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

Abstract

Obesity is a global pandemic that has been threatening the worldwide population. It has been reported to be associated with an increase in the risk of chronic diseases such as type 2 diabetes mellitus (T2DM), cardiovascular disease, and other diseases, including some malignancies. Currently, the first line of management includes lifestyle modifications. However, recently, bariatric surgeries were introduced to combat obesity. The previous modalities of management are always challenging since lifestyle could have limited long-term effectiveness and difficulty to achieve, and surgeries are invasive and also require a lifestyle modification and commitment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were initially introduced as a rising star for managing T2DM, with patients benefiting from the control of blood sugar and weight loss. These medications work by enhancing feelings of fullness, slowing down digestion, and ultimately reducing calorie intake. However, GLP-1RAs are not without side effects and have some costs. Common side effects include gastrointestinal (GI) adverse events such as nausea, vomiting, diarrhea, and a lack of GI motility, which is the main mechanism through which the drug induces a feeling of fullness and promotes weight loss, potentially resulting in treatment discontinuation. More serious, though less frequent, risks include pancreatitis, gallbladder diseases, and, rarely, thyroid C-cell cancers. This review aimed to discuss the globally emerging role of GLP-1RAs in obesity management and highlight some safety considerations for patients taking these drugs.

Key Words: Glucagon-like peptide-1 receptor agonists; Obesity; Gastrointestinal; Adverse events; Diabetes

Core Tip: Obesity is a global pandemic causing chronic diseases like type 2 diabetes mellitus (T2DM) and cardiovascular disease. Lifestyle modifications and bariatric surgeries are the primary management methods. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a rising star for managing T2DM by controlling blood sugar and weight loss. However, they have side effects like nausea, vomiting, diarrhea, and gastrointestinal (GI) adverse events. More serious risks include pancreatitis, gallbladder diseases, and thyroid C-cell cancers. This review discusses GLP-1RAs' role in obesity management and GI safety considerations.

INTRODUCTION

The past decade has witnessed the growing burden of obesity and related comorbidities as a major public health problem across the globe[1,2]. Obesity is the ultimate result of a continuous state of positive energy balance where energy intake exceeds energy expenditure. The surplus of energy in the form of calories is stored as fatty acids in adipose tissue leading eventually to an overweight body phenotype with a body mass index (BMI) ≥ 25 kg/m², and ultimately to obesity, a body weight disorder, with a BMI ≥ 30 kg/m²[3]. Overall, obesity could be defined as the excessive or abnormal accumulation of body fat affecting the persons’ health-related quality of life[4-6]. Obesity was once considered a cosmetic problem, but is now considered by the American Medical Association as a multi-factorial disease where genetics, behavioral, and environmental factors play a role[3]. Obesity is an important risk factor for morbidity and mortality from type 2 diabetes mellitus (T2DM), cardiovascular diseases, stroke, dyslipidemia, hepatic steatosis, hypertension (HTN), gallbladder diseases, osteoarthritis, obstructive sleep apnoea, and some types of cancer (endometrial, breast, ovary, prostate, liver, gallbladder, kidney and colon)[7,8]. Obesity and overweight contribute to 35.8 million (2.3%) of the world's disability-adjusted life years, and to over 2.8 million deaths annually worldwide[9].

The obesity epidemic began in the United States over 40 years ago, and the obesity prevalence has increased by twofold in the United States from 1980 to 2010. Globally, obesity prevalence has doubled since 1980 to the point where one-third of the world’s population is classified as overweight or obese. In 2022, the World Health Organization reported that 890 million (16%) of the world's people aged 18 years and over were obese, and 2.5 billion (43%) were overweight[10]. If the current trends continue, it is estimated that by 2030, 57.8% of the world population will be overweight or obese[11]. The Noncommunicable Diseases Risk Factor Collaboration (NCD-RisC) expected that by 2025, the prevalence of obesity will reach 18% in men and 21% in women[12]. According to the latest statistics from the NCD-RisC, the prevalence of obesity (BMI ≥ 30 kg/m²) in adults aged 20 years and older has increased across the world (Figure 1)[13].

Figure 1 Distribution plod of global prevalence of obesity. Data on global trends in the prevalence of obesity (body mass index ≥ 30 kg/m²) in adults aged 20 years and older in 1990, 2000, 2010, and 2022 from selected regions of the world show an increase in obesity across the world.

This global burden of obesity represents the domino effect triggered by globalization, rapid urbanization, and economic growth which led to substantial lifestyle changes from diets to day life activities promoting a state of positive energy balance through increased consumption of empty caloric food with more sugar and fats than nutrients, and reduced physical activity (Figure 2)[14-16]. The risk of obesity is higher in developing and developed countries compared to low-income countries. While obesity affects people of all ages and sexes in high-income nations, it is disproportionately more common in underprivileged groups. In low-income countries, obesity is typically more common among middle-aged adults from high social class, particularly women[17]. In general, across all sociodemographic groups, women are more likely than males to be obese[18].

Figure 2  Schematic representation of the domino effect triggered by globalization, rapid urbanization, and economic growth which led to substantial lifestyle changes from diets to day-life activities promoting a state of positive energy balance through increased consumption of empty caloric food with more sugar and fats than nutrients and reduced physical activity.

Since energy balance is regulated by a variety of biological processes, treating obesity and maintaining weight loss afterward have proven difficult. The first-line treatment for obesity is non-pharmacological with behavioral modifications promoting healthy eating habits and regular exercise; however, non-pharmacological approaches could only lead to a weight loss of 1-6 kg, which is difficult to maintain[3,19-21]. Pharmacotherapy appears as a good adjunct when behavioral therapy fails to produce the desired weight loss; however, higher withdrawal rates and side effects limit the use of some drugs[22-24]. Moreover, bariatric surgery such as Roux-en-Y gastric bypass surgery, and implantable devices such as the Lap-band, the Realize Gastric band, and the Maestro Rechargeable system are options for morbidly obese patients with BMI ≥ 40 kg/m² or ≥ 35 kg/m² with one or more co-morbidities[25]. Although bariatric surgery can decrease the risk of developing obesity-related co-morbidities, it carries safety risks and high costs restricting its widespread application[25-27].

Bariatric surgeries could also be done endoscopically. This is done as part of endoscopic bariatric therapies, which provide a minimally invasive, cheaper, and safer modality to mitigate obesity[28]. The various types of endoscopic bariatric therapies include space-occupying devices (intragastric balloons, botulinum toxin injection, aspiration therapy, and transpyloric shuttle, etc.), stomach procedures (primary obesity surgery endoluminal, endoscopic sleeve gastroplasty, etc.), and small bowel procedures [duodenal jejunal bypass sleeve (endobarrier), gastroduodenal-jejunal bypass (endobypass system), duodenal mucosal resurfacing, etc.][28,29]. According to current guidelines, endoscopic bariatric therapies is the standard of care in treating obesity class I[29]. Additionally, a recent systematic review and meta-analysis by Zhu et al[30] deemed endoscopic bariatric surgery as an effective and safe method for weight reduction with a better 12-month effect than the non-adjustable intragastric balloon.

Over the past decades, pharmacotherapy for obesity has made significant progress[31]. However, many drugs were withdrawn in the human clinical trials phase due to various side effects, inability to be used beyond 3 months, or a moderate short-term efficacy[32]. An example of withdrawn drugs are riconabant, a cannabinoid receptor type 1 antagonist, and sibutramine, an inhibitor of neurotransmitter re-uptake[33,34]. Anti-obesity pharmacotherapy tries to mitigate common pathways regulating energy balance and feeding behavior including the opioid system, the leptin-melanocortin axis, glucagon-like peptide-1 (GLP-1)/ GLP-1 receptor (GLP-1R) system, and fibroblast growth factor 21/its receptor complex FGFR1c/b-klotho axis. GLP-1R agonists (GLP-1RAs) have revolutionized the treatment of metabolic diseases including T2DM and obesity. Nevertheless, a focus should be put on the cumulative arising evidence regarding GLP-1RAs-induced adverse events and how to prevent such complications from arising or, if they occur, to manage them properly. While GLP-1RAs are widely used, comparative analyses of GI tolerability across agents—especially dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs like tirzepatide—remain limited.

Herein, we will discuss gastrointestinal (GI) adverse events, and contraindications associated with GLP-1RAs.

GLP-1RAS

When nutrients are consumed, the gut-driven incretin hormone GLP-1 is released[35]. GLP-1 is a peptide hormone that regulates glucose homeostasis after ingestion of carbohydrates or fats. GLP-1 exists in two active forms: (1) GLP-1 (7-36) amide (30 amino acids); and (2) GLP-1 (7-37) (31 amino acids). GLP-1 increases insulin production, decreases glucagon secretion, slows stomach emptying, and decreases food intake[36]. GLP-1RAs have been proved to restore insulin secretory functions, improve glycemic control, and reduce bodyweight in patients with T2DM[37].

The source of GLP-1 secretion remained an enigma till 1983, when it was found to be derived from the proglucagon gene’s transcription product and secreted from: (1) Enteroendocrine L cells as the entral GLP-1 in the periphery; (2) A-cells in the pancreatic islet; and (3) Preproglucagon neurons in the solitary tract's caudal nucleus and nearby medullary reticular formation produce GLP-1 in the central nervous system (CNS)[38-42]. Neurons that produce GLP-1 extend across the brain to the hypothalamus and other areas that regulate energy balance.

Once GLP-1 is secreted, its hypoglycemic action is mediated via the GLP-1R, a class B G-protein coupled glucagon receptor abundantly expressed in the stomach, islet B-cells, intestine, and CNS[43,44]. GLP-1 exerts its action by inhibiting hepatic glucose production through alpha cells glucagon secretion, increasing insulin secretion from pancreatic beta-cells, improving insulin resistance via upregulation of the expression of glucokinase and glucose transporter genes, increasing satiety, decreasing appetite, and inhibiting gastric emptying[45-49]. Interestingly, natural GLP-1 exerts its actions within a very short half-life of approximately 2 minutes. GLP-1 has a rapid renal clearance and inactivation via dipeptidyl peptidase IV (DPP-IV). Due to these benefits and the short half-life, drug developers have tried to synthesize exogenous GLP-1RAs[36].

Although genetic studies report a limited link between the GLP-1/GLP-1R axis T2DM, GLP-1RAs are approved as the third-line therapy following metformin and oral medications such as DPP-IV inhibitors for treating T2DM[50]. The role of GLP-1RAs in T2DM emerged from the fact that endogenous GLP-1 concentrations are decreased in response to oral glucose load in T2DM patients. The first GLP-1RA to be approved for the clinical treatment of T2DM was exenatide. Subsequently, many GLP-1RA were approved (Table 1)[51]. GLP-1RAs are effective in lowering fasting plasma glucose and glycated hemoglobin in T2DM. The greatest hypoglycemic effects were reported with tirzepatide, followed by semaglutide once weekly, dulaglutide and liraglutide, then exenatide once weekly, followed by exenatide twice daily and lixisenatide[52-54]. In pediatric patients with T2DM who are 10 years and older, liraglutide and exenatide extended-release injections are the only GLP-1RAs approved of T2DM treatment[55,56].

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.

GLP-1RAs have pleiotropic actions with metabolic, renal, hepatic, and cardiovascular effects[57,58]. In addition to being effective anti-diabetic medications, GLP-1RAs also improve renal and cardiovascular outcomes, and have an anti-obesity effect[59]. Sattar et al[60] reported a reduction in major adverse cardiovascular events (i.e., cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), hospitalization for heart failure, and progression of chronic kidney disease. The currently commercialized GLP-1RAs with their uses are summarized in Table 2.

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.

GLP-1RAs trials in obese T2DM patients revealed a significant association between GLP-1RAs and a mean weight loss of -1 kg to -4.4 kg after 3 months to 4 months of treatment in overweight T2DM patients[37,61,62]. This opened the door for investigating the first non-oral weight loss GLP-1RA, liraglutide (saxenda) as a monotherapy for weight loss. Liraglutide was approved for the treatment of chronic weight management as an adjunct to behavioral therapy, although with a higher starting dose compared to that used in the treatment of T2DM. Liraglutide’s effect on weight is primarily mediated through decreased energy intake[63]. Anti-obesity GLP1-RAs are indicated for patients who are obese with BMI ≥ 30 kg/m², or overweight with BMI ≥ 27 kg/m² and at least one weight-related comorbid condition (i.e., T2DM, dyslipidemia, or HTN)[64,65]. Semaglutide is the only GLP-1RA available in both oral tablet (rybelsus) and injections[66]. Several randomized controlled trials (RCTs) investigated the effect of GLP-1RAs on weight loss in adults with obesity and without diabetes mellitus (Table 3)[67-82].

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.

The exact weight loss mechanism of GLP-1RAs is still not clear. However, it has been reported that GI adverse events associated with GLP-1RAs are likely to have desirable outcomes favoring anorexia and subsequent weight loss. Lean et al[83] reported that liraglutide-treated greater weight loss in patients who experienced at least one episode of nausea or vomiting compared to those who did not experience any such side effects. Another contributing factor to the cumulative weight loss of liraglutide was the following liraglutide-induced effects: (1) Increased satiety and fullness; (2) Decreased hunger; and (3) Slowed gastric emptying[63]. These CNS effects were postulated to be due to the activation of GLP-1RAs in satiety centers in the CNS. This was supported by the finding of radiolabeled liraglutide in the arcuate nucleus following subcutaneous liraglutide administration with higher doses than those used for T2DM treatment[84].

Tirzepatide (zepbound), a novel dual GIP/GLP-1RA has emerged. Dual GIP/GLP-1RA binds both GIP and GLP-1RAs, with more tendency to bind GIP receptors. GIP stimulates insulin secretion, inhibits lipolysis, promotes lipogenesis, and inhibits gastric secretion activity. The effects of GIP along with the satiating effects of GLP-1 add to desired weight-loss outcome[85-87]. This explains why tirzepatide is associated with greater weight loss than other anti-diabetic medications. Tirzepatide achieved greater weight loss (-20.9%) than semaglutide (-14.9%) but higher nausea rates (29% vs 15%)[54,67,88-90].

Tirzepatide is indicated for patients who are obese with BMI ≥ 30 kg/m² or overweight with BMI ≥ 27 kg/m² and at least one weight-related comorbid condition (i.e., T2DM, dyslipidemia, or HTN, obstructive sleep apnea or cardiovascular diseaes)[91]. The SURMOUNT-2 trial demonstrated tirzepatide’s superior weight loss (-14.7% to -20.9%) in T2DM patients[67,92,93] in the SURMOUNT-4 trial, the overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo[94].

ADVERSE EVENTS ASSOCIATED WITH GLP-1RAS

With the use of GLP-1RAs in clinical practice, several adverse events have been reported, most of which were GI (Table 4)[95,96]. Other reported adverse events included acute pancreatitis, cholelithiasis and cholecystitis, angioedema/anaphylaxis, injection site reactions, acute kidney injury (AKI), drug-induced immune thrombocytopenia (DITP), and thyroid C cell tumor.

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.

GI

GI disorders were the most common side effects in GLP-1RAs clinical trials[97]. Among GI symptoms[98-102], nausea[103], diarrhea, vomiting, constipation, abdominal pain, and dyspepsia are common[104-108]. A network meta-analysis of 236 clinical studies found that GLP-1RAs were linked to severe adverse events resulting in treatment discontinuation more often than other oral anti-diabetic medications[109]. Treatment interruption has been reported in up to 12% of GLP-1RA-treated patients while treatment discontinuation has been reported in 1.6%-6% of GLP-1RA treated patients[110-112]. On contrast, Wharton et al[112] reported that the 99.5% of GLP-1RA-induced GI adverse events were non-serious. In general, GI adverse events are transient, starting during the dose-escalation period, and resolving shortly after the maintenance dose is reached.

When used as anti-obesity agents, GLP-1RAs have been associated with more severe adverse effects, including obstruction and symptomatic gastroparesis[113]. A meta-analysis reported that the most frequent adverse events with GLP-1 were pancreatitis and acute gallbladder disease[114]. Nausea is the most frequent adverse event with exenatide once weekly. Patients on short-acting GLP-1RA experience higher rates of GI adverse events than those on long-acting GLP-1RA. Studies have reported a less frequent exenatide-induced nausea with once-weekly than with twice-daily administration (26% vs 50%) and also less frequently than with liraglutide (9% vs 21%)[102,115]. Long-acting GLP-1RAs exert a sustained effect on intestinal GLP-1RAs leading to more diarrhea and less nausea and vomiting[116,117]. Patients with estimated glomerular filtration rate > 60 mL/minute/1.73 m² and gastroparesis are more likely to suffer GI adverse effects with exenatide once weekly[118].

Regarding semaglutide, Rosenstock et al[119] reported nausea, vomiting, and diarrhea in 15%, 9%, and 12.3%, respectively, of patients on semaglutide (14 mg orally daily) compared with 6.9%, 4.1%, and 7.9%, respectively, of patients on sitagliptin (100 mg daily). Nausea may subside with duration of therapy and gradual dose titration[112,120,121].

Tirzepatide clinical trials for weight management showed GI adverse effects among patients receiving tirzepatide than placebo leading to higher discontinuation rates among patients receiving tirzepatide. The GI adverse effects included, nausea (25%-29%), vomiting (8%-13%), and diarrhea (19%-23%)[67,68].

GLP-1 and endoscopic examination

The GLP-1-induced delay in gastric transit can impact the quality of bowel preparation for procedures such as colonoscopy, leading to poor visualization of the GI tract during endoscopy[122,123].

Several studies have indicated that delayed gastric emptying and associated GI adverse events may pose risks during endoscopic examinations. Imam et al[93] highlighted that incorporating GLP-1RAs alongside bariatric therapies has shown promise in weight loss but emphasized the necessity of considering GI motility effects when planning surgical interventions, including endoscopic examinations.

Additionally, a retrospective study by Ghazanfar et al[124] raised questions about the necessity of temporarily discontinuing GLP-1 therapy before endoscopic procedures, as long-acting GLP-1RAs, such as liraglutide and dulaglutide, have prolonged effects on GI function. This withdrawal could reduce adverse GI events that might complicate endoscopy and improve the quality of procedures.

Pancreas

GLP-1RAs have been associated with acute pancreatitis[113,125]. GLP-1RAs should never be initiated in patients with a history of pancreatitis, and if a patient on GLP-1RAs developed persistent severe abdominal pain, pancreatitis should be suspected and GLP-1RAs should be stopped and never restarted. Retrospective cohort studies and meta-analyses of RCTs[126] reported that GLP-1RAs-induced pancreatitis usually does not increase the risk of hospitalization[127-131]. However, a large population-based case-control study revealed that exenatide and sitagliptin were associated with an increased risk of hospitalization for acute pancreatitis (adjusted odds ratio = 2.07, 95%CI: 1.36-3.13)[132].

Some studies reported an increase in pancreatic amylase and lipase from baseline levels, although remaining within the normal ranges[121,133]. Steinberg et al[134] reported isolated elevations of lipase and amylase levels above the upper limit in the liraglutide and placebo groups (51% and 32% of participants, respectively, for lipase and 29% and 23%, respectively, for amylase) with no association with subsequent acute pancreatitis.

Some case reports showed an increased risk of pancreatic cancer, neuroendocrine tumors, and subclinical pancreatic inflammation in exenatide users[125,135-137]. However, the United States Food and Drug Administration and the European Medicines Agency concluded that there was insufficient evidence to confirm an increased risk of pancreatic cancer with the use of GLP-1-based therapies[138].

Gallbladder and biliary diseases

Gallbladder and biliary diseases including cholelithiasis and cholecystitis have been associated with GLP-1RAs. A meta-analysis of 76 randomized clinical trials showed an increased risk of the composite outcome of gallbladder or biliary diseases (event rate 1.58% vs 1.19%, relative risk = 1.37, 95%CI: 1.23-1.52)[139]. A post-marketing report has shown an elevated risk of acute cholecystitis with GLP-1RAs[140]. If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated.

Hypersensitivity reactions

Angioedema/anaphylaxis: There are some reports of angioedema and anaphylaxis with GLP-1RAs[141,142]. The underlying immunogenicity varies among the GLP-1RAs. An immunological reaction against one GLP-1RA does not necessitate an immunological reaction to other drugs in the same class. Shamriz et al[143] reported an allergic reaction to exenatide and lixisenatide but not to liraglutide. It is recommended to use an alternative GLP-1RA once an immunological reaction appear.

Injection site reactions

Injection site reactions including abscess, cellulitis, and necrosis have been reported with GLP-1RA. When compared with insulin injections, once-weekly GLP-1RAs, especially albiglutide, and exenatide, appear to be more associated with injection site reactions compared to insulin (10% vs 1%-5%)[144,145]. Studies have shown injection site reactions were more common with exenatide once weekly or albiglutide than lirglutide[102,146].

Immunogenicity: Antibodies against GLP-1RAs have been reported. However, no significant clinical safety concerns have been confirmed[147].

Kidney: Several studies reported AKI with exenatide twice daily[121,149-151]. The AKI is usually driven by dehydration from the GI symptoms initially caused by GLP-1RAs. AKI has also been reported with liraglutide and semaglutide[152,153]. A kidney biopsy may be considered if the diagnosis remains unclear.

DITP: Exenatide has been associated with DITP[154]. In a case report, prolonged, severe thrombocytopenia resulted from the persistence of the drug at levels sufficient to permit binding of the patient's drug-dependent, platelet-reactive immunoglobulin G anti-body to platelets for more than 6 weeks after discontinuing treatment due to immune memory mechanisms[154]. Once DITP is suspected, Exenatide should be discontinued and never restarted.

Thyroid C cell tumors: Recent studies have yielded conflicting results regarding the association between GLP-1RAs and thyroid cancer risk. A Scandanavian cohort study evaluated thyroid cancer risk in patients on GLP-1RA, particularly liraglutide and semaglutide, compared to DPPI-4 and showed no association between GLP-1RA and risk of any thyroid cancer [hazard ratio (HR) = 0.93, 95%CI: 0.66-1.31] or medullary thyroid cancer (HR = 1.19, 95%CI: 0.37-3.86)[155]. In contrast, a study based on the French national health care insurance system database found an increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1RA, in particular after 1-3 years of treatment[156].

Animal studies have shown that liraglutide and dulaglutide were associated with thyroid C cell tumors[157]. Also, exenatide and liraglutide were associated with stimulation of calcitonin release[157,158]. There is no clear evidence of similar effects in humans. This may be due to the fact that humans have fewer c with low GLP-1R expression[157]. These findings highlight the need for continued monitoring and research on this potential safety concern.

In general, GLP-1RA and dual GIP/GLP-1RA are contraindicated in patients with a personal or family history of thyroid C cell tumors such as medullar thyroid carcinoma (MTC), or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Routine monitoring of serum calcitonin is not recommended; however, if measured and found elevated, the patient should be referred to an endocrinologist.

Contraindications

GLP-1RAs share several contraindications rooted in clinical and preclinical evidence. Absolute contraindications for exenatide, liraglutide, semaglutide, dulaglutide, and tirzepatide include a personal or family history of MTC or MEN 2, conditions linked to thyroid C-cell tumorigenesis in animal studies[159]. Additionally, a history of idiopathic pancreatitis (pancreatitis of unknown etiology) precludes their use, given concerns about exacerbating pancreatic inflammation[160]. Pregnancy is considered an absolute contraindication for liraglutide, semaglutide, and trizepatide. For trizepatide, hypersensitivity reactions are considered an absolute contraindication.

Relative contraindications for liraglutide, semaglutide, and tirzepatide include gastroparesis, as their mechanism of delaying gastric emptying may worsen symptoms such as nausea and vomiting. Similarly, severe gastroesophageal reflux disease may be aggravated by slowed GI motility. For liraglutide, there is a potential increased risk of acute pancreatitis and pancreatic cancer; thus, close monitoring is required[161,162]. For semaglutide, close monitoring and risk/benefit assessment are required in patients with diabetic retinopathy, gallbladder dysfunction, and acute pancreatitis. For tirzepatide, close monitoring and risk/benefit assessment are required in patients with gallbladder dysfunction and diabetic retinopathy.

MANAGEMENT STRATEGIES FOR ADVERSE EVENTS

Pre-treatment counseling

It is crucial to educate patients about the common GI side effects associated with medications such as tirzepatide, semaglutide, and liraglutide, including nausea, diarrhea, and constipation. Studies like Get-Goal-M[103], STEP-1 trial[69], STEP-3 trial[70], SURMOUNT-1[68] indicate that these side effects can lead to treatment discontinuation in a notable percentage of patients.

Encouraging patients to report any adverse effects early and reassuring them that many GI symptoms are mild to moderate and often improve over time can help manage patient expectations and improve adherence.

Dose adjustment and titration

Initiating treatment with a lower dose and gradually increasing it can help mitigate GI side effects.

Symptomatic management

Pharmacological options: For patients experiencing nausea or diarrhea, prescribing antiemetics or antidiarrheal agents may provide relief. These medications can help manage symptoms effectively, allowing patients to continue their treatment regimen.

Non-pharmacological strategies: Dietary adjustments, such as consuming smaller, more frequent meals and avoiding high-fat or spicy foods, can alleviate GI discomfort. Behavioral modifications, including gradual dose escalation and maintaining hydration, are also beneficial in managing symptoms.

When to discontinue treatment

Treatment should be reconsidered if patients experience severe GI symptoms that lead to significant distress or inability to maintain adequate nutrition. For example, if nausea or diarrhea leads to dehydration or weight loss, discontinuation may be necessary.

If treatment discontinuation occurs, it is essential to evaluate alternative therapies or adjust the current treatment plan. This may involve switching to a different medication with a more favorable side effect profile or considering non-pharmacological interventions for weight management.

Future directions

Potential developments in GLP-1RA formulations aimed at minimizing GI effects are critical for enhancing patient adherence and overall therapeutic outcomes.

These developments could focus on providing long-acting GLP-1RAs that necessitate less frequent dosing and have shown promise in reducing GI side effects. For instance, formulations such as semaglutide, dulaglutide, exenatide extended-release, albiglutide, and tirzepatide, which are administered once weekly, have demonstrated improved patient adherence and a more gradual onset of side effects compared to their shorter-acting counterparts. This extended-release mechanism may allow for a more stable pharmacokinetic profile, thereby mitigating the intensity of GI disturbances commonly associated with GLP-1 therapy[163]. However, complications of long acting formulations should be put into consideration including: (1) Cumulative toxicity; and (2) Immunogenicity risks.

Moreover, future research may focus on improving the bioavailability and therapeutic efficacy of GLP-1RAs via molecular modifications and targeted delivery systems[164]. This could lead to formulations that are more effective while causing fewer GI disturbances, thereby improving the overall patient experience with GLP-1 therapy. Additionally, genetic studies are needed to predict GI tolerability and personalize therapy

CONCLUSION

GLP-1RAs are novel anti-obesity medications that come with some adverse events, particularly GI adverse events. Physicians should prescribe GLP-1RAs with particular attention to the absolute and relative contraindications and possible adverse events in a patient-customized approach. In this regard, future studies are needed to enhance patient safety, mitigate side effects, and improve treatment outcomes for GLP-1RAs as anti-obesity medications.