Q&A: Liraglutide outperforms colesevelam in reducing stool frequency in bile acid diarrhea
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Liraglutide reduced stool frequency in a small subset of patients with bile acid diarrhea and warrants consideration as a potential new treatment modality, according to research in The Lancet Gastroenterology and Hepatology.
Researchers aimed to investigate the safety and efficacy of liraglutide, a glucagon-like peptide 1 receptor agonist, in patients with bile acid diarrhea, which is often underdiagnosed and estimated to affect 1% to 2% of the general population.
In a double-blind clinical trial in Denmark, 52 patients (mean age, 50.2 years) with verified bile acid diarrhea received either one daily subcutaneous injection of liraglutide (increasing from 0.6-1.8 mg per day over 3 weeks) or standard-of-care colesevelam (three capsules of 625 mg twice daily) for 6 weeks following one run-in week with no treatment.
According to study results, 77% of liraglutide patients and 50% of colesevelam patients achieved at least a 25% reduction in stool frequency (risk difference: –27% in favor of liraglutide).
In a Healio interview, study author Filip K. Knop, MD, PhD, professor of endocrinology and director of the Center for Clinical Metabolic Research at Gentofte Hospital at the University of Copenhagen, explained how these results might affect patient care going forward and what additional research is needed.
Healio: Why did your team explore this topic?
Knop: Back in 2009, in my effort to better understand how the gut hormone glucagon-like peptide 1 (GLP-1) is secreted, I read “TGR5-mediated bile acid sensing controls glucose homeostasis” (Thomas, et al.), which described how bile acids may stimulate the secretion of this glucose-lowering and satiety-promoting hormone. Based on the findings in that paper, I developed a clinical research program and was lucky to win a 5-year grant from the Novo Nordisk Foundation that allowed us to study the relationship between bile and GLP-1 in humans.
One of the studies in the research program involved patients with bile acid malabsorption — nowadays called bile acid diarrhea — in whom we hypothesized GLP-1 secretion would be high due to excess bile in the gut lumen. This was not the case, as recently described in a publication in Gastro Hep Advances, but the study opened our eyes to bile acid diarrhea as a debilitating and underdiagnosed condition with no effective therapies.
Coincidentally, we initiated treatment with the GLP-1 receptor agonist liraglutide for type 2 diabetes and obesity, respectively, in two patients who also suffered from bile acid diarrhea. As recently described in a brief communication in Gastroenterology, these patients surprisingly experienced complete remission of their bile acid diarrhea, in addition to the expected glucose- and body weight-lowering effects of liraglutide.
Based on these two cases and knowing from both patients and literature that no good medical therapies exist for the millions of people suffering from this debilitating disease, we designed this randomized, controlled trial.
Healio: What were the main takeaways?
Knop: Compared with the bile acid sequestrant colesevelam, 6 weeks treatment with liraglutide was superior in reducing stool frequency in patients with bile acid diarrhea. Both treatments were safe with benign safety profiles.
We also observed some added benefits of liraglutide treatment compared with colesevelam: Liraglutide showed beneficial effects on the dysmetabolic prediabetic-like state that also characterizes these patients. Interestingly, and in contrast to colesevelam, liraglutide increased reabsorption of bile acids [assessed by 75-selenium homocholic acid taurine test (SeHCAT)] and decreased bile acid synthesis (assessed by circulating C4), possibly via a liraglutide-induced increase in FGF-19 secretion from enterocytes, thus rectifying core pathophysiological features of bile acid diarrhea.
Healio: How will these results inform patients care going forward?
Knop: Despite the relatively small number of patients included in our study, it nevertheless represents one of the largest randomized, controlled trials investigating the effect of medical therapies for bile acid diarrhea. As we compared liraglutide head-to-head with the best-in-class colesevelam, our results inform patients and practitioners that liraglutide should be considered a first-line treatment in bile acid diarrhea.
Healio: What additional research is needed?
Knop: Trials confirming our results and establishing the long-term effectiveness of liraglutide are warranted, in addition to studies on the effect of liraglutide alone and/or in combination with bile acid sequestration in patients with the most severe forms of bile acid diarrhea (e.g., with stool frequencies of 10 or more).
Healio: What else should our readers to know about this study and topic?
Knop: Bile acid diarrhea is a poorly recognized disorder that may affect as much as 1% of the general population. The main symptoms of bile acid diarrhea are high stool frequency, defecation urgency and fecal incontinence, making it a socially debilitating disease. In most developed countries the disorder can be diagnosed by SeHCAT, in which the 7-day retention of orally administered 75-selenium homocholic acid taurine is measured with a gamma camera. Retention below 15% is diagnostic for bile acid diarrhea.
With liraglutide established as an effective treatment that also addresses the dysmetabolic prediabetic-like state that characterizes these patients, it is my hope that physicians will have the condition on their radar and discuss this new treatment option with relevant patients.
References:
- Thomas, C. Cell Metab. 2009;doi:10.1016/j.cmet.2009.08.001
- Walters, JRF. Lancet Gastroenterol Hepatol. 2022;doi:10.1016/S2468-1253(22)00213-8.
Perspective
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This is a very interesting observation that builds on case reports previously published by the same group headed by Professor Filip K. Knop. The strengths of the study include the randomized, controlled design comparing liraglutide with a positive comparator — a bile acid sequestrant and the traditional approach to treating bile acid diarrhea. The findings are novel, and the statistical significance based on non-inferiority statistics provides convincing evidence of benefit.
The missing piece of information that will require further research pertains to the mechanism of benefit. As suggested in the accompanying editorial by Julian R. F. Walters, MD, professor of gastroenterology at Imperial College London, it is conceivable that the beneficial effect of liraglutide results from retardation of gastric, small bowel and colonic transit. Indeed, liraglutide and other GLP-1 agonists have been shown to inhibit transit, particularly in the upper GI tract, but these effects may contribute to the efficacy in relief of bile acid diarrhea.
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