Different Effects of Once-weekly and Once-daily Administered GLP-1RA Semaglutide and Liraglutide on Bile Acid Diarrhea.

Bile acid diarrhea (BAD) is a socially debilitating disease. Typical symptoms include loose stools, urgency, and high stool frequency. Recently, we reported the superior efficacy of the glucagon like-peptide 1 receptor agonist (GLP-1RA) liraglutide (administered subcutaneously once daily) in reducing daily bowel movements compared with the traditionally used bile acid sequestrant colesevelam (considered the standard of care). This has generated proposals of testing longer acting and more potent GLP-1RAs for treating BAD. Here, we present a patient with severe BAD who experienced minimal effect of the once-weekly administered GLP-1RA semaglutide, but total remission of BAD symptoms during treatment with liraglutide.

Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial.

BACKGROUND: Bile acid diarrhoea is an underdiagnosed disease estimated to affect 1-2% of the general population. Case reports indicate that the glucagon-like peptide 1 receptor agonist liraglutide might be an effective treatment for bile acid diarrhoea. We aimed to investigate the safety and efficacy of liraglutide for the treatment of bile acid diarrhoea. METHODS: We conducted a randomised, double-blind, active-comparator, double-dummy, non-inferiority clinical trial at the Center for Clinical Metabolic Research at Copenhagen University Hospital-Herlev and Gentofte, Hellerup, Denmark. Patients aged 18-75 years with 75selenium-homotaurocholic acid test (SeHCAT)-verified moderate-to-severe primary bile acid diarrhoea were randomly assigned (1:1) to receive liraglutide (one daily subcutaneous injection uptitrated from 0·6-1·8 mg per day over 3 weeks) or colesevelam (three capsules of 625 mg twice daily), the standard of care, for 6 weeks following one run-in week with no treatment. The primary endpoint was the proportion of participants experiencing a reduction in daily stool frequency of 25% or greater after 6 weeks. Data from all participants were included in the analysis of the primary outcome. The non-inferiority limit was set to 15% in favour of colesevelam. This trial is registered with EudraCT (2018-003575-34) and is completed. FINDINGS: Between April 1, 2019, and Jan 31, 2021, 52 patients were enrolled; 26 were assigned to liraglutide and 26 to colesevelam. 20 (77%) of 26 participants on liraglutide and 13 (50%) of 26 on colesevelam experienced a 25% or greater reduction in stool frequency, corresponding to a significant risk difference of -27% in favour of liraglutide (one-sided 95% CI -100 to -6). Liraglutide was therefore superior to colesevelam in reducing daily stool frequency. Mild nausea with a duration of 10-21 days was reported by six participants in the liraglutide group and by one participant in the colesevelam group. No other adverse events were reported. INTERPRETATION: The superiority of liraglutide compared with colesevelam in reducing stool frequency suggests consideration of liraglutide as a potential new treatment modality for bile acid diarrhoea, although larger confirmatory trials powered for superiority are warranted. FUNDING: Novo Nordisk, Novo Nordisk Foundation, Foundation for the Advancement of Medical Science under The A.P. Møller and Chastine Mc-Kinney Møller Foundation.

Colonoscopy results are not enhanced by use of magnet endoguide in specialist practice.

INTRODUCTION: It is discussed whether the use of a magnetic positioning device (OLYMPUS; UPD (unit of magnetic positioning device)) enhances the success of the colonoscopic procedure. Concern for patient compliance and endoscopic efficiency has been voiced in connection with the implementation of colon cancer screening. UPD has been proposed as a tool for optimization of results and reduction of patient discomfort. In this study, we aimed to qualify the debate by examining the success rate and patient discomfort in an unselected colonoscopy population referred to specialist clinics with experienced investigators. Furthermore, the study assessed the effect of using a UPD. MATERIAL AND METHODS: A total of 1,068 consecutive patients referred for colonoscopy were enrolled and randomised for investigation with or without use of UPD. The evaluation endpoints were: success rate (coecum visualised, ileal intubation was carried out at the investigator's discretion), duration of procedure, and patient discomfort indicated by the patient as a visual analogue scale score. RESULTS: No significant differences between the two investigational procedures were demonstrated in relation to the chosen endpoints. CONCLUSION: UPD is convenient to have, but not a necessity for colonoscopy. FUNDING: The study was supported by the Danish Association of Medical Specialists. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency, journal no. 2009-41-3716, the National Ethics Committee, journal no.: H-1-2009-80, and registered with ClinicalTrials.gov., protocol no: NCT01055782.

Alpha-defensin DEFA1A3 gene copy number elevation in Danish Crohn's disease patients.

BACKGROUND AND PURPOSE OF STUDY: Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD. METHODS: Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location. RESULTS: Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001). CONCLUSIONS: Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.

[Colonic malacoplakia treated with sulfamethizole and trimethoprim]. / Malokoplaki i colon behandlet med sulfamethizol og trimetoprim.

We report a case of colonic malacoplakia in a 78-year-old woman, developed following short-term treatment with prednisolone. Clinically, the patient presented with diarrhoea (up to ten times a day) and malaise. Laboratory tests revealed severe anaemia and elevated inflammatory parameters. Colonoscopy showed macroscopic yellowish nodular changes throughout the colon. Biopsies were diagnostic for malacoplakia and exhibited moderate growth of Escherichia faecium and ciprofloxacin-resistant Escherichia coli. The condition resolved during three months of antibiotic treatment with sulfamethizole and trimethoprim.

Genetic and environmental factors as predictors of disease severity and extent at time of diagnosis in an inception cohort of inflammatory bowel disease, Copenhagen County and City 2003-2005.

BACKGROUND AND AIMS: The etiology of the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) remains unknown. We aimed to investigate the influence of genetic, serological, and environmental factors on phenotypic presentation of IBD at diagnosis in a population-based Danish inception cohort from 2003-2005. METHODS: Three-hundred-forty-seven (62%) of 562 cohort patients were genotyped. ASCA and p/c-ANCA were determined and patients answered a questionnaire concerning environmental factors with possible influence on IBD. RESULTS: Fourteen percent of CD patients vs. 11% of controls were positive for common CARD15 mutation (ns), whereas more CD patients than healthy controls were homozygous for the OCTN-TC haplotype (p=0.03). ASCA was more common in CD (22%) than UC (14%) (p=0.045) and was related to age and localization of CD. p-ANCA was more frequent in UC (p=0.00001) but was related to pure colonic CD (p=0.0001). Sugar consumption was significantly higher in CD patients than in UC patients (p=0.0001) and more CD patients than UC patients had undergone appendectomy prior to IBD diagnosis (p=0.03). A possible relation between tonsillectomy and disease severity in CD, and a relation between use of oral contraception and disease localization of UC to rectum/left-sided colon were found. CONCLUSIONS: In this cohort of unselected IBD patients we found a very low frequency of mutations in IBD susceptibility genes and observed a greater impact of ASCA and ANCA than of genetic factors on disease phenotypes. In addition, several environmental factors seemed to influence disease occurrence and disease presentation in both UC and especially CD.

Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database.

OBJECTIVES: A continuous increase in the incidence of inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) has been suggested. Since Denmark provides excellent conditions for epidemiological research, we aimed to describe contemporary IBD incidence rates and patient characteristics in Copenhagen County and City. METHODS: All patients diagnosed with IBD during 2003-2005 were followed prospectively. Demographic and clinical characteristics, such as disease extent, extraintestinal manifestations, smoking habits, medical treatment, surgical interventions, cancer, and death, were registered. RESULTS: Five-hundred sixty-two patients were diagnosed with IBD, resulting in mean annual incidences of 8.6/10(5) for CD, 13.4/10(5) for UC, and 1.1/10(5) for IC. Time from onset to diagnosis was 8.3 months in CD and 4.5 months in UC patients. A family history of IBD, smoking, and extraintestinal manifestations was significantly more common in CD than in UC patients. Only 0.6% of UC patients had primary sclerosing cholangitis. In CD, old age at diagnosis was related to pure colonic disease, whereas children significantly more often had proximal and extensive involvement. Twelve percent of CD patients and 6% of UC patients underwent surgery during the year of diagnosis, significantly less than earlier reported. CONCLUSIONS: The incidence of IBD in Copenhagen increased noticeably during the last decades. Time from onset of symptoms until diagnosis decreased markedly, extent of CD was related to age at diagnosis, and the risk of surgery was low in UC.

Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.

In 328 type 2 diabetic patients followed for 9.0 years (mean), we investigated whether endothelial dysfunction and chronic inflammation (estimated from plasma markers) can explain the association between (micro)albuminuria and mortality. Of the patients, 113 died. Mortality was increased in patients with baseline microalbuminuria or macroalbuminuria (odds ratios as compared with normoalbuminuria, 1.78 [P < 0.05] and 2.86 [P < 0.01]) and in patients with soluble vascular cell adhesion molecule 1 in the third tertile and C-reactive protein in the second and third tertiles (odds ratios as compared with the first tertile, 2.05 [ P < 0.01], and 1.80 [P < 0.05] and 2.92 [ P < 0.01]). These associations were mutually independent. The mean yearly change in urinary albumin excretion was 9.4%; in von Willebrand factor, 8.1%; in tissue-type plasminogen activator, 2.8%; in soluble vascular cell adhesion molecule 1, 5.2%; in soluble E-selectin, -2.3%; in C-reactive protein, 3.8%; and in fibrinogen, 2.3%. The longitudinal development of urinary albumin excretion was significantly and independently determined by baseline levels of and the longitudinal development of BMI, systolic blood pressure, serum creatinine, glycated hemoglobin and plasma von Willebrand factor (baseline only), soluble E-selectin (baseline only), tissue-type plasminogen activator, C-reactive protein, and fibrinogen. The longitudinal developments of markers of endothelial function and inflammation were interrelated. In type 2 diabetes, increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time, and are strongly and independently associated with risk of death.