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Background: Weight loss decreases energy expenditure and increases appetite, leading to weight regain. Energy expenditure can be targeted with exercise, and appetite with the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide.The objective was to investigate 1-year weight loss maintenance and change in body composition with liraglutide, exercise, and the combination in individuals with obesity after a very low-calorie diet (VLCD). Methods: Double-blinded, randomized placebo-controlled trial. Following 8-weeks of VLCD (800 kcal/day), inducing a body weight loss of ≥ 5%, the participants were randomized to 1-year of treatment with 1) liraglutide 3.0 mg/day (LIRA), 2) exercise 150 min/week + placebo (EX), 3) exercise 150 min/week + liraglutide 3.0 mg/day (LIRA + EX), or 4) placebo (PLA). Results: Participants with obesity were included (n = 215, 64% women, age 42 years (IQR 30.7 to 51.9), BMI 36.6 kg/m2 (34.5 to 39.2)). See Table 1 for all results. Conclusion: The combination of liraglutide and exercise was superior to placebo and exercise alone, and numerically better to liraglutide, in weight loss maintenance and further weight reduction. Fat percentage loss with the combination treatment was superior to liraglutide and exercise alone, supporting the combined treatment for healthy weight loss maintenance. Disclosure: C. Janus: Research Support; Spouse/Partner; Mercodia, Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Research Support; Spouse/Partner; Novo Nordisk Foundation. Speaker's Bureau; Spouse/Partner; Merck Sharp & Dohme Corp. J.R. Lundgren: None. S. Jensen: None. L.M. Olsen: None. C. Juhl: None. M.B. Blond: None. R.M. Christensen: None. K.N. Bojsen-Moller: None. M.S. Svane: None. T. Bandholm: Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J.B. Jensen: None. B. Stallknecht: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.S. Torekov: Research Support; Self; Novo Nordisk Inc. Funding: Novo Nordisk Foundation (NNF16OC0019968); Novo Nordisk Center for Metabolic Research; Helsefonden [ABSTRACT FROM AUTHOR]

Background: Altered meal-associated secretion of gut peptides is key for the metabolic changes and weight-loss observed after Roux-en-Y gastric bypass (RYGB). Parenteral administration of the gut peptide neurotensin (NT) reduces food intake in rodents, and, like glucagon-like peptide-1 and peptide YY, the secretion of NT is markedly increased after RYGB. We therefore investigated the effect of intravenous (IV) NT on ad libitum food intake and appetite sensations. Design: Using a double-blinded, randomized placebo-controlled design, NT (2.5pmol/kg/min) or saline was infused IV in healthy young men to obtain NT concentrations similar to NT levels observed postprandially after RYGB. Four visits were performed in random order, after an acclimatization visit, to evaluate the main outcomes - ad libitum food intake and appetite sensations (visual analogue scale (VAS) questionnaires). Blood samples were collected for plasma and serum analyses (including entero-pancreatic peptides and glucose). NT or saline was infused after a basal period (t= -60 to 0 min). On two study days (n=18), an ad libitum meal was served after one hour of infusion (t= 60 min) followed by blood sampling/VAS until t= 120 min (infusion discontinued). On two other study days (n=16), a liquid mixed meal was ingested after one hour of infusion (t = 60 min) followed by blood sampling and VAS until an ad libitum meal was served at t= 240 min (infusion discontinued at t=270min). Results: Food intake was similar on the ad libitum meal (t = 60 min) days - NT (4150 (3607-4696)kJ, mean (95% confidence interval) vs. saline (3820 (3250-4405) kJ, P=0.062 (paired t-test)) and on the LMM + ad libitum meal (t= 240 min) days - NT (4320 (3698-5008)kJ vs. saline (4250 (3739-4870)kJ, P=0.80). NT infusions did not influence appetite sensations or elicit gastrointestinal side effects. Conclusions: Despite obtaining NT concentrations similar to what is observed postprandially after RYGB, we did not observe any differences in appetite sensations or food intake. Disclosure: S. Veedfald: None. C. Martinussen: None. M.S. Svane: None. T. Justinussen: None. M.G. Hindsø: None. N. Hedbäck: None. C.B. Christiansen: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. K.N. Bojsen-Moller: None. B. Hartmann: None. M. Fenger: None. J.F. Rehfeld: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. Funding: Desirée og Niels Ydes Fond; Læge Sophus og hustru Olga Friis Legat; Beckett Fonden; Hørslev Fonden; Aase og Ejnar Danielsens Fond; Fabrikant Frands Køhler Nielsen og hustrus legat; Carl og Ellen Hertz' Legat [ABSTRACT FROM AUTHOR]

Plasma concentrations of the two pancreatic enzymes, amylase and lipase, are increased within the normal physiological range after initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment. An association between the use of GLR-1RA and incidence of acute pancreatitis or pancreatic cancer has not been found - neither in rodent studies nor in preclinical studies or in the large cardiovascular outcome trials with GLP-1RAs. The increased concentrations of pancreatic enzymes have been suggested to be explained by increased DNA or protein synthesis found in rodent and acinar cell studies. However, whether this translates into humans is unknown. We therefore investigated the effect of liraglutide, a GLP-1RA, on pancreatic volume, edema and DNA synthesis reflected by 18F-flourothymidine (FLT)-uptake using state-of-the-art positron emission tomography (PET)-magnetic resonance imaging (MRI) before initiation, after four weeks during titration of liraglutide and after six weeks during steady state on maximum dose of liraglutide 3.0 mg in 14 obese men (age 38 ± 3 years, BMI 32 ± 1 kg/m2) without diabetes. Plasma concentrations of amylase and lipase were assessed in parallel. Amylase (+7 U/L [95% confidence intervals, 3 - 11] p<0.01) and lipase (+19 U/L [7-30] p<0.01) increased during liraglutide treatment while body weight decreased (-4.5 kg [-5,9 - -3,1] p<0.01). Pancreatic volume did not change from baseline to steady state of treatment (+2.1 cm3 [-10 - 14] p=0.72]) and no signs of change in cellular infiltration of the pancreas were found (p=0.22). During titration of liraglutide, FLT-uptake increased (+0.09 g/mL [0.000 - 0.17], p=0.05). In conclusion, six weeks of treatment with liraglutide did not affect pancreatic volume, edema or cellularity in obese individuals. Increased DNA synthesis reflected by FLT-uptake in the pancreas seen after four weeks of liraglutide treatment may be responsible for the increase in pancreatic enzymes. Disclosure: M.S. Svane: None. H.H. Johannesen: None. C. Martinussen: None. K.N. Bojsen-Moller: None. M.L. Hansen: None. A.E. Hansen: None. C.F. Deacon: Employee; Spouse/Partner; Merck & Co., Inc. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S. B. Hartmann: None. S.H. Keller: None. T.L. Klausen: None. A. Loft: None. A. Kjaer: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.O. Löfgren: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. [ABSTRACT FROM AUTHOR]

Roux-en-Y gastric bypass (RYGB) induces large and sustained weight loss in most patients. However, a minority of patients (5-10%) never obtain a successful weight loss after RYGB. The aim of this study was to characterize the role of gut hormones for appetite regulation in patients with primary weight loss (WL) failure defined as maximal excess BMI loss (EBLmax= ΔBMIpreoperative-postoperative/ΔBMIpreoperative-25) <50% compared with patients with successful WL (EBLmax >60%) after RYGB. Twenty women with primary WL failure (EBL 24% [9;27], median [IQR]) were matched to 20 women with successful WL (EBL 74% [70;83]) on age (51±9 vs. 51±9 years, mean ± sd), preoperative BMI (43.1±4.0 vs. 43.0±3.6 kg/m2) and time from RYGB (4.8±2.0 vs. 4.8±1.4 years). On separate days, a patient blinded subcutaneous injection of the somatostatin analogue Octreotide (Oct) 1 µg/kg bodyweight (max 100 µg) or saline (placebo) was given in randomized order followed by a mixed meal test at T=30 min and an ad libitum meal with measurement of food intake at T=270 min. The WL failure group had similar GLP-1 (tAUC, median [IQR], 4039 [3336;6018] vs. 4669 [3006;5891] pM·min, p=0.30) and PYY secretion (tAUC, 1935 [1493;2783], 1778 [1163;2756] pM·min, p=0.65) on the placebo day compared with the successful WL group. Injection of Oct diminished GLP-1 and PYY secretion in both groups. Oct had no effect on ad libitum food intake in the WL failure group (-0.5% [-13, 12], mean [95% CI]), while food intake was increased after Oct in the successful WL group (+23% [1.6, 44]) (ANOVA Group x Oct p=0.04). In conclusion, primary WL failure after RYGB was not explained by lower secretion of GLP-1 or PYY. However, inhibition of hormone secretion with octreotide increased food intake only in patients with successful WL, whereas the effect was absent in patients with primary WL failure. These results support that an impaired gut-hormone mediated suppression of appetite could contribute to primary weight loss failure after RYGB. Disclosure: K.N. Bojsen-Moller: None. M.S. Svane: None. C. Martinussen: None. C. Dirksen: None. N.B. Jørgensen: Stock/Shareholder; Self; Novo Nordisk A/S. V. Kristiansen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. Funding: Danish Council for Independent Research [ABSTRACT FROM AUTHOR]

Postprandial GLP-1 secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB) and seems important for the reduced food intake and improved insulin secretion postoperatively. Understanding the mechanisms of gut hormone release after RYGB could aid the discovery of new drugs for the treatment of diabetes and obesity. Glucose is particularly potent for stimulating the release of GLP-1 as well as GIP compared with protein and fat in RYGB operated patients. It is unclear how glucose triggers gut hormone secretion in humans, but animal studies suggest a crucial role of sodium-glucose transporter 1 (SGLT1). Our aim was to investigate secretion of GLP-1 and GIP in response to an oral glucose load (50 g) on two separate days with or without acute pretreatment of 600 mg of the dual SGLT1/SGLT2 inhibitor canagliflozin (CANA) in 10 RYGB operated patients with no history of diabetes (age 47 ± 5 years, BMI 36 ± 7 kg/m2, HbA1c 35 ± 4 mmol/mol, time from surgery 6 ± 1 years, mean ± SD). CANA lowered peak glucose (11.8 vs. 8.4 mmol/l, p<0.01) and tended to decrease glucose concentrations during the 4-hour test period (AUC placebo: 1453, CANA: 1343 min mmol/l, p=0.08). CANA inhibited the early rise in GLP-1 secretion with a 28% reduction in peak concentration (p=0.03, 95% CI [-46%, -2.9%]), but a prolonged secretion was seen at later timepoints and overall GLP-1 secretion was comparable (AUC above basal 6067 vs. 7273 min pmol/l, p=0.23). GIP secretion was diminished by CANA (peak by 57%, p>0.01, and AUC above basal by 28%, p=0.01, respectively). In addition, CANA reduced the postprandial rise in lactate concentrations and pulse rate and caused marked glucosuria (0.2 vs. 11 g). SGLT1/2 inhibition by canagliflozin during glucose ingestion reduced glycemic excursions and diminished early release of GLP-1 and GIP in RYGB operated patients. The results support that glucose absorption via SGLT1 is important for incretin hormone secretion after gastric bypass. Disclosure: C. Martinussen: None. S. Veedfald: None. K.N. Bojsen-Moller: None. C. Dirksen: None. M.S. Svane: None. V. Kristiansen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. Funding: European Union Horizon 2020 Research and Innovation Program (695069-Bypass Without Surgery); Danish Diabetes Academy; Novo Nordisk Foundation (NNF15OC0017188); Research Foundation for Health Research of the Capital Region of Denmark; Hvidovre Hospital [ABSTRACT FROM AUTHOR]

Enhanced glucagon-like peptide-1 (GLP-1) secretion is important for improved glycemic control after Roux-en-Y gastric bypass (RYGB) and higher concentrations of circulating bile acids (BA) have been suggested to be involved. The BA chenodeoxycholic acid (CDCA) stimulates GLP-1 secretion after RYGB in the absence of nutrients. In this study we investigated the effects of oral intake of CDCA or the BA sequestrant colesevelam (COL) on postprandial GLP-1 secretion in RYGB operated subjects. We hypothesized that CDCA would increase secretion and that COL would decrease secretion by reducing re-absorption of endogenous BA. Twelve participants (BMI 31±2 (mean±SEM) kg/m2, age 43±3 years, time from RYGB 4.3±0.5 years, weight loss after RYGB 34±5 kg) were studied in a single-blinded, randomised study with four experimental days: 1) A mixed meal consisting of solid/semisolid components (1523 kJ, 53E% carb, 33E% fat, 14E% prot) 2) Mixed meal added 1250 mg CDCA 3) Mixed meal added COL 3750 mg 4) Mixed meal with COL administered both as 3750 mg tablets the evening before the experiment and as 3750 mg added to the meal. Oral intake of CDCA increased GLP-1 significantly compared with mixed meal alone (p=0.03), whereas neither single (p=0.74) nor double (p=0.28) dosage of COL affected GLP-1 secretion (Incremental AUC (iAUC) GLP-1: Meal: 2792±288 pmol x min, CDCA: 4362±618, COL: 2703±330, COLx2: 3328±380). Plasma glucose and C-peptide (iAUC) decreased after CDCA but both were unchanged after COL administration vs. meal alone. Beta-cell function (AUC C-peptide/AUC plasma glucose) was equal between all study days. In summary, administration of the exogenous BA CDCA potentiated mixed-meal stimulated GLP-1 secretion after RYGB but did not affect beta-cell function. Administration of the BA sequestrant COL did not affect GLP-1 secretion, glucose concentrations or beta-cell function, suggesting a limited role for endogenous BA for regulation of postprandial glucose metabolism after RYGB. Disclosure: M.S. Svane: None. I. Jonsson: None. V. Kristiansen: None. R.E. Kuhre: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. K.N. Bojsen-Moller: None. Funding: European Research Council (695069) [ABSTRACT FROM AUTHOR]

Background: Weight regain after weight loss is a major problem in the treatment of persons with obesity.Methods: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.Results: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group.Conclusions: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.). [ABSTRACT FROM AUTHOR]