Background
A key step in bile acid (BA) homeostasis is the active uptake of BAs through the apical enterocyte membranes of the distal ileum by the ileal apical sodium-dependent bile acid transporter (IBAT or ASBT [apical sodium-dependent BA transporter]). Inhibition of IBAT reduces the active ileal absorption of BAs, increasing the content of BAs in the colon, thereby stimulating colonic secretion and motility [
1,
2]. Studies of one such inhibitor (elobixibat, previously A3309), have proven beneficial in chronic constipation (CC) [
3‐
5]. In addition to their role as detergents facilitating dietary lipid absorption, BAs modulate various metabolic events after binding to specific BA receptors such as the farnesoid x receptor (FXR) and the G-protein-coupled receptor TGR5 [
6,
7]. Thus, BAs regulate glucose and lipid metabolism as well as energy expenditure [
6].
When ileal BA absorption decreases, fecal loss of BAs increases resulting in an upregulation of hepatic BA synthesis to maintain BA homeostasis. BA synthesis can be monitored from the level of C4 (7α-hydroxy-4-cholesten-3-one) in serum, a marker for the enzymatic activity of cholesterol 7α-hydroxylase [
8], the rate-limiting enzyme in BA synthesis. Cholesterol is precursor in the synthesis of BAs. Induction of BA synthesis depletes hepatic cholesterol stores, which is compensated for through increased hepatic synthesis of cholesterol in combination with an increased number of hepatic low density lipoprotein (LDL) receptors that subsequently reduce plasma LDL cholesterol levels. How BAs modulate glucose homeostasis has lately gained renewed interest with studies claiming increased release of glucagon-like peptide-1 (GLP-1) from the intestine following administration with a bile acid binding sequestrant [
9] and after rectal administration of taurocholate [
10]. Also the mode of action of the hypoglycemic agent metformin has been suggested to include decreased intestinal bile acid absorption [
11‐
13].
Elobixibat is a selective and partial inhibitor of IBAT with a novel and unique mechanism of action. After oral administration, systemic exposure is minimal [
14]. In three studies in patients with CC [
3‐
5], elobixibat enhanced colonic transit, thereby improving symptoms of CC such as increased stool frequency concomitant with reduced straining, bloating and hard stools.
The aim of the present investigation was to evaluate metabolic responses of elobixibat. For this purpose, the level of BA synthesis and serum lipid profiles were monitored in dyslipidemic patients treated with elobixibat for 28 days. In addition, we also evaluated whether such treatment may increase serum levels of the incretin GLP-1 in a study of CC patients treated with elobixibat at high dose.
Discussion
The current results provide insight in metabolic responses obtained when administering an IBAT inhibitor to dyslipidemic patients with elevated cholesterol levels, and when employed at high dose to patients with CC. At a dose of 5 mg elobixibat reduced LDL cholesterol by 7.4 % and decreased the LDL/HDL ratio by 18 %. The reduced LDL/HDL ratio is of particular interest since it is an important risk factor for the development of cardiovascular disease (CVD) [
18]. The beneficial effects of elobixibat on serum lipids confirm previous findings by Chey et al. [
3]. A limitation of this paper is the fact that data have been collected from two different populations (patients with dyslipidemia or with chronic constipation). It would have been of interest to assess GLP-1 in patients with dyslipidemia as well and to perform a thorough analysis of subfractions of LDL and HDL but given the set-up of the study, this was not possible due to restrictions in the sampling.
Although no patient discontinued the study, signs of increased colonic transit were identified (Table
2). On the other hand, the improved LDL/HDL ratio should be beneficial in patients with CC. This because it has been reported that constipation is a risk factor for CVD events [
19] as shown from women with severe constipation having a 23 % higher risk for CVD events, and an unadjusted risk of death due to CVD almost five-fold higher: 3.25 (95 % CI 1.76–5.01) in severe constipation as compared to 0.76 (95 % CI 0.54–1.06)/1000 person-years in subjects without constipation. Moreover, Salmoirago et al. [
19] reported that the more severe state of constipation at baseline, the more frequent is the use of cholesterol-lowering medication. Further support for a relation between atherosclerosis and constipation was found in a study [
20] on patients with known CVD having a 2.5-fold higher prevalence of constipation as compared to subjects without constipation. Cholesterol is to a great extent eliminated from the body through fecal loss of BAs [
21] (21) that is clearly reduced in patients with CC [
22‐
24]. Interestingly, also in patients with CVD, fecal BA excretion is significantly reduced as compared with non-CVD patients [
25].
Considering the above findings, it is conceivable that an IBAT inhibitor like elobixibat administered for the treatment of CC may be particularly attractive not only to relieve symptoms of constipation but also to lower LDL cholesterol and reduce the increased risk for CVD observed in subjects with constipation.
The significantly increased levels of GLP-1 in response to a dose level of elobixibat approximately twice the target dose for patients with CC suggests that IBAT inhibition stimulates intestinal L cells, presumably through elevated BAs in the intestine interacting with TGR5 receptors, thereby stimulating synthesis and secretion of GLP-1 [
6,
7,
9,
26,
27]. As compared to treatment with DPP-4 inhibitors, the meal-induced plasma GLP-1 levels with elobixibat treatment are smaller [
28]. However, it is important to point out that the meal stimulus in this study was a standardized low calorie chicken breast lunch, and that GLP-1 AUC measurements were evaluated over a longer time period, most likely inducing a lower response than a high calorie load or an oral glucose tolerance test.
The most commonly used drug in T2DM, metformin, probably in part acts through enhancing GLP-1 secretion [
28]. This effect may be mediated through IBAT inhibition since metformin is known to suppress active BA absorption from the ileum [
11]. Although data are not uniform [
29] other IBAT-inhibitors have demonstrated incretin-releasing properties in animals [
30]. Intriguingly, BA sequestrants like cholestyramine bind BAs and therefore reduce free BAs in the colon, have been reported beneficial in T2DM [
31]. Results have shown that colesevelam when bound to BAs may activate TGR-5 receptors in vitro [
10]. On the other hand, in healthy humans cholestyramine-induced changes of serum glucose can appear independent of serum GLP-1 levels (Rudling M, unpublished research).
The positive effects of IBAT-inhibition on GLP-1 secretion may thus be particularly beneficial in CC patients with T2DM or pre-diabetes; two disease entities associated with increased risk for constipation [
18,
32,
33].
Conclusion
In summary, the studies reported here provide evidence of decreased LDL cholesterol and increased GLP-1 levels when using elobixibat in patients with dyslipidemia and with CC respectively; these effects are consistent with metabolic effects of BAs in the ileocolonic region in humans. Further development of IBAT-inhibitors to combat metabolic disease will possibly be restricted by the effects of IBAT inhibition on colonic transit, resulting in diarrhea. However, given the association between symptoms of constipation with cardiovascular disease and T2DM, it seems that an IBAT inhibitor like elobixibat, in addition to positive effects on symptoms and signs of constipation, may provide positive metabolic side effects reducing the risk for CVD and T2DM.
Competing interests
Dr. Rudling has received a scientific grant from Albireo.
Dr. Camilleri serves as a member of an advisory board of Albireo with compensation to his employer, Mayo Clinic only and not to him. Dr. Graffner and Mr. Rikner are employees of Albireo, Goteborg, Sweden.
Authors’ contributions
MR: Principal investigator in the dyslipidemia study, study design, data analysis and interpretation, writing protocol and paper. MC: Principal investigator in the CC study, study conception and design, data analysis and interpretation, writing protocol and paper. HG: Study conception and design, data analysis and interpretation, writing protocol and paper. JJH: Analysis of GLP-1, data analysis and interpretation, writing paper. LR: Study conception and design, data analysis and interpretation, writing protocol and paper. All author read and approved the final manuscript.