and Sweden, respectively: 59.0%, 60.3% and 31.3% of linaclotide users had a recorded IBS diagnosis, among them 68.8%. 61.3% and 92.7% were classified as IBS-C.
The proportions of linaclotide users considered at risk for potential off-label use for weight loss or as a laxative were 17.1%, 29.7%, and 1.7%, and the proportions of users considered at risk for misuse due to a history of MBO or IBD were 3.5%, 4.6% and 5.7% in the United Kingdom, Spain and Sweden, respectively.
| Discussion |
This study is the first to report on the use of linaclotide in a real-world setting using data from three large sources in three European countries: the United Kingdom, Spain and Sweden.
The new data presented here are important for doctors because patients with common problems were not included in the large randomized clinical trials that led to the approval of linaclotide and because the drugs can be used inappropriately or off-label. the label. For example, patients with kidney or liver failure were not studied in the drug development program. This study found that 9.6%, 19.0% and 3.4% of linaclotide users had hepatic or renal failure at the start of treatment in the United Kingdom, Spain and Sweden, respectively, variability attributable to clinical practice. and to the corresponding database. These impairments are not expected to affect the effectiveness of linaclotide or cause an increase in side effects, since the drug is metabolized in the gastrointestinal tract.
In Spain, more than 36% of linaclotide users were 65 years or older, a patient population that should be carefully monitored since, in clinical trials, they reported diarrhea more frequently than the general IBS-C population. Linaclotide is indicated for use in adults and this study shows that less than 1% of linaclotide users were under 18 years of age. A very small number of women (⩽0.3%) started linaclotide during pregnancy, while others may have experienced an unplanned pregnancy during treatment.
The very small number of women using linaclotide during pregnancy agree with the recommendation to avoid linaclotide during pregnancy due to insufficient data on its safety. Some women could also be misclassified on the index date, as the date of pregnancy-related codes may not accurately reflect the exact date of gestation periods.
The use or abuse of laxatives is common in patients with ED. The prevalence of laxative abuse has been reported to range from approximately 18% to 75% among people with bulimia nervosa.
A study of 39 patients seeking treatment for bulimia nervosa in the United States reported that laxatives had been used at some point to control weight or "get rid of food" by 67% of patients with this ED. laxatives can result in a number of health complications and cause life-threatening conditions. In this study, the proportion of patients with a history of diagnosis of was low (2.5% in Spain, 1.2% in Sweden and 0.6% in the United Kingdom), suggesting that off-label use of linaclotide is not common in this patient group.
Additionally, the potential off-label use of linaclotide is likely overestimated, as some lean patients (e.g., BMI = 18.5 to <20) may have a true diagnosis of IBS-C and are prescribed linaclotide in accordance with the terms of the marketing authorization.
Obese patients were also considered at potential risk for off-label use of linaclotide, as some use laxatives in an attempt to lose weight. The proportions of patients with obesity in this study were identified as 12% in the United Kingdom and 17% in Spain, using the recorded diagnosis and the patients’ BMI records (value⩾30 kg/m2). In Sweden, since BMI and primary care diagnoses are not available in databases, the proportion of patients with obesity is likely not recorded. A survey conducted in an outpatient setting in Germany between 2011 and 2016 showed that 59.0% of IBS patients were in the normal weight range, 30.3% were overweight or obese, and 10.7% were under weight. The proportion of obese linaclotide users in the United Kingdom and Spain is consistent with the figures reported in Germany. Obese patients who potentially used linaclotide to help with weight loss could not be distinguished in this study from obese patients who used linaclotide to treat IBS-C.
The results of this study should be interpreted with the caveat that data in the healthcare databases of each of the three countries are collected differently. There is a large variation in the prevalence of IBS reported by previous studies depending on the data sources used. A review in 2014 reported that the estimate ranges between 6.1% and 21.6% in the United Kingdom, between 3.3% and 14.1% in Spain, and 12.5% to 15% in Sweden. The current study reports on many linaclotide users who were not labeled with the IBSC subtype using the algorithm described above.
Both SIDIAP (Spain) and CPRD (United Kingdom) are primary care databases; In these databases, secondary care diagnoses are updated by GPs, and are not expected to do so systematically. The Swedish National Patient Registry only captures secondary care diagnoses and there is no record of diagnoses made in primary care settings. The lack of primary care diagnoses in Sweden could explain the higher proportion of linaclotide users without a diagnosis of IBS (69% in Sweden versus 40% in Spain and 41% in the United Kingdom). Additionally, many patients may have been appropriately prescribed linaclotide for symptoms of chronic constipation, a diagnosis that overlaps significantly with IBS-C.
The prevalence of some comorbidities was similar in the three countries, while that of other comorbidities showed great variability. For example, the prevalence of hypertension or the prevalence of celiac disease was quite similar, while the prevalence of psychiatric disorders or the prevalence of cardiovascular disorders was different. Such discrepancies could reflect real differences in the prevalence of those conditions, and could also be caused by dissimilar criteria for diagnosing and recording data rather than real differences in disease prevalence. There was also variability in time to treatment discontinuation between the three countries. Patients from Spain had the highest proportion of linaclotide discontinuation, the shortest duration of follow-up, and the longest median prescription duration among those who discontinued. Consistent with other reports, most discontinuations occurred during the first months of treatment. From the available secondary data, it was not possible to know the reasons for discontinuation of treatment.
| Conclusion |
Off-label use and potential misuse of linaclotide appear limited, as evidenced by the small size of patient subgroups at risk for off-label use and misuse.
