Ileal bile acid transporter inhibitors for chronic constipation in the elderly

Abstract

We read with great interest and commended Sakai et al for their valuable study on the efficacy of elobixibat in elderly patients with chronic constipation (CC). This study provides valuable insights into the safety and efficacy of elobixibat in elderly patients with CC. We have a few critical points regarding the study methodology and evaluation of CC in the elderly population. The authors have not commented on the exclusion of possible drug-related constipation, as most of their elderly patients have comorbid illness, structural causes of constipation, evaluation of gastrointestinal motility, and advocating for a more comprehensive workup for CC in the elderly. This article also provides a comprehensive review of the workup of CC in the elderly, as well as a review of the available evidence on ileal bile acid transporter inhibitor - elobixibat in CC.

Key Words: Ileal bile acid transporter; Elobixibat; Chronic constipation; Elderly; Colonic motility

Core Tip: This article offers a critical review of a recently published study on elobixibat in the treatment of chronic constipation (CC) in the elderly. The therapeutic arsenal against CC is expanding with new drugs and approaches. Elobixibat is a potent and selective inhibitor of the ileal bile acid transporter. It increases the colonic bile acid pool, which enhances colonic motility and secretion. Elobixibat improves bowel movements, stool consistency, and quality of life. Elobixibat is generally well-tolerated and effective in the elderly, as well as in patients with renal failure, heart failure, and Parkinson’s disease suffering from CC.

INTRODUCTION

We read with great interest and commend Sakai et al[1] for their valuable study on the efficacy of elobixibat in elderly patients with chronic constipation (CC) in a clinic. We have a few critical points regarding the study methodology and evaluation of CC in the elderly. Furthermore, this article provides a review of the evaluation of CC in the elderly and discusses the available evidence of elobixibat in the treatment of CC.

Firstly, in the study by Sakai et al[1] basis of the sample size calculation and the projected power of the study was not clear. Intriguingly, there were no dropouts or lost-to-follow-up cases in either group. 35% (28 out of 80) of the patients were treatment-naïve, and the remaining 65% had exposure to one or two laxatives only, thus essentially avoiding difficult-to-treat or refractory constipation. It would be interesting to know about the total duration of constipation in both groups, as well as associated symptoms such as bloating, dyspepsia-like symptoms, history of digital evacuation, bleeding per rectum suggestive of hemorrhoids or anal fissure, and any history of anorexia or weight loss. As most subjects were > 65 years of age, colonoscopy is recommended in all standard published international practice guidelines, and the same data were not provided in this study[2,3]. Psychiatric comorbidities have also been reported in patients with constipation[2,4,5]. Therefore, it would be interesting to know what percentage of patients in this study had associated comorbidities.

Few tests for CC are desirable, especially when the illness is long-standing or refractory to frontline or basic laxatives. These include radio-opaque marker-based colonic transit studies, anorectal manometry, balloon expulsion tests, and magnetic resonance or barium defecography. It is unclear whether any of the study participants underwent any of these tests. Additionally, breath methane analysis may be beneficial in individuals with refractory CC[6,7].

It is unclear how many patients in either group responded to therapy and how many did not respond. It would have been interesting if the authors could have analyzed the potential predictors of response to this new drug in the elderly population. The use of Indian or Japanese study toilets has been reported to be beneficial in managing constipation and facilitating better stool evacuation than Western-style toilets[2]. It would be interesting to know whether the study subjects were using Western or alternative toilets. Demographic lifestyle factors such as urban, rural, sedentary, or active lifestyle and substance addiction also influence the occurrence and severity of constipation[8]. Hence, this information would be worthwhile. The prevalence of CC increases with age, and this critical study confirms the efficacy and tolerability of elobixibat in the elderly, expanding the therapeutic arsenal.

CC IN THE ELDERLY

CC is a common disorder in the geriatric population and is associated with impaired quality of life. Although the prevalence of CC varies across different studies due to a lack of uniformity in defining CC, the global prevalence of CC is approximately 15%-20%, making it the sixth most common gastrointestinal symptom[9]. Major risk factors that contribute to constipation in the elderly include a sedentary lifestyle, weakened abdominal and pelvic muscles, malnutrition, underlying medical conditions, medications that aggravate constipation, rectal hyposensitivity, and impairment of colonic motility due to ageing[10,11]. CC can be classified as primary or secondary depending on the etiology. Primary CC is due to abnormal neuromuscular function in the colon and anorectum. In contrast, secondary CC is caused by an organic factor, such as a structural abnormality of the colon and rectum, or medication-induced or underlying systemic disease[12,13]. Addressing the underlying etiology helps improve constipation symptoms in secondary CC. However, primary CC is complex and may not always respond to first-line treatments (lifestyle modifications and laxatives). Primary CC is further classified into slow transit constipation (STC), normal transit constipation, and defecatory disorders based on the pathophysiological mechanism[12,14,15]. These three subtypes are not always separate entities; there may be an overlap between them. Primary STC is attributed to colonic neuromuscular dysfunction in the absence of underlying systemic disease and is characterised by a reduced frequency of high-amplitude propagated contractions, leading to decreased colonic peristalsis and impaired water reabsorption, resulting in stool hardening and infrequent urge to defecate[12,15]. Evidence also suggests that increased intestinal methanogenic bacteria contribute to reduced colonic transit, thereby causing STC[6,7,16]. Unlike STC, colonic transit time is normal in normal transit constipation; however, patients experience constipation symptoms due to altered rectal sensation and dietary habits. Defecatory disorders are often associated with underlying dyssynergic defecation, which occurs because of impaired coordination between the abdominal and pelvic floor muscles[17,18]. These defecatory disorders may also be related to anatomical abnormalities of the rectum (intussusception, rectocele, etc.)[12,15].

EVALUATION OF CC

The primary aim of evaluation in patients with CC is to rule out the organic causes of CC. A detailed history regarding the patient’s medications that can aggravate constipation and any underlying comorbidities like diabetes mellitus, hypothyroidism, and neurological disorders must be taken. One should also look for the presence of any alarming features such as age ≥ 45 years, rectal bleeding, recent iron deficiency anaemia, fever, unintended weight loss, abdominal mass and family or personal history of gastrointestinal malignancies, which necessitates evaluation with colonoscopy[2]. Defecatory disorders should be suspected in a patient who gives a history of sensation of anorectal blockade or a history of manual evacuation of feces and should be evaluated with physiological tests.

Physical examination should include examination of the perianal area for any fissures, fistulas, excoriation, and hemorrhoids. Simultaneous lower abdominal palpation along with per-rectal examination helps in the assessment of dyssynergic defecation[19-21]. Blood investigations should include a complete blood count, blood glucose level, renal and liver function tests, electrolyte levels, and thyroid function tests. If organic causes of constipation are ruled out, and constipation is refractory to lifestyle modifications and laxatives, patients should be subjected to physiological testing[19]. Physiological tests include high-resolution anorectal manometry, balloon expulsion test, defecography, and colonic transit studies. Recommended first-line physiological tests for the evaluation of refractory constipation or suspected dyssynergic defecation would be anorectal manometry and balloon expulsion tests (Figure 1)[22,23]. Anorectal manometry assesses the pressure changes in the anorectum at rest and simulated defecation using an inflated intrarectal balloon, sphincter tone, and recto-anal reflexes. It aids in diagnosing dyssynergic defecation and other neuromuscular and sensory disorders, and helps identify individuals who may benefit from biofeedback therapy. The balloon expulsion test is a simple office-based test, but it lacks standardisation. Generally, an expulsion time longer than 1-2 minutes is considered abnormal[22].

Figure 1 Flow chart for evaluation of chronic constipation in the elderly. ARM: Anorectal manometry; BET: Balloon expulsion test; CC: Chronic constipation; CTT: Colonic transit time; DD: Defecatory disorders; IBS-C: Irritable bowel syndrome with constipation; MOM: Milk of magnesia; NTC: Normal transit constipation; PEG: Polyethylene glycol; STC: Slow transit constipation.

Defecography, using either barium or magnetic resonance imaging, helps evaluate the structure and function of the anorectal and pelvic floor muscles during voluntary defecation[24]. Multiple tests, including the balloon expulsion test, anorectal manometry, and defecography, have greater accuracy than a single test for diagnosing defecatory disorders[2]. Lastly, assessing colonic transit time is recommended in the evaluation of laxative-refractory constipation. This was performed using radiopaque markers, wireless motility capsules, or scintigraphy[25]. These studies must be performed when patients are not taking laxatives. Ambulatory 24-hour colonic manometry is recommended in patients with severe slow-transit constipation and suspected colonic inertia[26]. The first-line treatment for CC is lifestyle and dietary modifications, stool softeners, and bulk-forming laxatives. Those who are refractory to first line therapies can be considered for stimulant laxatives, secretagogues.

ILEAL BILE ACID TRANSPORTER INHIBITORS FOR CC

The apical sodium-dependent bile acid transporter [ASBT (SLC10A2)], also known as ileal bile acid transporter (IBAT), is a protein located in the terminal ileum[27]. This transporter facilitates the active transport of conjugated bile acids across the ileal brush border membrane into intestinal cells. These bile acids are subsequently effluxed into the portal circulation by the organic solute transporter α-β (Figure 2). Therefore, IBAT plays a crucial role in the enterohepatic circulation of bile acids and is essential for maintaining cholesterol homeostasis, as well as facilitating the digestion and absorption of fats and fat-soluble vitamins[27]. Over the past decade, IBAT has been studied as a therapeutic target for several conditions, such as cholestatic liver diseases, including Alagille syndrome, progressive familial intrahepatic cholestasis, and chronic idiopathic constipation (CIC)[28,29].

Figure 2 Mechanism of action of elobixibat (ileal bile acid transporter inhibitor) and effect of increased bile acid pool on colonocytes. ASBT: Apical sodium-dependent bile acid transporter; CFTR: Cystic fibrosis transmembrane conductance regulator; cAMP: Cyclic adenosine monophosphate; OSTα/β: Organic solute transporter alpha/beta; TGR5: Takeda G-protein coupled receptor.

Pharmacological inhibition of IBAT by IBAT inhibitors (IBATi) reduces the absorption of bile acids in the terminal ileum, leading to an increased flow of bile acids into the colon. This larger bile acid pool in the colon causes increased intracolonic water secretion, enhanced colonic mucosal permeability, stimulated colonic motility, and reduced water reabsorption (Figure 2). Amplifying this endogenous pathway is beneficial for increasing colonic movement in patients with constipation-predominant irritable bowel syndrome and CIC[30].

Elobixibat, an IBATi, is highly potent and selective for IBAT in humans, as indicated by in vitro studies[31]. It has low bioavailability, resulting in minimal systemic exposure, and acts locally in the lumen of the small intestine. It is well tolerated but may cause side effects such as nausea, abdominal pain, and diarrhea. The efficacy of elobixibat in CIC was first examined in a randomized controlled trial (RCT) by Simrén et al[32] in 2011. This study, involving 30 patients treated with various doses, showed an increase in bowel movements, improved stool consistency, and a reduction in colonic transit time, with an acceptable safety profile. A RCT conducted in India demonstrated a statistically significant improvement in the weekly frequency of spontaneous bowel movements (SBMs), with the response rate for complete SBMs significantly higher with elobixibat than with placebo (49.33% vs 26.76%, P = 0.005)[33]. A summary of various RCTs on elobixibat in CC is presented in Table 1[32-40]. An interim post-marketing analysis from Japan indicated that elobixibat is well-tolerated, with a median time to bowel movement of 5 hours among the elderly population after drug intake[41]. Elobixibat has also been shown to be tolerable and effective in CIC patients with chronic kidney disease, heart failure, and Parkinson’s disease[40,42,43].

Table 1 Summary of randomized controlled trials of elobixibat in chronic constipation.

No.	Ref.	Study population, sample size	Dose of elobixibat	Outcome	Adverse events
1	Wong et al[34], 2011, United States	Women with functional constipation, n = 36	15 mg, 20 mg	Increased colonic transit at 48 hours with both doses (P < 0.001); increased stool looseness vs placebo (P < 0.005)	Abdominal cramping/pain
2	Chey et al[35], 2011, United States	Chronic idiopathic constipation, n = 190	5 mg, 10 mg, 15 mg	Increased SBM in week 1; sustained stool frequency over 8 weeks; reduced time to first SBM and CSBM in 10/15 mg groups; reduced straining and bloating (P < 0.05)	Abdominal pain, diarrhea
3	Simrén et al[32], 2011, Sweden	Idiopathic constipation, early RCT, n = 30	0.1-10 mg	Decreased colonic transit time at higher doses; increased SBM frequency and improved stool consistency	Nausea, pain, abdominal distention, diarrhea
4	Nakajima et al[36], 2018, Japan	Chronic constipation, n = 163	5 mg, 10 mg, 15 mg	Increased SBM frequency in 10/15 mg groups vs baseline and placebo (P = 0.0001); effective in CC and IBS-C subgroups	Abdominal pain, diarrhea
5	Kumagai et al[37], 2018, Japan	Adults with CC ≥ 6 months, n = 120	2.5-20 mg; PK studied	SBM ≤ 24 hours: 100% (10 mg), 88.9% (15 mg) vs 40% placebo; reduced time to first SBM	Non-dose-dependent AEs; abdominal pain more common than diarrhea and distention
6	Nakajima et al[38], 2018, Japan	Adults 20-80 years with CC ≥ 6 months; trial 1: n = 70; trial 2: n = 341	Trial 1: 10 mg for 2 weeks; trial 2: 5-15 mg for 1 year	Trial 1: Increased SBM/week at week 1 vs placebo (P < 0.0001); trial 2: Sustained increase in SBM and CSBM over 1 year	Mild abdominal pain, diarrhea
7	Manabe et al[39], 2023, Japan	Adults ≥ 60 years with CC, n = 17	10 mg vs placebo	Decreased threshold for first constant sensation (P = 0.0018); trend toward decreased desire-to-defecate volume (P = 0.0899)	None reported
8	Hatano et al[40], 2024, Japan	CC in Parkinson’s disease, n = 74	10 mg vs placebo	Increased SBM/week from 4.2 ± 2.6 to 5.9 ± 3.2 at week 4 (P = 0.0079); improved stool form, satisfaction, reduced stigma	Diarrhea most common
9	Agarwal et al[33], 2025, India	Adults with CC ≥ 6 months, n = 150	10 mg in week 1, titrated to 10-15 mg in week 2	Increased SBM frequency (P = 0.008); CSBM response 493% vs 26.8% placebo (difference 226%, 95%CI: 8.4-36.8, P = 0.005); SBM ≤ 24 hours: 51% vs 37% placebo	15.3% reported ≥ 1 AE; abdominal pain, distention, dry mouth

AE: Adverse event; CC: Chronic constipation; CI: Confidence interval; CSBM: Complete spontaneous bowel movement; CTT: Colonic transit time; IBS-C: Irritable bowel syndrome with constipation; PK: Pharmacokinetics; RCT: Randomized controlled trial; SBM: Spontaneous bowel movement.

Suprianto and Sariza[44] recently published a systematic review and meta-analysis on elobixibat in refractory CC. In their meta-analysis, they screened RCTs published between 2015 and 2025 and included six RCTs. A total of 2155 patients were included in this review, with a predominance of females (85.4%). Elobixibat increased the mean number of SBMs per week (mean difference = 1.65; 95%CI: 1.19-2.11; P < 0.00001; I² = 64%). Elobixibat treatment is likely to provide a clinical response 2.5 times more than placebo, with a number needed to treat of 5 (95%CI: 4-7)[44]. The most common adverse events of elobixibat were diarrhea (risk ratio = 4.21; 95%CI: 3.01-5.89) and abdominal pain (risk ratio = 2.35; 95%CI: 1.63-3.38). However, most of the events are mild to moderate, although they are a common cause of discontinuation. Rao et al[45] conducted a comparative systematic review and meta-analysis comparing linaclotide, lubiprostone, and elobixibat for the treatment of CC. In this analysis, no difference was found in the efficacy regarding SBMs and quality of life among the three drugs. However, the number needed to treat was lower in elobixibat than in linaclotide and lubiprostone (3 vs 5). The most common adverse effect associated with elobixibat is nausea, whereas diarrhea is common with lubiprostone and abdominal pain in patients treated with linaclotide[45].

Various RCTs have demonstrated the consistent efficacy of elobixibat, with improvements in bowel movements and stool consistency observed within one week of use in patients with CC. It also showed that these effects are well-maintained over a 52-week treatment period. However, most of these studies were conducted among the Japanese population; therefore, further multicenter, multi-ethnic RCTs are needed. Based on available evidence, multiple gastroenterological societies have included elobixibat in their therapeutic armamentarium for CC and irritable bowel syndrome with predominant constipation[46,47]. It is approved for use in Japan and India; however, it remains unapproved in the European Union and the United States.

CONCLUSION

CC is a prevalent multifactorial disorder in the elderly, often underpinned by age-related physiological changes, comorbidities, and medication use. A structured evaluation incorporating a comprehensive history, physical examination, laboratory investigations, colonoscopy when indicated, and physiological tests in refractory cases is essential to exclude secondary causes and guide effective therapy. Elobixibat, an IBATi, has demonstrated consistent efficacy and tolerability in clinical trials, including elderly patients and those with comorbidities. Its rapid onset of action, favourable safety profile, and sustained benefits over long-term use make it a promising addition to the therapeutic armamentarium for CC. However, the majority of evidence arises from Japanese cohorts, highlighting the need for further well-designed, multicenter, multi-ethnic trials to confirm its generalizability. Overall, elobixibat represents an effective and practical therapeutic option that may significantly improve the quality of life of elderly patients with CC.