Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults.
ABSTRACT: Mechanisms for liraglutide-induced weight loss are poorly understood.We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.Participants (N=49, 18-75 years, body mass index: 30-40?kg?m(-2)) were randomized to two of three treatments: liraglutide 1.8?mg, 3.0?mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed.Five-hour gastric emptying (AUC(0-300?min)) was found to be equivalent for liraglutide 1.8 versus 3.0?mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80-1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0?mg (P=0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8?mg (P=0.14). Both liraglutide doses similarly reduced fasting glucose (0.5-0.6?mmol?l(-1) versus placebo, P<0.0001), glucose Cmax and 1-h AUC versus placebo; only liraglutide 3.0?mg reduced iAUC(0-300?min) (by ?26% versus placebo, P=0.02). Glucagon iAUC(0-300?min) decreased by ?30%, and iAUC(0-60?min) for insulin and C-peptide was ?20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ?16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393.Novo Nordisk.Gastric emptying AUC(0-300?min) was equivalent for liraglutide 1.8 and 3.0?mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0?mg and 13% with 1.8?mg versus placebo were observed. Liraglutide 3.0?mg improved postprandial glycemia to a greater extent than liraglutide 1.8?mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.
Project description:<h4>Introduction</h4>To evaluate the effects of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), on gastric emptying, glucose metabolism, and islet beta-cell function versus liraglutide and placebo in people with type 2 diabetes.<h4>Research design and methods</h4>This phase Ib study (ClinicalTrials.gov identifier: NCT02059564) randomized participants (n=47) to three cohorts. Within the first two cohorts, participants were randomized to placebo, efpeglenatide 6 mg weekly (QW; first cohort), or efpeglenatide 16 mg monthly (QM; second cohort). The third cohort received liraglutide 1.8 mg daily (QD). Gastric emptying was assessed through the pharmacokinetic (PK) profile of acetaminophen at baseline and steady state. Glucose metabolism and beta-cell function were assessed based on mixed-meal tolerance testing and a graded glucose infusion procedure.<h4>Results</h4>Treatment duration was approximately 3 months for efpeglenatide 16 mg QM and 1 month for efpeglenatide 6 mg QW and liraglutide. At peak drug concentrations, efpeglenatide 6 mg QW was non-inferior to liraglutide 1.8 mg QD in delaying gastric emptying, as assessed by acetaminophen PK (lower bound of 90% CI for the efpeglenatide:liraglutide ratio >0.8 for area under the curve (AUC)<sub>0-120</sub>, AUC<sub>0-180</sub>, AUC<sub>0-360</sub> and maximum concentration (C<sub>max</sub>)). Efpeglenatide 16 mg QM did not decrease the rate of gastric emptying to as great an extent as liraglutide (ie, non-inferiority was not shown). Compared with liraglutide, both efpeglenatide dosing regimens demonstrated comparable or more favorable glucometabolic effects and improved beta-cell function. All gastrointestinal adverse events reported with efpeglenatide were mild or moderate in severity and transient over treatment and follow-up.<h4>Conclusions</h4>The glucometabolic effects of efpeglenatide 6 mg QW and 16 mg QM were comparable to liraglutide. Additional studies are necessary to further examine these benefits of efpeglenatide.<h4>Trial registration number</h4>NCT02059564.
Project description:<h4>Aim</h4>To assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).<h4>Materials and methods</h4>In this randomized, double-blind, single-centre, crossover trial, subjects with T2D received once-daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12-week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat-rich) at the end of each treatment period. The primary endpoint was area under the glucose 0-5-h curve (AUC<sub>0-5h</sub> ) after the standard breakfast.<h4>Results</h4>Fifteen subjects were enrolled (mean age 58.2 years, HbA1c 6.9%, body weight 93.9 kg, diabetes duration 3.1 years; 13 [86.7%] males). Fasting concentrations of glucose were significantly lower, and C-peptide significantly greater, with oral semaglutide versus placebo. Postprandial glucose (AUC<sub>0-5h</sub> ) was significantly lower with oral semaglutide versus placebo (estimated treatment ratio, 0.71; 95% CI, 0.63, 0.81; p < .0001); glucose incremental AUC (iAUC<sub>0-5h/5h</sub> ) and glucagon AUC<sub>0-5h</sub> were also significantly reduced, with similar results after the fat-rich breakfast. Fasting concentrations of triglycerides, very low-density lipoprotein (VLDL) and apolipoprotein B48 (ApoB48) were significantly lower with oral semaglutide versus placebo. AUC<sub>0-8h</sub> for triglycerides, VLDL and ApoB48, and triglycerides iAUC<sub>0-8h/8h</sub> , were significantly reduced after oral semaglutide versus placebo. During the first postprandial hour, gastric emptying was delayed (a 31% decrease in paracetamol AUC<sub>0-1h</sub> ) with oral semaglutide versus placebo. One serious adverse event (acute myocardial infarction) occurred during oral semaglutide treatment.<h4>Conclusion</h4>Oral semaglutide significantly improved fasting and postprandial glucose and lipid metabolism, and delayed gastric emptying.
Project description:AIMS:Treatment with liraglutide 3.0 mg has been associated with gallbladder-related adverse events. To conduct a single-centre, double-blind, 12-week trial comparing the effect of 0.6?mg liraglutide and steady-state liraglutide 3.0?mg with placebo on gallbladder emptying in adults with body mass index (BMI) ?27?kg/m2 and without diabetes. METHODS:Participants were randomized 1:1 to once-daily subcutaneous liraglutide (n?=?26) or placebo (n?=?26), starting at 0.6?mg with 0.6-mg weekly increments to 3.0?mg, with nutritional and physical activity counselling. A 600-kcal (23.7?g fat) liquid meal test was performed at baseline, after the first dose and after 12?weeks. The primary endpoint was the 12-week maximum postprandial gallbladder ejection fraction (GBEFmax ), measured over 240?minutes after starting the meal. RESULTS:Baseline characteristics were similar between groups (mean?±?SD overall age 47.6?±?10.0?years, BMI 32.6?±3.4?kg/m2 , 50% women). Mean 12-week GBEFmax (treatment difference -3.7%, 95% confidence interval [CI] -13.1, 5.7) and area under the GBEF curve in the first 60?minutes (-390%?×?min, 95% CI -919, 140) did not differ for liraglutide 3.0?mg (n?=?23) vs placebo (n?=?24). The median (range) time to GBEFmax was 151 (11-240) minutes with liraglutide 3.0?mg and 77 (22-212) minutes with placebo. Similar findings were noted after the first 0.6-mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events. CONCLUSIONS:Treatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax .
Project description:BACKGROUND:Glucagon-like peptide-1 receptor agonists, such as liraglutide, reduce hyperglycaemia and induce weight loss and are used as a treatment in diabetes. However, common adverse effects include nausea, loss of appetite and prolonged gastric emptying. It is not known whether these changes are centrally generated or if liraglutide alters the enteric motility. OBJECTIVE:To investigate the effects of liraglutide on gastrointestinal function and symptoms. METHODS:A total of 48 adults with type 1 diabetes and confirmed distal symmetric polyneuropathy were randomised to receive liraglutide 1.8 mg/day or placebo for 26 weeks. Regional transit times and motility indexes were assessed with a wireless motility capsule, whereas symptoms were evaluated using the validated gastroparesis cardinal symptom index. RESULTS:Liraglutide treatment reduced large bowel transit time (31.7%, p?=?0.04) and decreased motility index (6.1%, p?=?0.04) compared to placebo, whereas the groups did not differ in gastric emptying or small-bowel transit times. Liraglutide increased postprandial fullness with 29% (p?=?0.01). Increased small bowel transit time was associated with decreased bloating (p?=?0.008). CONCLUSION:Liraglutide accelerates large bowel transit and decreases motility index, which may indicate better coordination of propulsive motility. This potentially improves the function of the enteric nervous system, leading to normalised colonic function and positive effects in type 1 diabetes.
Project description:OBJECTIVE:To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS:This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2). RESULTS:Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS:Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.
Project description:<h4>Background and objective</h4>Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short-term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single-meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide.<h4>Methods</h4>In this randomized, double-blind, placebo-controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24- and 48-h EI, weight, appetite scores, and gastric emptying measures.<h4>Results</h4>Sixty-one participants were randomized (<i>n</i> = 32, liraglutide; <i>n</i> = 29, placebo). The least squares mean (LSM) difference (95% CI; <i>p</i>-value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was -236 (-322, -149; <i>p</i> < 0.0001) kcal at week 3 and -244 (-339, -148, <i>p</i> < 0.0001) kcal at week 6. The liraglutide group experienced significant weight loss at weeks 3 and 6, compared with placebo. Weight loss was significantly correlated with EI, but not with appetite score or gastric emptying.<h4>Conclusions</h4>EI during a single meal is a robust clinical predictor of weight changes in participants with obesity. Future clinical trials can utilize EI at a single meal as a predictor of weight loss.
Project description:Abstract In this 56-week, randomized, double-blind, US-based multicenter trial (NCT02963935) we investigated the effects of liraglutide 3.0 mg vs placebo, as adjunct to intensive behavior therapy (IBT) (i.e. reduced calorie intake, increased physical activity [max target: 250 min/week], and 23 counseling sessions). Here we report the effects of treatment on weight change (co-primary endpoints: mean change in body weight [%] and proportion of individuals losing ?5%), glycemic variables, cardiometabolic risk factors, safety and tolerability. Individuals aged ?18 years with a body mass index (BMI) ?30 kg/m2 and without diabetes were randomized 1:1 to liraglutide 3.0 mg or placebo along with IBT. Continuous and categorical variables were calculated using analysis of covariance (ANCOVA) and logistic regression respectively, with treatment, gender and BMI as factors and baseline endpoint as a covariate. Missing values were handled using a jump-to-reference multiple imputation model. There were 282 individuals in the full analysis set; 142 were randomized to liraglutide 3.0 mg (45 y, 16% male, 109 kg, 39 kg/m2) and 140 to placebo (49 y, 17% male, 107 kg, 39 kg/m2); 99% and 93% completed the trial, respectively. The intention to treat analysis demonstrated weight loss at 56 weeks of 7.5% with liraglutide 3.0 mg and 4.0% with placebo (estimated treatment difference (ETD) [95% CI], 3.5% [5.3, 1.6]; p=0.0003). Weight loss in individuals on trial product at 56 weeks was 9.1% (n=114) and 4.8% (n=103), respectively. The proportion of individuals achieving ?5% weight loss was 61.5% with liraglutide 3.0 mg and 38.8% with placebo (estimated odds ratio (OR) 2.5 [1.5, 4.1], p=0.0003). The proportion who lost >10% was 30.5% and 19.8% (OR 1.8 [1.01, 3.1], p=0.0469), and >15% was 18.1% and 8.9% (OR 2.3 [1.1, 4.7], p=0.0311, respectively. Change in waist circumference was -9.4 cm with liraglutide 3.0 mg vs -6.7 cm with placebo (ETD -2.7 cm [-4.7, -0.8], p=0.006). Significant improvements at 56 weeks were seen for liraglutide 3.0 mg vs placebo in both HbA1c (ETD -0.10% [-0.16, -0.04], p=0.0008) and fasting plasma glucose (ETD ?0.23 mmol/L [-0.36, -0.11] p=0.0002). Blood pressure (BP) reductions were observed in both treatment arms at 56 weeks, but there were no significant differences between groups in systolic (ETD -2.2 mmHg [?4.9, 0.5], p=0.11) or diastolic BP (ETD -0.2 mmHg [?2.2, 1.8], p=0.87), or heart rate (ETD 1.3 bpm [-0.8, 3.4], p=0.23). Lipids were improved vs baseline but no significant differences between treatment arms were observed at 56 weeks (all p>0.05). Liraglutide 3.0 mg was generally well tolerated and no new safety signals were observed in this study. The most frequent adverse events were gastrointestinal (liraglutide 3.0 mg: 71%; placebo: 49%). In conclusion, liraglutide 3.0 mg as an adjunct to IBT resulted in significantly greater weight loss, as compared to IBT and placebo. Supported by Novo Nordisk.
Project description:<h4>Objective</h4>Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.<h4>Research design and methods</h4>Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ?2 oral antidiabetic drugs.<h4>Results</h4>Individuals were randomized to liraglutide 3.0 mg (<i>n</i> = 198) or placebo (<i>n</i> = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; <i>P</i> < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ?5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; <i>P</i> < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA<sub>1c</sub> and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed.<h4>Conclusions</h4>In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.
Project description:Liraglutide 3.0?mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect.To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight.A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058).After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40?kg?m(-2)) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0?mg), placebo or open-label orlistat (120?mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4?mg, and subsequently, to liraglutide 3.0?mg (based on 20-week and 1-year results, respectively).The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9±10.3 years, BMI 34.8±2.7?kg?m(-2) (mean±s.d.)). In year 1, more participants reported ?1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0?mg (17-38%) than with placebo or orlistat (both 4%, P?0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0?mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0?mg from randomization was 9.2?kg for participants reporting nausea/vomiting episodes, versus 6.3?kg for those with none (a treatment difference of 2.9?kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0?mg.Transient nausea and vomiting on treatment with liraglutide 3.0?mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.
Project description:OBJECTIVE:Previous studies have shown additive weight loss when intensive behavioral therapy (IBT) was combined with weight-loss medication. The present multisite study provides the first evaluation, in primary care, of the effect of the Centers for Medicare and Medicaid Services-based IBT benefit, delivered alone (with placebo) or in combination with liraglutide 3.0 mg. METHODS:The Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE) IBT was a 56-week, randomized, double-blind, placebo-controlled, multicenter trial in individuals with obesity who received liraglutide 3.0 mg (n?=?142) or placebo (n?=?140) as an adjunct to IBT. RESULTS:At week 56, mean weight loss with liraglutide 3.0 mg plus IBT was 7.5% and 4.0% with placebo combined with IBT (estimated treatment difference [95% CI]-3.4% [-5.3% to -1.6%], P?=?0.0003). Significantly more individuals on liraglutide 3.0 mg than placebo achieved ??5% weight loss (61.5% vs. 38.8%; odds ratio [OR] 2.5% [1.5% to 4.1%], P?=?0.0003), >?10% weight loss (30.5% vs. 19.8%; OR 1.8% [1.0% to 3.1%], P?=?0.0469), and >?15% weight loss (18.1% vs. 8.9%; OR 2.3% [1.1% to 4.7%], P?=?0.0311). Liraglutide 3.0 mg in combination with IBT was well tolerated, with no new safety signals identified. CONCLUSIONS:In a primary care setting, Centers for Medicare and Medicaid Services-based IBT produced clinically meaningful weight loss at 56 weeks, enhanced by the addition of liraglutide 3.0 mg.