Glucagon-like peptide-1 receptor agonists: Evolution, gastrointestinal adverse effects, and future directions

Table 1 Glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists	Injection frequency	Manufacturer	Approval year	Dosage concerns in hepatic patients	Dosage concerns in renal patients
Short-acting agonists
Exenatide	Twice daily	AstraZeneca	2011	Safe	Avoid if eGFR less than 30 mL/minute/1.73 m2
Lixisenatide1	Once daily	Sanofi	2013	Safe	Avoid if eGFR less than 15 mL/minute/1.73 m2
Long-acting agonists
Liraglutide	Once daily	Novo nordisk	2009	Safe	Safe
Exenatide extended-release	Once weekly	AstraZeneca	2017	Safe	Avoid if eGFR less than 45 mL/minute/1.73 m2
Semaglutide	Once weekly	Novo nordisk	2017	Safe	Safe
Dulaglutide	Once weekly	Eli lilly	2014	Safe	Safe
Albiglutide	Once weekly	Glycogen synthase kinase	2014	Safe	Safe
Tirzepatide	Once weekly	Eli lilly	2023	Safe	Safe

¹Sanofi discontinued lixisenatide from the United States market in 2023 for business reasons.

EGFR: Estimated glomerular filtration rate.

Table 2 Glucagon-like peptide-1 receptor agonists: Generic and trade names, indications, and regimen

Generic name	Trade name	Indications				Regimen
		Type 2 diabetes mellitus		Obesity	Major adverse cardiovascular events reduction
		Adults	Pediatrics ≥ 10 years
Exenatide1	Bydureon®	Yes	Yes	Yes		2 mg, s.c./week
	Byetta®	Yes		Yes		0.01 mg s.c. twice a day
Liraglutide	Victoza®	Yes	Yes		Yes	1.2 mg, 1.8 mg s.c. QD
	Saxenda®			Yes	Yes	3 mg, s.c. QD
Semaglutide	Ozempic®	Yes			Yes	0.5 mg, 1.0 mg, 2.0 mg, s.c./week
	Rybelsus®	Yes			Yes	7 mg, 14 mg, oral QD
	Wegovy®			Yes	Yes	2.4 mg s.c./week
Lixisenatide2	Lyxumia®	Yes				0.02 mg s.c. QD
Dulaglutide	Trulicity®	Yes			Yes	0.75 mg (monotherapy), 1.5 mg (add-on therapy) s.c./week
Tirzepatide3	Zepbound®	Yes		Yes		2.5 mg, 5 mg, 10 mg, 15 mg, s.c./week

¹The anti-obesity use of exenatide is an off label.

²Lixisenatide went off-market in 2023 for business reasons.

³Tirzepatide is dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists.

Major adverse cardiovascular events (i.e., non-fatal myocardial infarction or non-fatal stroke, cardiovascular mortality). QD: Once a day; S.c.: Subcutaneous.

Table 3 Summary of selected studies investigating the effect of glucagon-like peptide-1 receptor agonists on weight loss

Ref.	Design	Regimen	Number of participants	Number of centers	Duration (weeks)	BMI (kg/m2)	Glycated hemoglobin	Results and NNT for ≥ 5% weight loss	Conclusion
Garvey et al[67]	Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of tirzepatide once weekly for chronic weight management in adults with a BMI of 27 kg/m2 of higher who have T2DM	Tirzepatide (10 mg/week, or 15 mg/week)	938	77	72	36	8%	Change in body weight: Tirzepatide 10 mg: 12.8% (-12.9 kg); tirzepatide 15 mg: 14.7% (-14.8 kg); placebo: 3.2% (-3.2 kg). Percentage of patients that lost at least 5% of body weight: Tirzepatide 10 mg: 79%; tirzepatide 15 mg: 83%; placebo: 32%. NNT for achieving ≥ 5% weight loss: Tirzepatide 10 mg vs placebo: 3; tirzepatide 15 mg vs placebo: 2	Tirzepatide 10 mg, or 15 mg once weekly provided substantial and clinically meaningful reductions in body weight over 72 weeks in adults with obesity and T2DM, with a safety profile that was similar to other incretin-based therapies for weight management
Jastreboff et al[68]	A 72-week, phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of tirzepatide in adults without T2DM who were obese (BMI 30 kg/m2 or greater) or overweight (BMI 27 to less than 30 kg/m2) with at least 1 weight-related comorbid condition	Tirzepatide (5 mg/week, 10 mg/week, or 15 mg/week)	2539	119	72	38	5.6%	Change in body weight: Tirzepatide 5 mg: 15% (95%CI: -15.9 to -14.2); tirzepatide 10 mg: 19.5% (95%CI: -20.4 to -18.5); tirzepatide 15 mg: 20.9% (95%CI: -21.8 to -19.9); placebo: 3.1% (95%CI: -4.3 to -1.9). Percentage of patients that lost at least 5% of body weight: Tirzepatide 5 mg: 85% (95%CI: 82-89); tirzepatide 10 mg: 89% (95%CI: 86-92); tirzepatide 15 mg: 91% (95%CI: 88-94); placebo: 35% (95%CI: 30-39). NNT for achieving ≥ 5% weight loss: Tirzepatide 5 mg, 10 mg, 15 mg: 2	Tirzepatide 5 mg, 10 mg, or 15 mg once weekly provided substantial reductions in body weight over 72 weeks in adults with obesity
Wilding et al[69]	Four 68-week randomized, double-blind control trials comparing efficacy and safety of semaglutide 2.4 mg for weight management in patients with a BMI of at least 30 without T2DM, a BMI 27 or more without T2DM with at least 1 weight-related comorbidity, or a BMI 27 or more with T2DM	Semaglutide 24 mg/week	1961	129	68	38	5.7%	Mean change in body weight: Semaglutide vs placebo: -9.6% to -17.4% vs -2.4% to -5.9%. Percentage of patients that lost at least 5% of body weight: Semaglutide vs placebo: 68.8%-88.7% vs 28.5%-47.6%. NNT for achieving ≥ 5% weight loss: Worst-case (minimum ARR): 5; best-case (maximum ARR): 2	Compared to placebo, semaglutide significantly reduced overall body weight, with weight loss of at least 5% and up to 15% of initial weight. The most common adverse events with semaglutide were nausea and vomiting; a dose escalation period is required
Wadden et al[70]			611	41		38	5.7%
Davies et al[71]			1210	149		36	8.1%
Rubino et al[72]			902	73		38%	5.7%
O'Neil et al[73]	A 52-week, double-blind, placebo and active controlled, multicenter, dose-ranging, phase 2 trial, comparing efficacy and safety of semaglutide with liraglutide and placebo for weight management in adults (≥ 18 years) without diabetes and with a BMI of 30 kg/m² or more	Semaglutide 0.4 mg/day and 0.4 mg/day fast dose escalation, liraglutide 30 mg/day	957	71	52	39	5.5%	Mean change in body weight: Mean changes at week 59 for semaglutide escalated on the 4-weekly schedule were -4.9% (SD = 6.2; 0.05 mg) to -13.5% (SD = 7.9; 0.4 mg), for the 2-weekly escalation were -12.0% (SD = 7.9; 0.3 mg) and -15.5% (SD = 9.3; 0.4 mg), for liraglutide 3.0 mg was -7.7% (6.9), and for pooled placebo was -1.8% (5.5). Percentage of patients that lost at least 5% of body weight: Semaglutide vs placebo vs liraglutide: 60%-91% vs 23% vs 72%. NNT for achieving ≥ 5% weight loss: Semaglutide vs placebo; worst case: 2; best case: 3. Semaglutide vs liraglutide 30 mg. NNT is only applicable in the best case with NNT of 6. In the worst case, liraglutide outperforms semaglutide	Compared to placebo and liraglutide, semaglutide significantly reduced overall body weight, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea
Pi-Sunyer et al[74]	A 56-week, double-blind trial comparing efficacy and safety of liraglutide 3 mg for weight management in patients with a BMI of at least 30 without T2DM or a BMI of 27 or more if they had treated or untreated dyslipidemia or hypertension	Liraglutide 30 mg/day	3731	191	56	38	5.6%	Mean weight loss: liraglutide: -5.6 kg (95%CI: -6 to -5.1) (P < 0.001). Percentage of patients that lost at least 5% of body weight: Liraglutide vs placebo: 63.2% vs 27.1% (P < 0.001). NNT for achieving ≥ 5% weight loss: Liraglutide vs placebo: 3	Compared to placebo, liraglutide significantly reduced overall body weight, with weight loss of at least 5% and up to 10% or more of initial weight. The most common adverse events with liraglutide were mild or moderate nausea, diarrhea and vomiting; a dose escalation period is required. Serious events occurred in 6.2% of the patients in the liraglutide group vs 5% in the placebo group
le Roux et al[75]	A 160-week randomized, double-blind, placebo-controlled trial comparing liraglutide 3 mg with placebo for T2DM risk reduction and weight management in adults with prediabetes and a body-mass index of at least 30 kg/m², or at least 27 kg/m² with comorbidities	Liraglutide 30 mg/day	2254	191	160	39	5.8%	Mean change in body weight: Mean changes at week 160 for liraglutide was -6.5 (SD = 8.1) and for placebo was -2.0 (SD = 7.3). Percentage of patients that lost at least 5% of body weight: Liraglutide vs placebo: 49.6% vs 23.7%. NNT for achieving ≥ 5% weight loss: Liraglutide vs placebo: 4	Compared to placebo, liraglutide induced greater weight loss than placebo at week 160 [-6.1 (SD = 7.3)] vs -1.9% (SD = 6.3); estimated treatment difference -4.3%, 95%CI: -4.9 to -3.7, P < 0.0001
Astrup et al[76]	A 20-week randomized, double-blind, placebo-controlled trial comparing liraglutide with placebo and orlistat for treatment of obesity in obese individuals without T2DM	Liraglutide 12 mg/day, 1.8 mg/day, 2.4 mg/day, or 3.0 mg/day	564	19	20	35	-	Mean change in body weight: Mean changes at week 20 for liraglutide 12 mg was: -4.8 (-5.7 to -3.9); liraglutide 18 mg: -5.5 (-6.5 to -4.6); liraglutide 24 mg: -6.3 (-7.2 to -5.3); liraglutide 3 mg: -7.2 (-8.1 to -6.2); orlistat: -4.1 (-5.0 to -3.2); and placebo: -2.8 (-3.7 to -1.8). Percentage of patients that lost at least 5% of body weight: Liraglutide 3 mg vs placebo vs orlistat: 76% vs 30% vs 44%. NNT for achieving ≥ 5% weight loss: Liraglutide 3 mg vs placebo: 3; liraglutide 3 mg vs orlistat: 4	Compared to placebo and orlistat, liraglutide treatment over 20 weeks is well tolerated, induces weight loss, improves certain obesity-related risk factors, and reduces prediabetes. Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment
Astrup et al[77]	A 52-week randomized, double-blind, placebo-controlled trial comparing liraglutide with placebo and orlistat for treatment of obesity	Liraglutide 30 mg/day	398	19	52	-	-	Mean change in body weight: Mean changes for liraglutide 12 mg was: -3.8; liraglutide 18 mg: -5.4; liraglutide 24 mg: -6.1; liraglutide 3 mg: -7.8; orlistat: -3.9; and placebo: -2. Percentage of patients that lost at least 5% of body weight: Liraglutide 24/3 mg vs placebo vs orlistat: 70% vs 28% vs 44%. NNT for achieving ≥ 5% weight loss: Liraglutide 24/3 mg vs placebo: 3; liraglutide 24/3 mg vs orlistat: 4	Compared to placebo and orlistat, liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting
Blackman et al[78]	A 32-week randomized, double-blind, placebo-controlled trial comparing the effect of liraglutide with placebo in reducing OSA severity and treatment of obesity in non-diabetic individuals with obesity and moderate or severe OSA	Liraglutide 30 mg/day	359	40	32	39	5.7%	Mean change in body weight: Mean change for liraglutide 3 mg: -6.7 (SD = 0.5), and placebo: -1.9 (SD = 0.4). Percentage of patients that lost at least 5% of body weight: Liraglutide 3 mg vs placebo: 87% vs 64%. NNT for achieving ≥ 5% weight loss: Liraglutide 3 mg vs placebo: 5	Compared to placebo and orlistat, liraglutide 30 mg was generally well tolerated and produced significantly greater reductions than placebo. The results confirm that weight loss improves OSA-related parameters
Kim et al[79]	A 14-week randomized, double-blind, placebo-controlled trial to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, CVD risk factors, and inflammation in a high-risk population for T2DM and CVD	Liraglutide 18 mg/day	68	1	14	32	-	Mean change in body weight: Mean change for liraglutide 18 mg: -6.8 (-7.8 to -5.9), and placebo: -3.3 (-4.1 to -2.5). Percentage of patients that lost at least 5% of body weight: Liraglutide 18 mg vs placebo: 88% vs 22%. NNT for achieving ≥ 5% weight loss: Liraglutide 18 mg vs placebo: 2	Compared to placebo, the addition of liraglutide 18 mg to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD
Rosenstock et al[80]	A 24-week randomized, placebo-controlled trial to assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or IGT or IFG	Exenatide 10 μg/day	152	-	24	39	-	Mean change in body weight: Mean change for exenatide with nausea: -5.1 (SD = 0.5), placebo: -1.6 (SD = 0.5). Percentage of patients that lost at least 5% of body weight: Exenatide vs placebo: 32% vs 17%. NNT for achieving ≥ 5% weight loss: Exenatide vs placebo: 7	Compared to placebo, the addition of exenatide to lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG
Dushay et al[81]	A 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week wash-out period to investigate the effect of exenatide on weight loss and metabolic parameters in obese nondiabetic women	Exenatide 10 μg/day	41	1	35	33	-	Mean change in body weight: Mean change for exenatide: -2.49 (SD = 0.66); placebo: +0.43 (SD = 0.63). Percentage of patients that lost at least 5% of body weight: Exenatide vs placebo: 30% vs 17%. NNT for achieving ≥ 5% weight loss: Exenatide vs placebo: 8	Compared to placebo, short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss
Pratley et al[82]	A 20-week phase II, randomized, placebo-controlled, double-blind trial to evaluate the safety of efpeglenatide and its effects on body weight management in adults without diabetes	Efpeglenatide 6 mg/week	295	-	20	35	5.5%	Mean change in body weight: Mean change for efpeglenatide 4 mg once weekly: -6.6 (SD = 0.6); efpeglenatide 6 mg once weekly: -7.3 (SD = 0.6); efpeglenatide 6 mg once every 2 weeks: -6.4 (SD = 0.6); efpeglenatide 8 mg once every 2 weeks: -7.1 (SD = 0.6); placebo: -0.1 (SD = 0.6). Percentage of patients that lost at least 5% of body weight: Efpeglenatide 4 mg once weekly: 48%; efpeglenatide 6 mg once weekly: 51%; efpeglenatide 6 mg once every 2 weeks: 46%; efpeglenatide 8 mg once every 2 weeks: 53%; placebo: 3%. NNT for achieving ≥ 5% weight loss: Efpeglenatide 4 mg weekly: 3; efpeglenatide 6 mg weekly: 3; efpeglenatide 6 mg every 2 weeks: 3; efpeglenatide 8 mg every 2 weeks: 2	Efpeglenatide once weekly and once every 2 weeks led to significant body weight reduction and improved glycaemic and lipid variables vs placebo. It was also well tolerated for weight management in adults without diabetes

BMI: Body mass index; CVDs: Cardiovascular diseases; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; NNT: Number needed to treat; OSA: Obstructive sleep apnoea; T2DM: Type 2 diabetes mellitus.

Table 4 Frequency of gastrointestinal adverse events in clinical trials with glucagon-like peptide-1 receptor agonist in people with obesity or Type 2 diabetes mellitus

Adverse events	Exenatide (%)	Liraglutide (%)	Semaglutide (%)	Dulaglutide (%)	Lixisenatide (%)	Tirzepatide (%)
Abdominal pain	Reported	5.40	5.7-20	6.5-9.4	2-2.2	5-10
Biliary diseases	1.99	2.22	0.52	1.55	0.78	-
Antibody formation	6-64	< 12	0.5-3	1.6-6	2.40	51-64.5
Constipation	2.10	4.8-19.4	3.1-24	3.7-3.9	2.80	6-17
Diarrhea	6-18	9.3-22.4	8.5-30	8.9-12.6	8	12-23
Hypoglycemia	1.7-5.2	1.6-24.2	1-6	Reported	2	0.3-4.2
Injection site reaction	1.6-23.9	2-13.9	0.2-1.4	0.5-3.9	4	3.2-8
Nausea	8-44	23.9-42.4	11-44	12.4-21.1	< 25	12-29
Vomiting	3.4-13	8.7-34.4	5-36	6-12.7	< 10	5-13
Dizziness	2.5-9	5.8-12.1	0.4-8	-	7	4-5
Anorexia	1-2	10	-	4.9-8.6	-	5-11
Fatigue	-	4.8-7.5	0.4-11	4.2-5.6	-	5-7
Fever	-	8	-	-	-	-
Pharyngitis	-	-	12	-	-	-

Values correspond to the minimum and maximum values reported across the literature.