The Efficacy of GLP-1 Analogues on Appetite Parameters, Gastric Emptying, Food Preference and Taste Among Adults with Obesity: Systematic Review of Randomized Controlled Trials

Figures & data

Table 1 PICOS Structure Used for Search Strategy

Acronym	Definition	Description
P	Population	Adults with obesity without any other medical diseases.
I	Intervention	GLP-1 analogues.
C	Comparison	Placebo or any other intervention.
O	Outcome	Alteration on appetite, gastric emptying, food preferences, and/or taste.
T	Time	Any time and any duration.
S	Study design	RCTs.

Abbreviations: GLP-1, Glucagon-like Peptide-1; RCTs, Randomized clinical trials.

Table 2 Characteristics of the Population in This Systematic Review

Characteristic	Comments
Design	RCTs
Sample sizes	445 participants.
Gender	Female and male
Age	18 −75 years old.
Health status	Adults with obesity without any other medical diseases.
Interventions	GLP-1 analogues, (5 studies used GLP-1 infusion, 4 studies used Liraglutide, and 3 studies used Semaglutide).
Comparisons	Placebo, GIP, GIP+GLP-1, or IBT.
Duration	5 days – 52 weeks.
Outcome	Appetite, gastric emptying, food preferences, and taste.
Location	United State, Netherlands, Sweden, Denmark, United Kingdom, and Germany.

Abbreviations: RCTs, Randomized Controlled Trials; GLP-1, Glucagon-Like Peptide-1; GIP, Glucose-dependent Insulinotropic Polypeptide; IBT, Intensive Behavioral Therapy.

Table 3 Characteristics for All RCTs Studies Included in This Systematic Review

	Author	Country	Study Design	Number of Participants	Age	Intervention	Type of GLP-1	Placebo	Duration	Outcomes	Statistical Significance	Tool
GLP-1 (Liraglutide)
1	Saxena et al | 2021^Citation24	United State	RCT, double-blind, two-arm, parallel-group.	56 adults with obesity (28, 26).	18–75 years old.	Liraglutide (Saxenda^®, initiated at a dose of 0.6 mg/day and escalated by 0.6 mg/week up to a maximum of 3.0 mg/day).	Liraglutide	Placebo (0.9% w/v sodium chloride).	6 weeks	Appetite and gastric emptying.	Appetite: significant differences in appetite (indicating decreased appetite) at weeks 3 and 6, in prospective food consumption in 30-min postprandial at weeks 3 and 6, and for hunger at week 3 only. Gastric emptying: Liraglutide caused a significant delay in gastric emptying when administered over six weeks. There was a statistically significant difference between the groups at week 6 (1 hour, p = 0.0348; 5 hours, p = 0.0152).		100-m VAS + acetaminophen absorption.
2	Kadouh et al | 2020^Citation17	United States	Single-center, double-blind, parallel group, RCT.	35 adults with obesity, in 2 groups (17, 18).	18–65 years old.	Liraglutide 3.0mg (escalated by 0.6 mg per week to a maintenance dose of 3.0 mg SQ daily).	Liraglutide	Placebo. No mention regarding the type of placebo.	16 weeks.	Appetite and taste.	Appetite: Liraglutide group was reported more fullness (P = 0.02) and lower prospective food consumption (P = 0.03) compared to baseline. Taste: Liraglutide resulted in a significantly less desire for sweet, salty, fatty, and savory foods with (p < 0.05) when compared to placebo.		Standardized nutrient drink test +100-m VAS.
3	Tronieri et al | 2020^Citation25	United States	Single-site, open-label, parallel-group RCT.	113 adults with obesity, in 3 groups (36,37,40).	21–70 years old.	3 groups: - 1- IBT-alone. 2- IBT- Liraglutide: IBT intervention combined with once daily subcutaneous injections of Liraglutide 3.0mg/day (Dosing started at 0.6 mg per day and increased by weekly 0.6 mg increments). 3- Multi-component: IBT intervention combined with once daily subcutaneous injections of Liraglutide 3.0mg/day (Dosing started at 0.6 mg per day and increased by weekly 0.6 mg increments), combined with the prescription at week 4 of a 12-week, 1000–1200 kcal/day meal replacement diet (this diet included four daily servings of a liquid shake (Health Management Resources–HMR; 160 kcal/shake), a prepackaged entrée (250–300 kcal), 1–2 servings of fruit, and a salad).	Liraglutide.	No placebo.	52 weeks	Appetite.	Appetite: compared to IBT-alone, IBT- Liraglutide participants reported larger reductions at week 6 in hunger (, p = 0.005) and food preoccupation (p = 0.002) and larger increases in fullness (p = 0.001). Significant differences in appetite persisted for 24 weeks but were not maintained at week 52. IBT- Liraglutide participants reported greater improvements in hunger, fullness, and food preoccupation than those assigned to IBT-alone.		100-m VAS.
4	Van Can et al | 2014^Citation26	Netherlands.	Single-center, RCT, double-blind, two-period incomplete crossover trial.	49 adults with obesity.	18–75 years old.	3 groups: - 1- Liraglutide 1.8 mg. 2- Liraglutide 3.0 mg 3- Placebo were administered once daily by evening subcutaneous injections.	Liraglutide.	Placebo. No mention regarding the type of placebo.	2 treatment periods, each consisting of 5 weeks at home plus a subsequent 2-day stay in the clinic, with 6–8 weeks washout period.	Gastric emptying and appetite.	Appetite: all Liraglutide doses showed similar effects on appetite, increased satiety and fullness, and decreased hunger. Overall appetite score (indicating reduced appetite), satiety, fullness and ‘100-prospective food consumption’ were statistically significantly and similarly increased with Liraglutide 1.8 and 3.0 mg groups compared with placebo group Gastric emptying: significant difference between the Liraglutide 3.0 mg group and the placebo group after 1 hour. The Liraglutide 3.0 mg group was lower by 23% of gastric emptying than the placebo with (P = 0.007), but there was no significant difference between the placebo group with the Liraglutide 1.8 mg group gastric emptying was lower 13% only (P = 0.14).		100-m VAS + acetaminophen absorption.
GLP-1 (infusion)
5	Näslund et al | 1998^Citation27	Sweden	RCT, double-blind fashion on 2 occasions 5 d apart.	6 males with obesity.	Mean age 34.7 years old.	GLP-1 infusion (0.75 pmol kgU1 minU1).	GLP-1 (0.75 pmol GLP-1 · kg-1 · min-1;)	Normal saline (9 g/L)	2 occasions, 5 days apart.	Appetite, gastric emptying, and food Preferences.	Appetite: hunger and prospective consumption of food were significantly lower (P = 0.03, P = 0.04, respectively) with GLP-1 than with placebo (saline infusion). In contrast, feelings of fullness were not significantly different between GLP-1 infusion and placebo (saline infusion) (P = 0.4). Gastric emptying: was significantly slower during GLP-1 infusion (P = 0.0001) Food Preferences: no significant difference between the GLP-1 analogous (GLP-1 infusion) group and the placebo group in the proportion of food selected as carbohydrate, protein, fat, or low energy from the food-choice list (data not shown). Also, no significant difference in the ratio of high-carbohydrate to high-protein items selected between the GLP-1 analogous (GLP-1 infusion) group and the placebo group (P = 0.7). There was a significant difference in the number of items selected from the food-choice list. It was significantly lower in the GLP-1 analogous (GLP-1 infusion) group than in the placebo group immediately after food intake and four hours after intake (P = 0.03).	100-m VAS + acetaminophen absorption+ The forced-choice list
6	Näslund et al | 1999^Citation28	Sweden	RCT, double-blind, cross-over fashion on 2 occasions, 1 week apart.	8 males with obesity.	Mean 35 years old.	GLP-1 infusion (0.75 pmol /kg/ min) dissolved in 0.9% saline containing 1% albumin (Albumin Kabi 200mgaml)	Intravenous infusion of GLP-1.	Normal saline.	2 occasions, 1 week apart.	Appetite, and gastric emptying.	Appetite: GLP-1 infusion during the period between breakfast and lunch and between lunch and dinner decreased the ratings of hunger (P`0.05; P = 0.01 respectively) and prospective consumption (P ` 0.05; P = 0.07 respectively) and fullness (P ` 0.05; P = 0.09 respectively). Gastric emptying: was significantly slower during GLP-1 infusion (P = 0.0001)	100-m VAS + paracetamol absorption
7	Flint et al | 2001^Citation16	Denmark	RCT, single-blinded, cross-over study.	18 males with obesity (9,9).	21–57 years old.	GLP-1 infusion (0.75 pmol kg-1 min-1).	GLP-1 infusion.	Normal saline.	Two test days were separated by at least 3 weeks and by no more than 8 weeks.	Appetite, gastric emptying and palatability	Appetite: decreased the ratings of hunger and prospective food consumption decreased in the GLP-1 infusion compared with saline (P ` 0.05). Gastric emptying: was significantly slower during GLP-1 infusion (P = 0.0001) No differences were seen in palatability ratings (appearance, smell, taste, after taste and overall palatability) of the breakfast, whereas the appearance of the lunch was found to be more attractive during the GLP-1 infusion (P < 0.05).	100-m VAS + paracetamol absorption.
8	Näslund et al | 2004^Citation20	Sweden	RCT, cross-over, double-blind.	17 adults with obesity.	18–65 years old.	GLP-1 infusion (45 to 75 pmol/kg per h). Two methods of administration for each GLP-1 and Placebo: prandial subcutaneous injections (PSI) and continuous subcutaneous infusion (CSI).	GLP-1 infusion.	Normal saline.	5 days for each intervention with a wash-out period of 9 d in between.	Appetite, and gastric emptying.	Appetite: group PSI reported increased satiety ratings compared with the placebo group after day one (P=0·03), but after day five, they did not find significant differences in satiety. Group CSI has no effects on satiety and hunger. Gastric emptying: gastric emptying rate was reduced during both PSI (P,0·001) and CSI (P,0·05) treatment. However, it was more effective and faster with the PSI of GLP-1.	100-m VAS + paracetamol absorption.
9	Bergmann et al | 2019.^Citation29	Denmark	RCT, double-blind, crossover study.	17 males with obesity/overweight.	25–70 years old.	Four groups: 1. IIGI+ GIP (4 pmol kg−1 min−1). 2. IIGI+ GLP-1 (1 pmol kg−1 min−1). 3. IIGI+ GIP+ GLP-1 (4 and 1 pmol kg−1 min−1). 4. IIGI+ saline.	GLP-1 infusion	Normal saline (154 mmol/l NaCl).	5 days.	Appetite.	No significant differences among the interventions were observed for the appetite profile at the beginning of the study. But at the end of the study, hunger and prospective food consumption were significantly lower (P= 0.031, P= 0.028 respectively) in the groups that used GLP-1 infusion as part of the intervention than the placebo group.	100-m VAS.
GLP-1 (Semaglutide)
10	Blundell et al | 2017^Citation18	United Kingdom	RCT, double‐blind, 2‐period crossover trial.	28 adults with obesity.	≥18 years old.	Semaglutide (1.34 mg/mL) once weekly.	Semaglutide	Placebo. No mention regarding the type of placebo.	12 weeks. a wash-out period of 5–7 weeks	Appetite and food preferences.	Appetite: the overall appetite suppression score indicates decreases in appetite (P = 0.0023). Food references: the study evaluated the effect of Semaglutide on hedonics (food preferences and cravings), indicating a lower liking for high-fat and non-sweet foods (P=0.0016).^Citation25 In addition to lower ratings of wanting high-fat and non-sweet foods (P=0.0203) compared to placebo	100-m VAS + validated 16-item short form CoEQ. + LFPQ
11	Hjerpsted et al | 2018^Citation22	United Kingdom	RCT, double-blind, 2-period, crossover trial.	28 adults with obesity.	≥18 years old.	Semaglutide subcutaneously once weekly. The starting dose was 0.25mg (4 weeks), escalating to 0.5 mg (4 weeks) and thereafter to 1.0 mg (4 weeks).	Semaglutide	Placebo. No mention regarding the type of placebo.	12-week treatment period. The 2 treatment periods were separated by a washout period of 5 to 7 weeks.	Gastric emptying.	Gastric emptying: There was no significant difference between treatments for the overall postprandial gastric emptying [95% CI: 0.88; P=1.01]) Overall gastric emptying was not statistically different between treatments. Semaglutide group was 27% lower gastric emptying during the first hour than the placebo (P = 0.0012). However, there was no significant difference between treatments for overall postprandial gastric emptying (P = 1.01).	Paracetamol concentration
12	Friedrichsen et al | 2021^Citation23	Germany	RCT, single‐center, double‐blind, parallel‐group.	72 adults with obesity (36,36).	18–65 years old.	Subcutaneous Semaglutide (dose-escalated to 2.4 mg/week).	Semaglutide	Placebo. No mention regarding the type of placebo.	20 weeks.	Appetite, gastric emptying, and food preferences.	Appetite: the overall postprandial appetite suppression score with the Semaglutide group (p = 0.001). Increases in fullness and satiety and decreases in hunger and prospective food consumption with the Semaglutide group compared to the placebo (P <0.02). Gastric emptying: subcutaneous Semaglutide (dose-escalated to 2.4 mg/week) for 20 weeks. No differences were found between Semaglutide and placebo (P = 0.8474) Food reference: significantly less craving for sweet, savory, and dairy products after 20 weeks of Semaglutide intervention compared to placebo (P <0.05)	100-m VAS + paracetamol absorption + CoEQ

Abbreviations: RCT, Randomized Clinical Trial; VAS, Visual Analog Scale; IBT, Intensive Behavioral Therapy; GLP-1, Glucagon-Like Peptide-1; PSI, Prandial Subcutaneous Injections; CSI, Continuous Subcutaneous Infusion; rGLP-1, recombinant glucagon-like peptide-1; OGTT, oral glucose tolerance test; IIGI, Isoglycaemiciv. Glucose Infusion; GIP, Glucose-dependent Insulinotropic Polypeptide; CoEQ, Control of Eating Questionnaire; LFPQ, Leeds Food Preference Questionnaire; mg, Milligram; pmol, Picomoles Per Liter; kg, Kilogram; min, Minute; w/v, weight in volume; GI, Gastrointestinal; CNS, Central Nervous System; VAS, Visual Analogues Scale; PRISMA, Preferred Reporting Items for Systematic Reviews And Meta-Analyses; PICOTS, Population, Intervention, Comparison, Outcome, Time, and Study design; RCTs, Randomized Clinical Trials; DOI, Digital Object Identifier; MRI, Magnetic Resonance Imaging; RYGB, Roux-en-Y gastric bypass; VSG, Vertical sleeve gastrectomy; fMRI, functional MRI.

Figure 1 PRISMA flow diagram for the study.

Notes: PRISMA figure adapted from Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160. Creative Commons.³⁰

Figure 2 Summary of risk of bias for all included studies.

Figure 3 Risk of bias graph for all included studies.

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