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Background:
Systematic Review

Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects

by
Robert F. Kushner
1,
Odd Erik Johansen
2,
Krysmaru Araujo Torres
3,
Trà-Mi Phan
2 and
Agnieszka Marczewska
2,*
1
Center for Lifestyle Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2
Nestlé Health Science, 1800 Vevey, Switzerland
3
Nestlé Health Science, Bridgewater, NJ 08807, USA
*
Author to whom correspondence should be addressed.
Obesities 2025, 5(2), 29; https://doi.org/10.3390/obesities5020029
Submission received: 13 March 2025 / Revised: 11 April 2025 / Accepted: 16 April 2025 / Published: 24 April 2025
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Review Reports Versions Notes

Abstract

:
Background/Objectives: Obesity is a chronic, progressive, recurrent disease associated with impaired health, affecting an increasing proportion of the population worldwide. Newer-generation incretin-based therapies (IBTs) (liraglutide, semaglutide, and tirzepatide) have shown greater efficacy than older anti-obesity medications. This systematic literature review provides an overview of the evidence on the symptomatic adverse events (AEs) and patient-reported outcomes of IBTs to facilitate clinical decision-making. Methods: A systematic search was conducted using a predefined search strategy to identify controlled trials and real-world evidence (RWE) studies assessing IBTs. Results: Among 4414 publications identified, 81 (>400,000 participants) were included. Liraglutide (n = 49), semaglutide (n = 34), and tirzepatide (n = 7) were used in 48 clinical and 33 RWE studies. Gastrointestinal (GI) AEs were most common: placebo-subtracted incidences were 5–39% for nausea, −7–39% for diarrhea, 2–31% for constipation, 0–26% for vomiting, and 2–20% for abdominal pain, with no clear difference across IBTs. Most AEs were mild or moderate and mainly occurred during dose escalation. Quality of life outcomes were reported in 27 publications and generally showed improvements with IBTs. Conclusions: This study confirms that GI AEs are common with IBTs. Clinicians should keep the AE profile of IBTs in mind and consider where additional preventative measures may be required.

1. Introduction

The prevalence of obesity continues to rise globally, with 0.81 billion adults affected by obesity in 2020, a number projected to reach 1.53 billion by 2035 [1]. Treating obesity, which is a chronic, progressive, and recurrent disease, remains an ongoing and considerable challenge.
The aim of obesity treatment is to help patients achieve and maintain a healthy weight, promote overall health, and reduce the risk of complications [2]. A 5–10% reduction in body weight improves the inflammatory and pro-thrombotic state and reduces the incidence of chronic complications [3]. Current treatment guidelines for obesity recommend lifestyle modification as the foundation for weight reduction, with or without anti-obesity medications (AOMs) [4,5]. Lifestyle changes can induce clinically meaningful average weight loss of 3–5%, which has a positive impact on body composition [6] and cardiometabolic risk factors, including systolic blood pressure, waist circumference, and lipid profile [7]; however, long-term efficacy is often limited [8]. Approaches using very-low or low-calorie diets, e.g., meal replacements, may induce weight loss of >10% over 52 weeks compared with a regular food-based diet [7], but this approach may be difficult to sustain for many individuals.
Earlier generation AOM use was limited, due to modest weight loss achieved or the occurrence of intolerable adverse events (AEs) [9,10]. Since 2021, a newer generation of AOMs, known as incretin-based therapies (IBTs) that include liraglutide, semaglutide, and tirzepatide, offer greater weight loss (generally ≥10%) and a more favorable safety profile [11,12]. These medications are currently indicated for individuals with a body mass index (BMI) of ≥30 kg/m2 and ≥27 kg/m2 with ≥1 weight-related comorbidity [4,5]. Notably, the United States Food and Drug Administration (FDA) recently removed the BMI restrictions for three AOMs (phentermine/topiramate, semaglutide, and tirzepatide). IBTs also have been shown to reduce cardiometabolic risk factors [12,13] and several obesity-related complications. Additionally, liraglutide, semaglutide, and tirzepatide have demonstrated considerable cardiovascular benefits [14,15,16].
Incretin-based therapies are commonly associated with gastrointestinal (GI) AEs (e.g., nausea, vomiting, diarrhea, and constipation), which may affect tolerability and treatment adherence [11,12,17]. Furthermore, IBT use decreases caloric intake and alters food preferences, potentially impacting diet adequacy, which may result in insufficient protein and micronutrient intake, leading to nutritional deficits [18,19,20,21,22,23] and potentially excessive loss of lean body mass (LBM). In clinical practice, the beneficial effects of IBTs must be considered in the context of their overall risk–benefit profile [24]. The aim of this systematic literature review is to provide an overview of the symptomatic AEs and patient-reported outcomes related to IBTs and highlight areas where further research may be needed.

2. Materials and Methods

A systematic search was conducted via the Ovid platform (Wolters Kluwer, Alphen aan den Rijn, The Netherlands) on 4 June 2024 using a predefined search strategy in the Embase (1980–present), MEDLINE (1946–present), the Cochrane Library, and EconLit (1961–present) electronic databases. The database search strings identified all relevant studies (full papers or abstracts from any conferences) indexed in Embase and were modified for MEDLINE and EconLit. Search terms included free text and medical subject heading (MeSH) terms related to glucagon-like peptide 1 (GLP-1), liraglutide, semaglutide, tirzepatide, weight gain, obesity, and AEs. Details of the search strategies and additional hand searches are provided in the Supplementary Materials (Tables S2–S5). We excluded studies where IBTs were used for non-weight-related conditions, studies in type 1 diabetes mellitus, and those with <50 participants (see Table S1 for full eligibility criteria).
We followed the Cochrane review methodology to identify citations [25]. Two independent reviewers evaluated all identified citations based on title/abstract (first pass). Subsequently, two independent reviewers examined full publications of relevant citations (second pass) for inclusion or exclusion. The project lead resolved any disputes. Quality appraisal of randomized trials, non-RCTs, and RWE was conducted using the Cochrane risk-of-bias (RoB) tool [26], the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies [27], and the methodology checklist provided in Appendix D of the NICE guidelines manual [28], respectively. Relevant data from included studies were extracted into pre-designed summary tables which collected data on all relevant outcomes. A second reviewer conducted quality assessments of the extracted data.

3. Results

3.1. Search Results

The electronic database searches yielded 4414 publications (Figure 1), with 1391 duplicates subsequently excluded. Screening based on title and abstract led to the exclusion of 2429 out of the remaining 3023 citations, resulting in 594 citations to be screened based on the full publications. Full-text screening resulted in the inclusion of 77 publications in the systematic literature review (SLR). Hand searching identified four additional citations that met eligibility criteria, resulting in 81 included publications [11,12,13,14,21,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104] relating to 72 unique studies (Supplementary Materials Table S6). Based on the Cochrane RoB tool, the quality of the RCT studies was rated as high, although there was one open-label study, and reporting of attrition and detection bias was unclear in 23/41 and 18/41 publications, respectively. Based on the EPHPP Quality Assessment Tool for Quantitative Studies, the quality of the two non-RCT studies included was moderate. For the RWE publications, the assessment was generally positive, or the questions were not applicable.
The identified publications evaluated liraglutide (49 publications), semaglutide (34 publications), and tirzepatide (7 publications). Among these, 47 publications were randomized control trials (RCTs), 33 were real-world evidence (RWE) studies, and 1 study was a non-randomized pilot study [37]. The patient population size was ≥10,000 in six publications, ≥1000–<10,000 in 15 publications, between ≥500 and <1000 in 13 publications, and <500 in the remaining 47 publications. In total, more than 400,000 participants were involved across the studies.

Patient Demographics

In the 81 included publications, the mean patient age ranged from 31 to 73 years (mean <50 years in 60 of 81 publications). The majority of studies (66 publications) enrolled more female than male patients. The most prevalent ethnic group (>50%) was White. The second most prevalent group(s) were Asian and Black/African American. Forty publications did not report race demographics. Mean BMI was ≥30 kg/m2 in 71 publications and ≥35 kg/m2 in 52 publications. Thirteen publications included patients with type 2 diabetes mellitus (T2DM), three with prediabetes, twenty-five included both patients with and without T2DM, and forty included patients without T2DM. The remaining seven studies did not collect or report T2DM status.

3.2. Gastrointestinal AEs

3.2.1. Severe/Serious GI Adverse Events

Gastrointestinal serious AEs (SAEs) were reported in nine publications [12,36,52,81,85,89,94,98,103] including the SCALE (liraglutide), STEP (semaglutide), and SURMOUNT (tirzepatide) clinical studies. In the SCALE Obesity and Prediabetes study, no patients reported GI SAEs [81]. In the STEP 1–3 pooled analysis, 4.1% and 1.3% of patients on semaglutide reported severe and serious GI AEs, respectively, compared with 0.9% and 0.4% for the placebo group, respectively [98]. In STEP 4, 2.1% and 0.2% of patients reported severe and serious GI AEs on semaglutide, respectively, compared with 1.9% and 1.5% of patients that switched to placebo, respectively [98]. In STEP 8 [85], severe GI AEs were reported in 2.4% and 3.2% of patients treated with liraglutide and semaglutide, respectively. In the SURMOUNT-1, -2, -3, -4, and -CN clinical studies, the percentage of patients reporting GI SAEs during treatment with tirzepatide 15 mg once weekly was 3.3%, 3.0%, 5.6%, 1.8%, and 5.6%, respectively.

3.2.2. Nausea

In the 60 publications that captured nausea (including 7 reporting nausea and vomiting as a combined AE) (Table S6), severity was generally mild or moderate. One publication measured serious nausea AEs; however, no AEs were reported in the study [68]. The placebo-adjusted incidence (subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm) of nausea with IBTs in clinical studies overall indicated an increased rate (vs placebo) and appeared to be generally higher for liraglutide and semaglutide than tirzepatide (Figure 2). The placebo-adjusted incidence ranges of clinical data for liraglutide, semaglutide, and tirzepatide were 11–43.3%, 9.1–38.7%, and 5.4–30.8%, respectively. The distribution of values of RWE data showed no clear difference across individual IBTs. Incidence ranges of RWE data were 4–33.9%, 9.4–38% and 15% (n = 1) for liraglutide, semaglutide, and tirzepatide, respectively. Placebo-adjusted discontinuation rates due to nausea were <6% [12,36,52,68,70,94,103]. In one RWE study, patients with diabetes treated with liraglutide reported a 35% control-adjusted discontinuation rate over three months [69].

3.2.3. Diarrhea

Diarrhea (56 publications) occurred at higher incidence with IBTs than placebo and was typically mild or moderate (where severity was reported) [12,36,52,70,94,103], transient, and occurred during the dose-escalation phase (where timing was reported) [12,94,103] (Table S6). In clinical studies, placebo-adjusted incidences of diarrhea were similar across IBTs. There was one publication where the incidence of diarrhea was greater in the placebo than the liraglutide arm [85]. The placebo-adjusted incidence ranges for liraglutide, semaglutide, and tirzepatide were −7.3–20.1%, 1.9–33%, and 5.9–38.8%, respectively. The incidence ranges of RWE data for liraglutide and semaglutide were 0.7–10%, and 2–10.5%, respectively, with no clear difference between semaglutide and liraglutide (Figure 3). No RWE data on diarrhea for tirzepatide were identified (Table S6). Placebo-adjusted discontinuation due to diarrhea was ≤2% in all publications that reported the AE [12,36,52,70,94,103].

3.2.4. Constipation

Constipation was reported in 55 publications, and occurred at higher rates with IBTs than placebos, but never as a severe or serious AE (Table S6). In clinical studies, there was no clear difference across IBTs in the placebo-adjusted incidence of constipation; the incidence ranges for liraglutide, semaglutide, and tirzepatide were 1.8–31%, 5.3–23%, and 4.4–16.2%, respectively. A similar pattern of no difference between IBTs was seen in the RWE (Figure 4). The incidence ranges of RWE data were 1.2–25.6%, 2.6–23%, and 3% (n = 1) for liraglutide, semaglutide, and tirzepatide, respectively. Reported constipation discontinuation rates were 0.7% (placebo-adjusted) and 0.5% (no placebo data) in clinical studies (both evaluating tirzepatide) [36,94]. In one semaglutide RWE study, the discontinuation rate was 24.6%; however, the population was small (n = 61) [39].

3.2.5. Vomiting

Fifty-four publications reported vomiting (seven publications reported nausea and vomiting as a combined AE) (Table S6), with only one vomiting event reported as an SAE [68]. In clinical studies, semaglutide appeared to have a higher placebo-adjusted vomiting incidence than liraglutide and tirzepatide. The placebo-adjusted incidence ranges for liraglutide, semaglutide, and tirzepatide were 0–21%, 7–25.7%, and 4.5–15.4%, respectively. RWE studies showed no clear difference across IBTs (Figure 5). The incidence ranges of RWE data for liraglutide, semaglutide, and tirzepatide were 0–15.3%, 1–38%, and 15% (n = 1), respectively. Placebo-adjusted discontinuation due to vomiting AEs was reported by five publications [12,36,52,94,103] and ranged from 0 to 2.1%.

3.2.6. Abdominal Pain

Abdominal pain/discomfort (38 publications) was generally mild or moderate (Table S6). One publication reported a single AE of severe stomach pain [83]. In clinical studies, the data showed no discernible difference across IBTs. The placebo-adjusted incidences for liraglutide, semaglutide, and tirzepatide were 1.5–20%, 2–16.6%, and 1.6–14.3%, respectively. RWE data also showed no clear difference between the IBTs (Figure 6). Incidence ranges for RWE data for liraglutide, semaglutide, and tirzepatide were 0–8.3%, 0.9–11.5%, and 3% (n = 1), respectively. Discontinuations due to abdominal pain were reported in three publications [12,36,104] and ranged from 0 to 1.4% (placebo-adjusted).

3.2.7. Pancreatitis

The percentage of patients experiencing pancreatitis was ≤2% across all studies that recorded this AE (22 publications) [11,12,13,14,36,40,47,52,62,63,73,77,78,80,81,84,85,89,91,93,94,103]. The net difference between treatment and placebo arms was 0% in 11 publications and <1% in the remaining six. However, a pharmacovigilance study of FDA AE reporting related to semaglutide found pancreatitis to be an AE signal with strong clinical priority [89]. In a study by Pi-Sunyer et al., 2015, pancreatitis was reported as an SAE by four (0.2%) patients treated with liraglutide compared with zero in the placebo group [81].

3.2.8. Gallbladder-Related Disorders

Nineteen publications reported gallstones or gallbladder-related disorders [11,12,13,14,30,36,40,52,62,65,74,77,78,84,85,93,94,103] in 0–3.1%, 0.2–7%, 0–2.9% of patients treated with liraglutide, semaglutide, and tirzepatide, respectively. Among publications with an IBT vs. placebo comparison, five and four reported numerically lower and higher AE incidences in the placebo cohorts, respectively, suggesting no consistent trend. No considerable numerical difference between AE incidences was observed (all between 0 and 3.7%). Severe or serious acute gallbladder disease was reported in two patients (0.7%) with tirzepatide (zero in the placebo group) by Wadden et al. 2023 [94], and seven patients (0.9%) with tirzepatide (three [0.9%] in the placebo group) by Aronne et al. 2024 [36]. The occurrence of gallstones was reported in a semaglutide RWE study in one patient (0.3%) [30]. A second RWE study measured gallbladder disorders in patients treated with liraglutide, but recorded 0 events [78]. Cholelithiasis and cholecystitis were reported in two publications as SAEs, affecting 0.2–1.4% of patients treated with liraglutide [67,81].

3.3. Body Composition Changes

Changes to lean body mass (LBM) defined as total body weight minus fat mass, and bone mineral density were reported in 8 of the 81 identified publications [12,13,37,45,50,73,75,87]. Reporting of outcomes was heterogeneous (vs placebo/comparator or vs. baseline, kg vs. percentage change), and are summarized in Table 1. Two studies reported a loss of LBM that was similar to the loss of fat mass (FM) [50,73]. There was a trend towards greater FM loss than LBM loss in the remaining studies. One publication reported changes in bone mineral density [73].

3.4. Hair Loss

Hair loss/alopecia, reported in six publications, occurred in 4.9–7.0% of patients treated with tirzepatide compared with 0.9–1.4% treated with placebo [12,30,36,63,83,94]. For oral semaglutide, hair loss was reported by 7% of patients, compared with 3% on placebo [63]. In a real-world setting, 0–0.6% of patients treated with semaglutide experienced hair loss [30,83].

3.5. Fatigue

Fatigue was reported as an AE in 19 publications [30,43,44,54,55,63,66,67,69,70,73,81,84,85,88,93,94,95,96]. Liraglutide was evaluated in 11 publications, of which 8 were clinical studies and 3 were RWE studies. In clinical studies, the placebo-adjusted incidence of fatigue ranged from 0 to 15.6%. In RWE studies evaluating liraglutide, fatigue was reported in 1–5% of patients.
Seven publications evaluated semaglutide: four clinical and three RWE studies. In the clinical studies, which included the STEP 3, 4, 8, and OASIS-1 trials, the placebo-adjusted incidence of fatigue ranged from 1 to 8%. In the RWE studies, the incidence of fatigue ranged from 5.4–7%.
Two studies reported fatigue AEs for patients treated with tirzepatide. In patients given the highest tolerable dose (10 or 15 mg), the placebo-adjusted incidence of fatigue was 6.4% and 3.9% [70,94].

3.6. Dermatological and Immunological Adverse Events

Dermatological AEs were reported in 29 publications [11,12,13,30,40,43,45,49,58,60,62,66,67,71,73,74,75,78,81,83,85,87,88,92,93,94,96,102], of which 24 reported injection site reactions (including bruising, euthymia, irritation, hematoma and itching) with a placebo-adjusted incidence range of 0–12.5%. Other dermatological AEs reported were rash (3.6%) [78], pruritus (1.7%) [43], urticaria (3%) [73], cellulitis (0–<1%) [67,81,93], and oedema peripheral (6.5%) [67].
Immune system disorders were investigated in one publication, but there were no events reported [102].

3.7. Serious Adverse Events

Serious AEs included death, disability, fatal AEs, fatal events, hospitalization (initial or prolonged), life-threatening events, events that required intervention in any system organ class category any SAE that was not further defined. SAEs were reported in 39 publications [8,11,12,13,14,21,32,35,36,40,42,51,52,58,62,63,65,66,67,68,70,74,76,77,81,84,85,86,89,93,94,96,98,102,103,104]. SAEs occurring in >5% of patients were reported in 26 studies [11,12,13,14,35,40,42,51,52,58,62,63,65,66,67,70,74,77,84,85,86,93,94,96,103,104], with 9 publications reporting SAEs in >10% of patients [11,14,66,67,85,86,89,103,104]. The placebo-adjusted incidence of any SAE ranged from −13.7–3.2%, −3.9–7.2%, and −3.9–2.6% for liraglutide, semaglutide, and tirzepatide, respectively (where negative values indicate a higher incidence of SAEs in the placebo/control arm). In one RWE study using the FAERS database, the incidence of other serious AEs was 9.5% and 17.6% for liraglutide and semaglutide, respectively [104].

3.8. Timing of Adverse Events

In clinical trials, AEs occurred most frequently during the dose-escalation phases for all therapies. In the SCALE clinical studies (liraglutide), most AEs were mild or moderate in severity, and occurred primarily within the first four to eight weeks of treatment (during dose escalation). The proportion of patients experiencing nausea then gradually decreased up to the end of the trial period [42,67,81,95].
In the STEP 1–4 trials (semaglutide), the proportion of participants experiencing nausea increased from 0 to ~20% from Week 0 to Week 20 (dose escalation or run-in period), then decreased to ~4% by Week 68 (maintenance phase) [13,65,84,93,98]. The frequency trends of diarrhea, vomiting, and constipation were similar to that of nausea, but with a lower incidence (i.e., increasing up to Week 20 and gradually decreasing up to the end of the trial).
In the SURMOUNT clinical trials (tirzepatide), AEs were also most frequent during the dose-escalation phase (first 20 weeks), with the proportion of patients experiencing AEs decreasing up to the trial endpoint [12,36,52,94,103].

3.9. Health-Related Quality of Life

Twenty-seven publications (all clinical studies) reported quality of life outcomes [8,12,13,14,36,42,51,52,58,61,62,63,64,65,66,67,68,71,73,74,77,81,84,93,94,96,103]. The Impact of Weight on Quality of Life (IWQoL) questionnaire (n = 16) [8,13,36,42,51,52,62,63,64,65,67,68,73,74,81,94,103], and the Short-Form 36 (SF-36) (n = 16) [8,12,13,36,51,61,62,63,65,67,74,81,84,93,94,96,103] were most frequently used. In almost all of these studies, a significant improvement in functional measures was observed for the IBT groups compared with the placebo groups, although this was often observed for physical function, but not mental domain scores. The results of the EuroQoL-5 dimension questionnaire [14] showed a similar pattern. Liraglutide also significantly improved treatment satisfaction vs. placebo (Diabetes Treatment Satisfaction Questionnaire) [42] (p = 0.007 for the 3 mg dose group). In contrast, liraglutide did not improve arthritis-associated pain vs. placebo (Knee Injury and Osteoarthritis Outcome Score, Intermittent and Constant Osteoarthritis Pain) [58], and did not affect Clinical Global Impression [71] or Schizophrenia Quality of Life Scale scores [66]. Lean et al. [68] found that vomiting did not negatively impact quality of life improvements with liraglutide.

4. Discussion

In the large number of publications identified in this review, GI AEs were most common. After subtracting placebo rates, the incidences of nausea, diarrhea, constipation and vomiting were largely in the range of 0–30% in clinical studies. Abdominal pain was less common, reported by 0–10% of patients (after adjustment for placebo). Historically, pancreatitis has been a concern for IBTs [91,105]. More women than men were included in the studies identified in the publications. In high-income countries like the US, Canada, Australia, and most of Europe, obesity rates are comparable between men and women. However, a higher proportion of women participate in weight-loss clinical trials [106]. This could be due to several reasons, including a higher health-seeking behavior and stronger societal pressures related to body image. While across the identified studies, pancreatitis incidence was low, it continues to be highlighted as a signal with strong clinical priority [89]. Gallbladder disorders, listed under “Warnings and Precautions” in IBT summaries of product characteristics [107,108,109], were rare and only reported in a small number of studies. Non-GI-related AEs included hair loss and fatigue, both reported in several publications. Although the reported incidences of these were much lower than those of the GI-related AEs, they warrant further research. Dermatological AEs were not systematically listed in all publications, most likely due to heterogeneity in study observations and the method of data capture. Injection site reactions were the most common dermatological AE, likely due to the subcutaneous mode of administration of IBTs.
Adverse events were most often mild or moderate, and they primarily occurred during the dose escalation period. The incidences of AEs were lower in RWE studies than in clinical trials. In the graphs presented, this fact is masked by the placebo adjustment, which makes the incidence appear similar. The difference is most likely due to RWE not necessarily capturing AE data as frequently or systematically as in clinical trials [12,68,70]. Furthermore, both treatment doses and adherence are often lower in RWE studies, which can reduce the incidence of AEs [12,68,69,70]. Rates of discontinuation due to AEs were low (<3% for nausea, ≤2% for diarrhea, <1% for constipation, <2.1% for vomiting, and <1.4% for abdominal pain), with the exception of two RWE studies (66% and 24.3%, respectively), which should be considered as outliers [39,69]. For all outcomes, the observed incidence ranges of AEs were wide, due to the variation in trial design, population, and setting, as well as intrinsic experimental variability. There were a small number of serious or severe AEs across all different types of AEs recorded, and further investigation of these is warranted, to ascertain, for example, whether specific patient groups are at particular risk of severe or serious events.
Quality of life was generally improved by IBTs over placebo, where the strongest benefits were seen in physical rather than mental component scores. Based on a single study, treatment satisfaction with IBTs was high [42]. The negative effects of GI AEs or nutritional AEs (i.e., changes in body composition and bone mineral density) were not captured in the patient-reported outcome tools used, except by Lean et al. [68], who found that vomiting did not significantly reduce the quality of life improvements seen with liraglutide.
Placebo was the most commonly used comparator across the included studies, while two studies compared IBTs with lifestyle modification programs [61,90] and one compared liraglutide and lifestyle modification with sleeve gastrectomy [37], not allowing any qualitative comparison of AE profiles between IBTs and other weight loss methods.

4.1. Incretin-Mimetic Medications and Nutrition

While sustainable weight loss is the primary goal of patients taking IBTs [2], there is a concern regarding adequate intake of macro- and micronutrients, due to overall reduced food intake [110]. Nutritional interventions provided alongside IBTs may help address these changes [111] and ensure that patients do not exacerbate AEs such as diarrhea and constipation. Recommending higher fiber intake and/or probiotics supplementation may provide benefits in such situations [112,113]. When managing obesity and weight-related conditions, comprehensive care could be achieved by incorporating registered dietitians, clinicians, lifestyle counselors, and integrating communication with patients to optimize outcomes and proactively manage IBT AEs [114,115]. Currently, there is a lack of data on dietary intakes of patients taking IBTs and on outcomes in terms macro- and micronutrient deficiencies; only one publication from this SLR recorded calorie intake [37], and none recorded dietary composition. Rapid weight loss can also result in a reduction in bone mineral density [116]; however, the single study identified in this review that reported results showed no such effect [73]. Further research is needed to assess the need and benefits of nutritional interventions, which should be tailored to individual patient needs [117].
Few publications provided any information on body composition changes (8 of 81 publications) [12,13,37,45,50,73,75,87]. Six publications reported a greater loss of FM than LBM. Contrary to expectations, two publications, both on liraglutide, indicated a similar reduction in LBM and FM [50,73]. The reporting of body composition outcomes was heterogenous across the studies with different study designs and measurements used (e.g., absolute change, percentage change, or FM/LBM). A 2024 meta-analysis of musculoskeletal health outcomes during GLP-1RA-based treatment identified 10 relevant publications [118]. Their findings were largely aligned with ours. The meta-analysis suggested that approximately 30% of weight loss was LBM; data were insufficient for analysis of other parameters [118]. Given that two studies identified in our review suggest a loss of LBM that is similar to that of FM [50,73], monitoring of body composition in clinical practice may be beneficial to avoid unfavorable changes in body composition.
The loss of LBM (including muscle mass) during weight loss may be an issue in people already affected by sarcopenic obesity or older patients who are at risk of age-related sarcopenia, potentially leading to frailty, disability, and loss of autonomy [119], although there is currently insufficient evidence. To measure these effects, long-term studies, specifically designed to answer this question, would be required. Due to the satiety effect of IBTs, patients may consume less protein than is required to maintain lean body mass [18]. The loss in LBM (50% of which may be assumed to be) [120] with IBTs can be greater than the expected age-related muscle loss [121]. While the effects of such losses remain controversial [120,121], they should be considered by clinicians. Nutritional interventions have been shown to support the preservation of lean muscle mass, as a proportion of total weight, during weight loss [117], and could be considered as a safety measure in patients at risk of excessive LBM loss.

4.2. Findings Compared with Other Literature and Future Directions

The body of evidence around the safety of IBTs for the treatment of obesity continues to grow, as demonstrated by the recent publication of a US pharmacovigilance study, not captured in our systematic searches [122], which highlights an increased risk of mortality and serious AEs for some treatments and certain patient groups. To the best of our knowledge, this is the first review to systematically gather data relating to AEs associated with IBTs for the treatment of obesity. A modeling study by Moll et al., 2024 [123], used data from eight RCTs to calculate the risks of individual AEs associated with treatment with liraglutide, semaglutide, or tirzepatide. The calculated risks were generally higher for tirzepatide than the other IBTs based on the limited sample included. A number of reviews on similar topics have also been previously published [124,125,126,127,128], focusing on efficacy [125] or case reports [126], being narrative reviews [127,128], or including a much smaller sample of studies [124]. The work by Vosoughi et al., 2021 [125], highlighted dulaglutide and exenatide, neither of which were included in our review, as being associated with the highest discontinuation rates due to AEs (based on 64 studies); they also noted nausea and vomiting as common side effects for all agents evaluated. A non-systematic review by Tobaiqy et al., 2024 [128] did not allow the authors to draw any firm conclusions, given the mixed results of the included trials. The AEs collated by Shetty et al., 2022 [126], from case reports, primarily include GI, renal, and hepatic events, but also found dermatologic and immunologic events, which were not identified in the studies included here. We can only speculate that this may be due to the outcome definition of the included clinical trials. Meta-analyses of the efficacy and safety of individual IBTs (liraglutide [seven studies] and semaglutide [four studies]) and of tirzepatide compared with semaglutide (twenty-eight studies) have also previously been published [129,130,131]. Their findings generally align with those reported here. The majority of previous publications focus on efficacy and cost-effectiveness. While they take AEs into consideration, they are largely included as discontinuation rates, or focus on SAEs, with few discussing the impact of IBTs on nutrition, body composition, or LBM. This lack of data on dietary intake quality and adequacy in patients with obesity who are taking IBTs has also been highlighted by a recent review, raising concerns around the potential loss of muscle mass and micronutrient deficiencies [110].

4.3. Strengths and Limitations

The current SLR focused on the currently approved IBTs and excluded some of the newer therapies that have not yet received approval by regulatory bodies. Since these newer therapies were supported by limited evidence, their exclusion would have little impact on the generalizability of our results. Although a date restriction of 2014 onwards could be considered a limitation, given the relatively recent approval of incretin mimetics for the treatment of obesity, this is unlikely to have introduced any meaningful bias into our findings. Excluded studies also included those with <50 patients, which could have introduced a greater degree of variability and reduced the generalizability of our findings. The data identified in this review should not be applied to the use of these therapies in the management of T2DM, given that the dosing in the obesity indication is approximately twice as high as that in the T2DM indication. The majority of studies had a low or unclear risk for all components of the RoB tool. Our review included both populations with and without T2DM, and was not designed to evaluate any differences in the AE profile between them. Differences in AE incidence between the treatment arms were generally not statistically analyzed. There was also a lack of long-term data and no data reporting the burden of AEs on patients have been identified. Strengths of our analysis include the robust, predefined methodology, conforming to published guidelines issued by the Cochrane Collaboration [132] and the Centre for Reviews and Dissemination (CRD) (York, UK) [133], the methodological requirements of the National Institute for Health and Care Excellence [134], and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [135] guidelines. As with any other medication, it is to be expected that the incidence of AEs will be dose-dependent. For our graphical representations, we have chosen the standard maintenance doses selected (i.e., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg).

5. Conclusions

To the best of our knowledge, this is the first review to systematically gather data relating to AEs associated with IBTs for the treatment of obesity. IBTs offer great efficacy and improvements in HRQoL, and clinicians should keep in mind the relatively high occurrence of associated AEs when considering prescribing IBT. Future research should capture if and how nutritional aspects are modulated with IBT and explore their impact in high-risk groups (such as older individuals and those with sarcopenic obesity) where additional nutritional preventive measures may be required.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/obesities5020029/s1, Table S1: Eligibility criteria for the SLR; Table S2: Search strategy for Embase (1974 to 2024 Week 22): accessed on 4 June 2024; Table S3: Search strategy for Ovid MEDLINE(R) Epub ahead of print and in-process, in-data review and other non-indexed citations and daily (3 June 2024): accessed on 4 June 2024; Table S4: Search strategy for EBM reviews—Cochrane Central Register of Controlled Trials (April 2024); EBM reviews—Cochrane Database of Systematic Reviews (2005 to 29 May 2024); EBM reviews—Database of Abstracts of Reviews of Effects <first Quarter 2016>; EBM reviews—Health Technology Assessment (4th Quarter 2016); EBM reviews—NHS Economic Evaluation Database (1st Quarter 2016): accessed on 4 June 2024; Table S5: search strategy for Econlit (1886 to 27 May 2024): accessed on 4 June 2024; Table S6: summary of included studies.

Author Contributions

Conceptualization, R.F.K., K.A.T. and A.M.; methodology, R.F.K., O.E.J. and A.M.; writing—original draft preparation, R.F.K., K.A.T. and A.M.; writing—review and editing, R.F.K., O.E.J., K.A.T., T.-M.P. and A.M.; visualization, R.F.K., O.E.J., K.A.T., T.-M.P. and A.M.; supervision, R.F.K. and A.M.; project administration, A.M. All authors have read and agreed to the published version of the manuscript.

Funding

Nestlé Health Science, Vevey, Switzerland, sponsored and funded this study.

Data Availability Statement

All the data reviewed in this manuscript are available online.

Acknowledgments

The authors would like to thank Paul Cowling (Clarivate) for support in preparing the manuscript.

Conflicts of Interest

R.F.K. is on the medical advisor board for Novo Nordisk and consultant to Eli Lilly. O.E.J., T.-M.P. and A.M. are employed by Nestlé Health Science, Switzerland. K.A.T. is employed by Nestle Health Science, Bridgewater, NJ, USA.

Abbreviations

The following abbreviations are used in this manuscript:
AEAdverse event
AOMAnti-obesity medication
BMIBody mass index
CAConference abstract
CIConfidence interval
CRDCentre for Reviews and Dissemination
FDAFood and Drug Administration
FMFat mass
GIGastrointestinal
GLP-1Glucagon-like peptide-1
GLP-1RAGlucagon-like peptide-1 receptor agonist
HRQoLHealth-related quality of life
IBTIncretin-based therapy
IWQoLImpact of Weight on Quality of Life
LBMLean body mass
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses
RCTRandomized control trials
RoBRisk-of-bias
RWEReal-world evidence
SAESerious adverse event
SDStandard deviation
SF-36Short-Form 36
SLRSystematic literature review
T2DMType 2 diabetes mellitus
USUnited States

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Figure 1. Study flow of included and excluded publications. Abbreviations: N, number of citations; CA, conference abstract; ref., reference.
Figure 1. Study flow of included and excluded publications. Abbreviations: N, number of citations; CA, conference abstract; ref., reference.
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Figure 2. Nausea incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm. The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
Figure 2. Nausea incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm. The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
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Figure 3. Diarrhea incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3379 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
Figure 3. Diarrhea incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3379 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
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Figure 4. Constipation incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm. The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
Figure 4. Constipation incidence reported in clinical publications (placebo-adjusted and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm. The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, the closest one to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
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Figure 5. Vomiting AE incidence reported in clinical publications (placebo-adjusted and RWE publications. The size of each bubble represents the combined number of patients in the treatment and comparator arms. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, that closest to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
Figure 5. Vomiting AE incidence reported in clinical publications (placebo-adjusted and RWE publications. The size of each bubble represents the combined number of patients in the treatment and comparator arms. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, that closest to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
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Figure 6. Abdominal pain incidence reported in clinical publications (placebo-adjusted) and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in the placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, that closest to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
Figure 6. Abdominal pain incidence reported in clinical publications (placebo-adjusted) and RWE publications. Placebo-adjusted incidence was calculated by subtracting the percentage of patients with an AE in the placebo/comparator arm from the intervention arm (a negative value indicates that the incidence of AEs was greater in the placebo group than the treatment group for that publication). The size of each bubble represents the combined number of patients in the treatment and comparator arms. For the clinical and RWE publications, the largest bubble is representative of 3731 and 11,326 patients in that study, respectively. Treatment arms for the maintenance dose (or highest dose where maintenance was not used) were selected (e.g., liraglutide 3 mg, semaglutide 2.4 mg, and tirzepatide 15 mg), where a study had more than one treatment arm for the same IBT. If applicable, slow/regular dose escalation group data were selected. If multiple timepoints were available, that closest to 52 weeks was selected. Pooled analyses were selected where available. If multiple studies were recorded in a single publication, these were included separately (where no duplication of data occurred). Abbreviations: IBT, incretin-based therapy; RWE, real-world evidence.
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Table 1. Summary of publications reporting changes to body composition.
Table 1. Summary of publications reporting changes to body composition.
Study and IBTOutcome MeasuresResults
Mok et al., 2023 [73]
Liraglutide		Change in body composition in kg (mean [SD]) after 24 weeksLBM: −4.2 (3.0) kg
FM: −4.1 (9.2) kg
LBM-adjusted mean difference vs. placebo (95% CI) of −3.2 (−4.8, −1.6) kg
FM-adjusted mean difference vs. placebo (95% CI) of −4.9 (−7.2, −2.5) kg
Frøssing et al., 2018 [50]
Liraglutide		Change in body composition in kg (mean [SD]) from baseline after 26 weeksLBM: −2.4 (0.4) kg
FM: −2.6 (0.5) kg
LBM treatment difference vs. placebo (95% CI) of −2.3 kg (−3.5, −1.2), p < 0.001
FM treatment difference vs. placebo (95% CI) of −2.8 kg (−4.6, −1.1), p = 0.002
Santini et al., 2023 [87]
Liraglutide		Change in body composition in kg (mean [SD]) after 10 months of treatmentLBM: 55.0 (±10.6) kg to 51.7 (±11.3) kg
FM: 54.4 (±11.8) kg to 44.0 (±10.6) kg
Capristo et al., 2018 [37]
Liraglutide		Change in body composition (mean [SD]) after 1 year of intensive lifestyle modification and liraglutide LBM: −8.3 (5.7) kg
FM: −16.4 (9.4) kg
Elkind-Hirsch et al., 2022 [45].
Liraglutide		Change in total LBM in kg before and after treatment vs. placebo and change in total body % fat vs. placebo after 36 weeksLBM change with liraglutide (−0.9 kg) vs. placebo (−0.3) was not significant, p = 0.24
Total body % FM change with liraglutide (−1.6%) vs. placebo (−0.3%) was significant (p = 0.028)
Neeland et al., 2021 [75]
Liraglutide		ETD (95% CI) in total body lean tissue and total body adipose tissue after 40 weeksLBM vs. placebo: −1.57% (−0.23, −2.91), p = 0.029
FM vs. placebo: −8.64% (−6.00, −11.27, p = 0.0001
Wilding, 2021 [13]
Semaglutide		Change in body composition from baseline in kg after 68 weeks and ETD (CI 95%) vs. placeboTotal LBM: −5.26 kg vs. placebo −1.83
Total FM: −8.36 kg vs. placebo −1.37
LBM ETD: −7.0 (−9.8, −4.2)
FM ETD: −3.3 (−5.0, −1.7)
Jastreboff et al., 2022 [12]
Tirzepatide		The ratio of total FM to LBM after 72 weeks of treatmentTirzepatide: 0.93 (at baseline) to 0.70
Placebo: 0.95 (at baseline) to 0.88
Mok et al., 2023 [73]
Liraglutide		Bone mineral density changes after 24 weeks of treatment compared with placeboAdjusted mean difference (95% CI): −0.00 (−0.02 to 0.02)
Abbreviations: CI, confidence interval; ETD, estimated treatment difference; FM, fat mass; LBM, lean body mass; SD, standard deviation.
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Kushner, R.F.; Johansen, O.E.; Araujo Torres, K.; Phan, T.-M.; Marczewska, A. Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects. Obesities 2025, 5, 29. https://doi.org/10.3390/obesities5020029

AMA Style

Kushner RF, Johansen OE, Araujo Torres K, Phan T-M, Marczewska A. Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects. Obesities. 2025; 5(2):29. https://doi.org/10.3390/obesities5020029

Chicago/Turabian Style

Kushner, Robert F., Odd Erik Johansen, Krysmaru Araujo Torres, Trà-Mi Phan, and Agnieszka Marczewska. 2025. "Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects" Obesities 5, no. 2: 29. https://doi.org/10.3390/obesities5020029

APA Style

Kushner, R. F., Johansen, O. E., Araujo Torres, K., Phan, T.-M., & Marczewska, A. (2025). Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects. Obesities, 5(2), 29. https://doi.org/10.3390/obesities5020029

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