- Email: [email protected]
Effects of Liraglutide on Gastric Emptying, Gastric Accommodation, Satiation and Satiety after 16 Weeks' Treatment: A Single-Center, Randomized, Placebo-Controlled Trial in 32 Patients
Su2028
Background: Clostridium difficile infection (CDI) accounts for 20%-30% of cases of antibioticassociated diarrhea and is the most commonly recognized cause of infectious diarrhea in healthcare settings. Based on previous experience at our institution, fecal microbiota transplantation (FMT) represents an effective therapeutic option for the treatment of recurrent CDI, with worldwide cure rates reported as high as 93%. It is generally safe and well tolerated by most patients and has applicability for patients with mild to complicated disease and appears to be useful even in high-risk populations. Our hope is that one institutions experience can elucidate potential clinically relevant risk factors that present a common theme among our 106 patients that have undergone the procedure thus far. Methods: We performed a retrospective chart review of selected patient data on the 106 patients that have undergone FMT at Ochsner Clinic Foundation from August 2012 to February 2016. Results: FMT was performed in 106 CDI patients. The 83 female and 23 male patients ranged in age from 17 to 94 years (mean 61 years), with 93 (88%) Caucasian patients, 10 (9%) African Americans, 2 (2%) Hispanic patients, and 1 (1%) Asian patient. One hundred patients (94%) had FMT done for recurrent CDI and 6 (6%) patients had severe/complicated CDI, with African Americans accounting for 2 of the 6 patients. In our 3.5 years performing the procedure we have repeated FMT in 4 patients for reoccurrence. Forty (38%) patients had undergone prior cholecystectomy. Seventy five (71%) patients had antibiotic use prior to their first CDI episode. At least 49 (46%) of our patients were on PPIs or H2 blockers, with 4 of these patients on both. Of the 21 (20%) patients considered immunosuppressed, 12 (11%) were on corticosteroid therapy and 6 (6%) were organ transplant recipients. The average distance traveled by our patients to receive FMT was 90 miles (range 3 - 463 miles). We had 78 patients (74%) that had to travel > 40 miles to undergo the procedure and 57 patients (54%) that traveled > 80 miles. Conclusions: Based on our experience, Caucasians, older adults, and women had a higher incidence of recurrent CDI and African Americans had a higher proportion of severe/complicated CDI with a greater number of risk factors overall in the patients observed. The small number of patients requiring repeat FMT each had unique clinical scenarios with several risk factors for recurrent disease. Similar to other studies we noted a high rate of antibiotic use and acid suppression therapy. Of interest, we report a significantly elevated cholecystectomy rate compared to national data, however this finding merits further inquiry. Finally, given the overall success of treatment and significant travel burden apparent in our population, increased access to this valuable treatment option is essential.
Fig. 1 AWR scores by treatment group (M, Q25-Q75). aP < 0.01, versus normal group; b P < 0.05, cP < 0.01, versus model group. NC: normal group; MC: IBS model group; MOX: moxibustion group; EA: electroacupuncture group; BTVC: Bifid-triple Viable Capsule group; PB: Pinaverium Bromide group.
Fig. 2 Microbiota comparison at phylum and genus level. A: normal group; B: IBS model group; C: moxibustion group; D: electroacupuncture group; E: Bifid-triple Viable Capsule group; F: Pinaverium Bromide group.
Su2027 THE INFLUENCE OF HELICOBACTER PYLORI ERADICATION THERAPY ON INTESTINAL MICROBIOTA Dilyara Safina, Sayar Abdulkhakov, Tatyana Grigoryeva, Dilyara Khusnutdinova, Boris Kovarsky, Alexander Tyakht, Maria Markelova, Eugenia A. Boulygina, Maria Siniagina, Sergey Malanin, Rustem Abdulkhakov, Vladislav Chernov
Chart 1: Quantitative date on the indication, sex, and race of patients recieving fecal microbiota transplant.
H. pylori eradication therapy including antibiotics as well as H. pylori itself can influence the normal intestinal microbiota content. The aim of the study was to describe the gut microbiota composition in H. pylori-positive and H. pylori-negative patients as well as the influence of eradication therapy on gut microbiota. 198 stool samples were taken for analysis: 74 samples from H. pylori-positive patients before eradication therapy, 74 - from the same patients after eradication, 50 - from H. pylori-negative patients (control group). Total DNA was isolated from the stool samples and subjected to whole-genome sequencing on SOLiD 5500 Wildfire platform. Intestinal microbiota was evaluated based on number of species, qualitative composition, Shannon diversity index and Bray-Curtis metrics. Results. Bacterial community was quite similar in all groups: Bacteroides, Prevotella, Eubacterium, Roseburia, Faecalibacterium and Clostridium genera were predominant in all samples. The spread in variations of the prevailing Firmicutes and Bacteroides phyla was wider after the treatment than in control samples. In about half of patients eradication therapy led to the decrease of both the number of species and the Shannon index indicating a decrease in the overall bacterial diversity with a possible predominance of individual species. Eradication therapy resulted in the reduction of the relative representation of Bifidobacterium, Collinsella, Coprococcus genera, accompanied with the increase of Clostridium, Bacteroides, Coprobacillus and Flavonifractor genera. Evaluation of taxonomic diversity changes based on Shannon index and Bray-Curtis metrics allows to differentiate patients into the groups with mild, moderate and severe changes. In 82% of cases mild and moderate changes in microbial community content were found - increased level of Bacteroides genus, decreasing levels of Bifidobacterium and Eubacterium genus, simultaneously. Escherichia genus had the increased abundance in the majority of patients with severe microbial shifts after eradication therapy. Changes in the composition of intestinal microbiota after H. pylori eradication therapy depend mostly on the initial content of the intestinal microbiota: the closer initial microbial state of H. pylori-positive patients to the control samples is, the milder changes could be detected after eradication therapy. Gene-centric analysis of the functional composition in paired samples taken before and after therapy showed an increase of the relative abundance of genes conferring antibiotic resistance. Conclusions. Evaluation of intestinal microflora content prior to treatment can probably predict the incidence of side effects related to changes in microbial composition. This work was financially supported by the Ministry of Education and Science of Russian Federation (agreement #14.575.21.0076, ID RFMEFI575I4X0076).
Chart 2: Medications and comorbid conditions surveyed in our fecal microbiota transplant population.
Su2029 EFFECTS OF LIRAGLUTIDE ON GASTRIC EMPTYING, GASTRIC ACCOMMODATION, SATIATION AND SATIETY AFTER 16 WEEKS' TREATMENT: A SINGLE-CENTER, RANDOMIZED, PLACEBOCONTROLLED TRIAL IN 32 PATIENTS Disha Khemani, Deborah J. Eckert, Jessica O'Neill, Alfred D. Nelson, Michael Ryks, Deborah Rhoten, Andres J. Acosta Cardenas, Houssam Halawi, Ibironke Oduyebo, Duane Burton, Matthew Clark, Alan R. Zinsmeister, Michael Camilleri Background: We previously showed that a short-acting GLP-1 agonist, exenatide, 5µg, SQ, BID, for 30 days, delays gastric emptying and induces weight loss (PMID: 26542264). Gastric emptying was delayed after 3 weeks of treatment with the long-acting GLP-1 agonist, liraglutide, escalated to 1.8mg/day, but not delayed after 24 weeks' treatment (PMID:
S-633
AGA Abstracts
AGA Abstracts
CHARACTERISTICS OF PATIENTS UNDERGOING FECAL MICROBIOTA TRANSPLANTATION FOR CLOSTRIDIUM DIFFICILE INFECTION: ONE INSTITUTION'S STORY Jacob L. Breaux, Arnab Ray, Sherif Michael
AGA Abstracts
26656289). Liraglutide is approved for treatment of obesity with standard dose escalation over 5 weeks reaching 3mg/day. Aim: To compare effects of liraglutide, 3mg SQ /day, and placebo administered for 12 weeks on gastric emptying, gastric accommodation, satiation, postprandial symptoms and satiety in overweight or obese patients. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants (BMI ≥30kg/m2). All participants received nutritional and behavioral counseling. Patients followed standard liraglutide dose escalation, increasing by 0.6mg/day each week for 5 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. Liraglutide was administered at maximum tolerated dose for the next 11 weeks. All participants included in this report underwent all measurements at baseline and after a total of 12 weeks of maximum tolerated dose of liraglutide (3mg/day). We measured: gastric emptying of solids by scintigraphy over 4 hours using a 320kcal, 30% fat meal; gastric volumes (fasting and post-300mL Ensure®) by SPECT; satiation [volume to fullness (VTF), maximum tolerated volume (MTV) and postprandial symptoms] with nutrient drink test (Ensure® 30kcal/min); and satiety by kcal intake at an ad libitum buffet meal. Statistical analysis examined effects of liraglutide compared to placebo using ANCOVA with the corresponding baseline measurement as a covariate. Results: There were 4 drop-outs, and complete data were available for 28 participants. All patients on liraglutide were taking 3mg/ day at the end of 12 weeks of therapy. Patients' demographic data, baseline gastric emptying T1/2, and effects on gastric motor functions, satiation and satiety parameters with treatments are shown in the table (mean+SEM). Conclusion: Liraglutide treatment at maximum escalated dose (3mg) for 12 weeks resulted in significant and persistent slowing of gastric emptying and reduced maximum tolerated volume relative to placebo. These results suggest an important role of gastric emptying in the beneficial effects of liraglutide on weight loss. Support: NIH RO1-DK67071
Su2031 HUMANIZATION OF A GASTRIC INHIBITORY POLYPEPTIDE (GIP)NEUTRALIZING MONOCLONAL ANTIBODY (MAB) AND WEIGHT REVERSAL IN DIET-INDUCED OBESE MICE M. Michael Wolfe, Michael O. Boylan, Raghav Sood, Alice A. Newman Background: We recently generated a specific mouse GIP mAb (mAbm) and reported significant prevention of weight gain without any effect on food intake. AIM: To determine whether this GIP mAbm could reverse weight gain in obese mice and to characterize a humanized GIP mAb (mAbh). Methods: Obesity was induced in C57BL/6 mice by feeding high-fat diet (HFD; 60% calories from fat) from weaning to 18 weeks. The mice were then fed a 45% HFD and administered the GIP mAbm (45 mg/kg BW) ip weekly for 6 wks. BW was recorded weekly, and HgA1c levels were measured after wk 6. The mAbm was "humanized" by grafting its complementary determining regions onto a human IgG "scaffold". Binding affinity was determined by surface plasmon resonance, and a reporter cell line expressing GIP receptors was used in a modified Schild's assay to demonstrate mAb-dependent GIP neutralization in vitro. Finally, the GIP mAbh (10 or 30 mg/kg BW) was administered to mice ip, and blood samples were collected over 2 wks, and the Cmax and T1/2 determined. In separate studies, mice fasted for 1 h were administered either 30 mg/kg BW mAbh or vehicle ip. The mice were then fasted for an additional 5 h before glucose (1.5 g/kg BW) was given by oral gavage, and blood was collected at 0 and 15 min; the protocol was repeated 1 and 2 wks later. Plasma insulin levels were measured by ELISA. Results: After 6 wks of GIP mAbm treatment, BW was reduced by 6.0±2.7%, while BW increased in control mice by 3.6±1.4% (P<0.002). The mean HgA1c levels for mAb-treated mice trended lower (4.4±0.2%), compared to control mice (4.8±2.7%, P=NS). The binding affinity (KD) of GIP for the mAbh was 0.9 nM, compared to the original mAbm KD of 3.3 nM. Similar to the mAbm, the mAbh neutralized GIP signaling in vitro in a concentration-dependent manner, and the Schild's assay showed mAbh and mAbm equilibrium dissociation constants of 2.2 µM and 3.2 µM, respectively, indicating similarly that mAbh binds more avidly to GIP than does mAbm. The plasma Cmax values for the 10 and 30 mg/kg BW doses of GIP mAbh were 10.1±0.7 µg/ml and 32.6±1.0 µg/ml, respectively. The GIP mAbh inhibited the15-min insulin responses to oral glucose at 5 h, 1 wk, and 2 wk after treatment by 47±21% (P=0.01), 45±21% (P=0.01), and 13.8±31%, respectively. Conclusion: Treatment of high-fat fed obese mice with the GIP mAb caused significant weight loss, which was accompanied by a trend toward improvement in HgA1c levels. The anti-GIP mAbh was shown to bind GIP with a higher affinity than the mAbm, and similarly it inhibits GIP signaling in vitro more potently than the original GIP mAbm. Furthermore, the calculated T1/2 for the GIP mAbh in vivo is comparable to other biological agents, indicating that a convenient bimonthly or once per month administration of the GIP mAbh might prove a tenable agent for treating obesity and related disorders in humans.
*p=0.046; **p=0.036
Su2030 Su2032
BAR130, A HYODEOXYCHOLIC ACID DERIVATIVE AS THE FIRST EXAMPLE OF DUAL LXRα/GPBAR1 AGONIST Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Angela Zampella, Simona De Martino, Stefano Fiorucci
A SINGLE-CENTER, RANDOMIZED, PLACEBO-CONTROLLED, 16-WEEK TRIAL OF EFFECTS OF LIRAGLUTIDE ON WEIGHT LOSS AND RELATIONSHIP TO CHANGE IN GASTRIC EMPTYING IN OBESE PATIENTS Hoda C. Kadouh, Matthew Clark, Sarah A. Kalsy, Karen M. Graszer, Karen Grothe, Houssam Halawi, Ibironke Oduyebo, Disha Khemani, Alfred D. Nelson, Deborah J. Eckert, Jessica O'Neill, Andres J. Acosta Cardenas, Alan R. Zinsmeister, Michael Camilleri
Background. The liver X receptors (LXRs), activated by oxysterol and by the secondary bile acid hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In the present study, we report the identification of a side chain modified HDCA (BAR130) that represents the first example of a potent dual LXRα/GPBAR1 agonist. Aim. To investigate in vitro and in vivo effects of BAR130 a dual GPBAR1/LXRα ligand. Material and methods. HepG2 and Glutag (a mouse counterpart of intestinal L cells) cells were exposed to GW3965 or TLCA (10 µM), HDCA (10 µM) along with increasing concentrations of BAR130 (1, 5, 10, 25, 50 µM); total RNA was isolated for rt-PCR. C57BL6 mice were administered with BAR130 (30 mg/Kg daily by gavage) or vehicle (distilled water) for 2 weeks. Mice were sacrificed and blood, liver and terminal ileum collected for plasma AST, cholesterol and tryglicerides measurement, liver histopathology analysis (H/E) and for evaluation of steatosis markers genes expression (rt-PCR). Results. BAR130 transactivates LXRα and GPBAR1 with an EC50 value of 3.2±0.03 and 4.9±0.2, respectively. When administered in vitro to HepG2 cells , BAR130 increases the expression of LXRα target genes, ABCA1 and SREBP1c, in a concentration-dependent manner with an EC50 of 8.3 µM and 5.8 µM respectively. BAR130 increases the expression of pro-glucagon mRNA (a GPBAR1 target gene) in GLUTAg cells with an EC50 of 6.5 µM. Treating mice with BAR130 did not increased AST, cholesterol and tryglicerides plasma levels (Figure). Further on, rtPCR analysis of liver samples demonstrated that the BAR130 did not induce the expression of lipidogenic genes including FAS, SREBP1C and CD36. The result was confirmed by Liver histology (H/E). BAR130 increased the expression of GPBAR1 target gene GLP1 in the ileum and reduced markers of inflammation in macrophages. Conclusions. This study shows the simultaneous activation of LXRα and GPBAR1 represents a promising approach to target metabolic disorders and ground the use of BAR130 in the setting of metabolic diseases.
AGA Abstracts
Background: Obesity is associated with accelerated gastric emptying (GE) and greater calories consumed to reach satiation or to evoke satiety with an ad libitum meal. A medication which could impact GE has the potential to assist with obesity management. One possible medication, exenatide, a short-acting GLP-1 receptor agonist, 5µg SQ BID for 30 days, has been shown to delay GE and induce weight loss (PMID 26542264). GE was delayed after 3 weeks' treatment with the longer acting GLP-1 agonist, liraglutide, escalated to 1.8mg/ day, but there was no difference after 24 weeks of treatment (PMID 26656289). The effect of liraglutide, 3mg/day, on GE and weight is unclear. Aim: To compare effects on weight loss of 16 weeks' treatment of dose-escalated liraglutide (up to 3mg/day) to placebo, and the relationship of weight loss to slowing of GE on treatment. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants; we used liraglutide dose escalation starting at 0.6mg/day and increasing by 0.6mg/day each week to reach a 3mg dose at week 5, followed by 3mg/day dose for the next 11 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. All participants underwent standardized health behavior counseling, nutrition education sessions (using LEARN manual), as well as structured follow-up visits, for a total of 17 visits to the Clinical Research Unit. In addition, GE of solids was measured over 4 hours, using a 315kcal, 33% fat meal, by means of scintigraphy at baseline and after 16 weeks of treatment. Statistical analysis examined effects of liraglutide compared to placebo on weight loss and on the relationship of weight loss with change (∆) in GE T1/2 of solids using Spearman correlation. Results: To date, 28 participants completed all studies, 4 dropped out, and 8 are currently on treatment. The ∆ in weight between baseline and week 16 of treatment is expressed as median (IQR), as data distribution was skewed (one placebo-treated participant lost 17.1kg). Other data are mean + SEM (Table). There was an inverse relationship between ∆ GE T1/2 and ∆ weight loss (Rs= -0.33, p=0.095), suggesting that the greater the retardation of GE, the greater the weight loss. Two patients underwent cholecystectomy during the study. Conclusions: Liraglutide (3mg/day over 12 weeks after standard weekly dose escalation of 0.6mg/day) results in significant weight loss compared to placebo. Greater retardation of GE is associated with greater weight loss, suggesting the hypothesis that liraglutide's effect on weight is mediated, in part, by retardation of GE. Support: NIH R01-DK67071
S-634
Background: Clostridium difficile infection (CDI) accounts for 20%-30% of cases of antibioticassociated diarrhea and is the most commonly recognized cause of infectious diarrhea in healthcare settings. Based on previous experience at our institution, fecal microbiota transplantation (FMT) represents an effective therapeutic option for the treatment of recurrent CDI, with worldwide cure rates reported as high as 93%. It is generally safe and well tolerated by most patients and has applicability for patients with mild to complicated disease and appears to be useful even in high-risk populations. Our hope is that one institutions experience can elucidate potential clinically relevant risk factors that present a common theme among our 106 patients that have undergone the procedure thus far. Methods: We performed a retrospective chart review of selected patient data on the 106 patients that have undergone FMT at Ochsner Clinic Foundation from August 2012 to February 2016. Results: FMT was performed in 106 CDI patients. The 83 female and 23 male patients ranged in age from 17 to 94 years (mean 61 years), with 93 (88%) Caucasian patients, 10 (9%) African Americans, 2 (2%) Hispanic patients, and 1 (1%) Asian patient. One hundred patients (94%) had FMT done for recurrent CDI and 6 (6%) patients had severe/complicated CDI, with African Americans accounting for 2 of the 6 patients. In our 3.5 years performing the procedure we have repeated FMT in 4 patients for reoccurrence. Forty (38%) patients had undergone prior cholecystectomy. Seventy five (71%) patients had antibiotic use prior to their first CDI episode. At least 49 (46%) of our patients were on PPIs or H2 blockers, with 4 of these patients on both. Of the 21 (20%) patients considered immunosuppressed, 12 (11%) were on corticosteroid therapy and 6 (6%) were organ transplant recipients. The average distance traveled by our patients to receive FMT was 90 miles (range 3 - 463 miles). We had 78 patients (74%) that had to travel > 40 miles to undergo the procedure and 57 patients (54%) that traveled > 80 miles. Conclusions: Based on our experience, Caucasians, older adults, and women had a higher incidence of recurrent CDI and African Americans had a higher proportion of severe/complicated CDI with a greater number of risk factors overall in the patients observed. The small number of patients requiring repeat FMT each had unique clinical scenarios with several risk factors for recurrent disease. Similar to other studies we noted a high rate of antibiotic use and acid suppression therapy. Of interest, we report a significantly elevated cholecystectomy rate compared to national data, however this finding merits further inquiry. Finally, given the overall success of treatment and significant travel burden apparent in our population, increased access to this valuable treatment option is essential.
Fig. 1 AWR scores by treatment group (M, Q25-Q75). aP < 0.01, versus normal group; b P < 0.05, cP < 0.01, versus model group. NC: normal group; MC: IBS model group; MOX: moxibustion group; EA: electroacupuncture group; BTVC: Bifid-triple Viable Capsule group; PB: Pinaverium Bromide group.
Fig. 2 Microbiota comparison at phylum and genus level. A: normal group; B: IBS model group; C: moxibustion group; D: electroacupuncture group; E: Bifid-triple Viable Capsule group; F: Pinaverium Bromide group.
Su2027 THE INFLUENCE OF HELICOBACTER PYLORI ERADICATION THERAPY ON INTESTINAL MICROBIOTA Dilyara Safina, Sayar Abdulkhakov, Tatyana Grigoryeva, Dilyara Khusnutdinova, Boris Kovarsky, Alexander Tyakht, Maria Markelova, Eugenia A. Boulygina, Maria Siniagina, Sergey Malanin, Rustem Abdulkhakov, Vladislav Chernov
Chart 1: Quantitative date on the indication, sex, and race of patients recieving fecal microbiota transplant.
H. pylori eradication therapy including antibiotics as well as H. pylori itself can influence the normal intestinal microbiota content. The aim of the study was to describe the gut microbiota composition in H. pylori-positive and H. pylori-negative patients as well as the influence of eradication therapy on gut microbiota. 198 stool samples were taken for analysis: 74 samples from H. pylori-positive patients before eradication therapy, 74 - from the same patients after eradication, 50 - from H. pylori-negative patients (control group). Total DNA was isolated from the stool samples and subjected to whole-genome sequencing on SOLiD 5500 Wildfire platform. Intestinal microbiota was evaluated based on number of species, qualitative composition, Shannon diversity index and Bray-Curtis metrics. Results. Bacterial community was quite similar in all groups: Bacteroides, Prevotella, Eubacterium, Roseburia, Faecalibacterium and Clostridium genera were predominant in all samples. The spread in variations of the prevailing Firmicutes and Bacteroides phyla was wider after the treatment than in control samples. In about half of patients eradication therapy led to the decrease of both the number of species and the Shannon index indicating a decrease in the overall bacterial diversity with a possible predominance of individual species. Eradication therapy resulted in the reduction of the relative representation of Bifidobacterium, Collinsella, Coprococcus genera, accompanied with the increase of Clostridium, Bacteroides, Coprobacillus and Flavonifractor genera. Evaluation of taxonomic diversity changes based on Shannon index and Bray-Curtis metrics allows to differentiate patients into the groups with mild, moderate and severe changes. In 82% of cases mild and moderate changes in microbial community content were found - increased level of Bacteroides genus, decreasing levels of Bifidobacterium and Eubacterium genus, simultaneously. Escherichia genus had the increased abundance in the majority of patients with severe microbial shifts after eradication therapy. Changes in the composition of intestinal microbiota after H. pylori eradication therapy depend mostly on the initial content of the intestinal microbiota: the closer initial microbial state of H. pylori-positive patients to the control samples is, the milder changes could be detected after eradication therapy. Gene-centric analysis of the functional composition in paired samples taken before and after therapy showed an increase of the relative abundance of genes conferring antibiotic resistance. Conclusions. Evaluation of intestinal microflora content prior to treatment can probably predict the incidence of side effects related to changes in microbial composition. This work was financially supported by the Ministry of Education and Science of Russian Federation (agreement #14.575.21.0076, ID RFMEFI575I4X0076).
Chart 2: Medications and comorbid conditions surveyed in our fecal microbiota transplant population.
Su2029 EFFECTS OF LIRAGLUTIDE ON GASTRIC EMPTYING, GASTRIC ACCOMMODATION, SATIATION AND SATIETY AFTER 16 WEEKS' TREATMENT: A SINGLE-CENTER, RANDOMIZED, PLACEBOCONTROLLED TRIAL IN 32 PATIENTS Disha Khemani, Deborah J. Eckert, Jessica O'Neill, Alfred D. Nelson, Michael Ryks, Deborah Rhoten, Andres J. Acosta Cardenas, Houssam Halawi, Ibironke Oduyebo, Duane Burton, Matthew Clark, Alan R. Zinsmeister, Michael Camilleri Background: We previously showed that a short-acting GLP-1 agonist, exenatide, 5µg, SQ, BID, for 30 days, delays gastric emptying and induces weight loss (PMID: 26542264). Gastric emptying was delayed after 3 weeks of treatment with the long-acting GLP-1 agonist, liraglutide, escalated to 1.8mg/day, but not delayed after 24 weeks' treatment (PMID:
S-633
AGA Abstracts
AGA Abstracts
CHARACTERISTICS OF PATIENTS UNDERGOING FECAL MICROBIOTA TRANSPLANTATION FOR CLOSTRIDIUM DIFFICILE INFECTION: ONE INSTITUTION'S STORY Jacob L. Breaux, Arnab Ray, Sherif Michael
AGA Abstracts
26656289). Liraglutide is approved for treatment of obesity with standard dose escalation over 5 weeks reaching 3mg/day. Aim: To compare effects of liraglutide, 3mg SQ /day, and placebo administered for 12 weeks on gastric emptying, gastric accommodation, satiation, postprandial symptoms and satiety in overweight or obese patients. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants (BMI ≥30kg/m2). All participants received nutritional and behavioral counseling. Patients followed standard liraglutide dose escalation, increasing by 0.6mg/day each week for 5 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. Liraglutide was administered at maximum tolerated dose for the next 11 weeks. All participants included in this report underwent all measurements at baseline and after a total of 12 weeks of maximum tolerated dose of liraglutide (3mg/day). We measured: gastric emptying of solids by scintigraphy over 4 hours using a 320kcal, 30% fat meal; gastric volumes (fasting and post-300mL Ensure®) by SPECT; satiation [volume to fullness (VTF), maximum tolerated volume (MTV) and postprandial symptoms] with nutrient drink test (Ensure® 30kcal/min); and satiety by kcal intake at an ad libitum buffet meal. Statistical analysis examined effects of liraglutide compared to placebo using ANCOVA with the corresponding baseline measurement as a covariate. Results: There were 4 drop-outs, and complete data were available for 28 participants. All patients on liraglutide were taking 3mg/ day at the end of 12 weeks of therapy. Patients' demographic data, baseline gastric emptying T1/2, and effects on gastric motor functions, satiation and satiety parameters with treatments are shown in the table (mean+SEM). Conclusion: Liraglutide treatment at maximum escalated dose (3mg) for 12 weeks resulted in significant and persistent slowing of gastric emptying and reduced maximum tolerated volume relative to placebo. These results suggest an important role of gastric emptying in the beneficial effects of liraglutide on weight loss. Support: NIH RO1-DK67071
Su2031 HUMANIZATION OF A GASTRIC INHIBITORY POLYPEPTIDE (GIP)NEUTRALIZING MONOCLONAL ANTIBODY (MAB) AND WEIGHT REVERSAL IN DIET-INDUCED OBESE MICE M. Michael Wolfe, Michael O. Boylan, Raghav Sood, Alice A. Newman Background: We recently generated a specific mouse GIP mAb (mAbm) and reported significant prevention of weight gain without any effect on food intake. AIM: To determine whether this GIP mAbm could reverse weight gain in obese mice and to characterize a humanized GIP mAb (mAbh). Methods: Obesity was induced in C57BL/6 mice by feeding high-fat diet (HFD; 60% calories from fat) from weaning to 18 weeks. The mice were then fed a 45% HFD and administered the GIP mAbm (45 mg/kg BW) ip weekly for 6 wks. BW was recorded weekly, and HgA1c levels were measured after wk 6. The mAbm was "humanized" by grafting its complementary determining regions onto a human IgG "scaffold". Binding affinity was determined by surface plasmon resonance, and a reporter cell line expressing GIP receptors was used in a modified Schild's assay to demonstrate mAb-dependent GIP neutralization in vitro. Finally, the GIP mAbh (10 or 30 mg/kg BW) was administered to mice ip, and blood samples were collected over 2 wks, and the Cmax and T1/2 determined. In separate studies, mice fasted for 1 h were administered either 30 mg/kg BW mAbh or vehicle ip. The mice were then fasted for an additional 5 h before glucose (1.5 g/kg BW) was given by oral gavage, and blood was collected at 0 and 15 min; the protocol was repeated 1 and 2 wks later. Plasma insulin levels were measured by ELISA. Results: After 6 wks of GIP mAbm treatment, BW was reduced by 6.0±2.7%, while BW increased in control mice by 3.6±1.4% (P<0.002). The mean HgA1c levels for mAb-treated mice trended lower (4.4±0.2%), compared to control mice (4.8±2.7%, P=NS). The binding affinity (KD) of GIP for the mAbh was 0.9 nM, compared to the original mAbm KD of 3.3 nM. Similar to the mAbm, the mAbh neutralized GIP signaling in vitro in a concentration-dependent manner, and the Schild's assay showed mAbh and mAbm equilibrium dissociation constants of 2.2 µM and 3.2 µM, respectively, indicating similarly that mAbh binds more avidly to GIP than does mAbm. The plasma Cmax values for the 10 and 30 mg/kg BW doses of GIP mAbh were 10.1±0.7 µg/ml and 32.6±1.0 µg/ml, respectively. The GIP mAbh inhibited the15-min insulin responses to oral glucose at 5 h, 1 wk, and 2 wk after treatment by 47±21% (P=0.01), 45±21% (P=0.01), and 13.8±31%, respectively. Conclusion: Treatment of high-fat fed obese mice with the GIP mAb caused significant weight loss, which was accompanied by a trend toward improvement in HgA1c levels. The anti-GIP mAbh was shown to bind GIP with a higher affinity than the mAbm, and similarly it inhibits GIP signaling in vitro more potently than the original GIP mAbm. Furthermore, the calculated T1/2 for the GIP mAbh in vivo is comparable to other biological agents, indicating that a convenient bimonthly or once per month administration of the GIP mAbh might prove a tenable agent for treating obesity and related disorders in humans.
*p=0.046; **p=0.036
Su2030 Su2032
BAR130, A HYODEOXYCHOLIC ACID DERIVATIVE AS THE FIRST EXAMPLE OF DUAL LXRα/GPBAR1 AGONIST Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Angela Zampella, Simona De Martino, Stefano Fiorucci
A SINGLE-CENTER, RANDOMIZED, PLACEBO-CONTROLLED, 16-WEEK TRIAL OF EFFECTS OF LIRAGLUTIDE ON WEIGHT LOSS AND RELATIONSHIP TO CHANGE IN GASTRIC EMPTYING IN OBESE PATIENTS Hoda C. Kadouh, Matthew Clark, Sarah A. Kalsy, Karen M. Graszer, Karen Grothe, Houssam Halawi, Ibironke Oduyebo, Disha Khemani, Alfred D. Nelson, Deborah J. Eckert, Jessica O'Neill, Andres J. Acosta Cardenas, Alan R. Zinsmeister, Michael Camilleri
Background. The liver X receptors (LXRs), activated by oxysterol and by the secondary bile acid hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In the present study, we report the identification of a side chain modified HDCA (BAR130) that represents the first example of a potent dual LXRα/GPBAR1 agonist. Aim. To investigate in vitro and in vivo effects of BAR130 a dual GPBAR1/LXRα ligand. Material and methods. HepG2 and Glutag (a mouse counterpart of intestinal L cells) cells were exposed to GW3965 or TLCA (10 µM), HDCA (10 µM) along with increasing concentrations of BAR130 (1, 5, 10, 25, 50 µM); total RNA was isolated for rt-PCR. C57BL6 mice were administered with BAR130 (30 mg/Kg daily by gavage) or vehicle (distilled water) for 2 weeks. Mice were sacrificed and blood, liver and terminal ileum collected for plasma AST, cholesterol and tryglicerides measurement, liver histopathology analysis (H/E) and for evaluation of steatosis markers genes expression (rt-PCR). Results. BAR130 transactivates LXRα and GPBAR1 with an EC50 value of 3.2±0.03 and 4.9±0.2, respectively. When administered in vitro to HepG2 cells , BAR130 increases the expression of LXRα target genes, ABCA1 and SREBP1c, in a concentration-dependent manner with an EC50 of 8.3 µM and 5.8 µM respectively. BAR130 increases the expression of pro-glucagon mRNA (a GPBAR1 target gene) in GLUTAg cells with an EC50 of 6.5 µM. Treating mice with BAR130 did not increased AST, cholesterol and tryglicerides plasma levels (Figure). Further on, rtPCR analysis of liver samples demonstrated that the BAR130 did not induce the expression of lipidogenic genes including FAS, SREBP1C and CD36. The result was confirmed by Liver histology (H/E). BAR130 increased the expression of GPBAR1 target gene GLP1 in the ileum and reduced markers of inflammation in macrophages. Conclusions. This study shows the simultaneous activation of LXRα and GPBAR1 represents a promising approach to target metabolic disorders and ground the use of BAR130 in the setting of metabolic diseases.
AGA Abstracts
Background: Obesity is associated with accelerated gastric emptying (GE) and greater calories consumed to reach satiation or to evoke satiety with an ad libitum meal. A medication which could impact GE has the potential to assist with obesity management. One possible medication, exenatide, a short-acting GLP-1 receptor agonist, 5µg SQ BID for 30 days, has been shown to delay GE and induce weight loss (PMID 26542264). GE was delayed after 3 weeks' treatment with the longer acting GLP-1 agonist, liraglutide, escalated to 1.8mg/ day, but there was no difference after 24 weeks of treatment (PMID 26656289). The effect of liraglutide, 3mg/day, on GE and weight is unclear. Aim: To compare effects on weight loss of 16 weeks' treatment of dose-escalated liraglutide (up to 3mg/day) to placebo, and the relationship of weight loss to slowing of GE on treatment. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants; we used liraglutide dose escalation starting at 0.6mg/day and increasing by 0.6mg/day each week to reach a 3mg dose at week 5, followed by 3mg/day dose for the next 11 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. All participants underwent standardized health behavior counseling, nutrition education sessions (using LEARN manual), as well as structured follow-up visits, for a total of 17 visits to the Clinical Research Unit. In addition, GE of solids was measured over 4 hours, using a 315kcal, 33% fat meal, by means of scintigraphy at baseline and after 16 weeks of treatment. Statistical analysis examined effects of liraglutide compared to placebo on weight loss and on the relationship of weight loss with change (∆) in GE T1/2 of solids using Spearman correlation. Results: To date, 28 participants completed all studies, 4 dropped out, and 8 are currently on treatment. The ∆ in weight between baseline and week 16 of treatment is expressed as median (IQR), as data distribution was skewed (one placebo-treated participant lost 17.1kg). Other data are mean + SEM (Table). There was an inverse relationship between ∆ GE T1/2 and ∆ weight loss (Rs= -0.33, p=0.095), suggesting that the greater the retardation of GE, the greater the weight loss. Two patients underwent cholecystectomy during the study. Conclusions: Liraglutide (3mg/day over 12 weeks after standard weekly dose escalation of 0.6mg/day) results in significant weight loss compared to placebo. Greater retardation of GE is associated with greater weight loss, suggesting the hypothesis that liraglutide's effect on weight is mediated, in part, by retardation of GE. Support: NIH R01-DK67071
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