Exploring Side Effects and Discontinuation Reasons of Glucagon-Like-Peptide-1 Agonist (Liraglutide, Semaglutide) for Weight Loss Among Patients at King Abdulaziz University, Jeddah in 2021 to 2023

Nesrain Mubarak Alhamedi^1*, Lamis Awad Alassiri³, Atheer Mohammed AlMalki³, Ghaythah Hamed Alkhathami³, Dima Mohammed Alsulami³, Relam Ibrahim Alhassani³, Fatima Saeed Allakhmi³, Hala Hisham Mosli²

¹Department of Family Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
²Department of Internal Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
³College of Medicine, King-Abdulaziz University, Jeddah, Saudi Arabia

*Correspondence author: Nesrain Mubarak Alhamedi, Department of Family Medicine, King Abdulaziz University, Jeddah, Saudi Arabia;
Email: [email protected]

Citation: Alhamedi NM, et al. Exploring Side Effects and Discontinuation Reasons of Glucagon-Like-Peptide-1 Agonist (Liraglutide, Semaglutide) for Weight Loss Among Patients at King Abdulaziz University, Jeddah in 2021 to 2023. Jour Clin Med Res. 2025;6(1):1-12.

Copyright^© 2025 by Alhamedi NM, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Table 1: Demographic characteristics of patients.

Table 2: Characteristics and outcomes of using GLP-1 Receptor Agonists.

Table 3: Statistical differences in the development of side of effects between different age groups.

Table 4: Statistical differences in the development of side of effects between different groups of duration of using GLP-1 agonists.

Discussion

In this retrospective study, we aimed to investigate the side effects and causes of GLP1 (liraglutide, semaglutide) discontinuation in patients who were using it to lose weight. We discovered that a significant portion of patients (80.2%) reported experiencing adverse symptoms, with nausea accounting for the majority (77.5%). The high rate of discontinuations may be explained by the high frequency of adverse effects. Despite this, the two main reasons why 73.4% of patients stopped taking the drug were cost (21.9%) and personal preference (45.8%). The fact that 63.6% of patients failed to meet their weight loss objectives is noteworthy and raises concerns regarding the efficacy and expectations around GLP-1 receptor therapy.

The overall development of adverse effects did not differ significantly between age groups, according to our study (p=0.356). But patients between the ages of 45 and 60 had significantly higher rates of depression (20.4%, p = 0.005), and younger patients (under 45) had higher rates of nausea (85.7%) than older patients (p = 0.011). These results point to variations in certain adverse effects with age, which may help with individualized patient care.

Our findings revealed that the duration of GLP-1 receptor agonist use significantly impacted both adverse effects and weight loss. Patients who used the medication for over six months experienced greater weight loss (20 kg or more in 24.3% of cases, p<0.001) and reported fewer side effects (28.8%, p<0.001) compared to those with shorter usage periods. This pattern suggests the possibility of an adaptation phase, where prolonged use leads to improved tolerability and effectiveness.

In our study, the majority of individuals (80.2%) developed adverse effects from using GLP-1RAs. The most common symptom reported was nausea (77.5%), which was followed by vomiting and loss of appetite (36.6%)  Each of loss of appetite and vomiting was reported by 36.6% of the patients. Abdominal discomfort (33.8%), and headache (19.0%). Given that semaglutide and liraglutide were the drugs evaluated in this research, a large percentage of individuals reporting adverse responses may be explained by the fact that Semaglutide and Liraglutide exhibited the highest rate of adverse events among different GLP-1RAs in a previous real-world analysis [8]. In keeping with previous studies, the majority of GLP-1RA side effects that occur in clinical practice are Gastrointestinal (GI) in nature. These effects include nausea, vomiting, diarrhea and constipation. Side effects seem to be dose-dependent, usually brief, mild to moderate in severity, and primarily occur during the start of treatment and upon uptitration [35]. In a clinical trial, which comprised older patients with overlapping illnesses, the prevalence of GI problems was greater than their counterparts controls [36].

One third of participants in the current study were middle-aged, within the age of 45 to 60 years old, and 79.1% of them were female. According to earlier studies, women experienced more adverse effects than men did (65.89% vs. 30.96%), and the median age of those patients was 56 years [37]. Age and duration of GLP1-RAs use were associated with a higher likelihood of adverse effects. Significantly, adverse effects decrease with extended usage, which may indicate improved tolerance or, conversely, drug tachyphylaxis. The duration of GLP-1 receptor agonist usage was found to have a significant impact on the development of side effects, with patients taking GLP-1 agonists for more than 6 months reporting a lower incidence of side effects (28.8%), compared to those using them for less than 3 months (90.9%) and those using them for 3 to 6 months (92.6%) (p < 0.001). indicating that adverse effects are an  uncommon phenomena after six months of usage and are more common during the initial stages of therapy, which occur within the first three to six months of using the medication as these side effects mostly develop at the beginning and at times of dose increase, this finding is consistent with previous results from several clinical trials that suggested there may be a dose and class effect dependency [35, 38-40].

It was observed that individuals using GLP-1RAs for less than three months experienced a significant increase in both vomiting and abdominal pain; those using the drug for three to six months experienced a delayed onset of headache, and those using it for more than six months experienced a late finding of depression (p = 0.019, p < 0.001, p = 0.029,p = 0.036, respectively). Nausea was also substantially more prevalent in patients under 30 years old (100%) and in individuals 30 to less than 45 years old (85.7%) compared to older age groups (p = 0.011). Depression was significantly more common in patients 45 to 60 years old (20.4%) (p = 0.005). It is implied that age is a factor that may influence the occurrence of depression and nausea in various patient populations. This might be explained by hormonal and metabolic variables that have not yet been identified but may interact with GLP-1RA usage in those specific age groups. This result, however, is at odds with other research that suggested GLP-1RAs had antidepressant effects [41-43]. The study’s self-reported nature may provide an explanation for this finding, since patients may have mistakenly classified feelings of worry, dread, or despair for depression.

Inflammation, mood and appetite hormones, such as cortisol and thyroid hormones, are also said to be regulated by GLP-1 RAs [43-45]. GLP-1 RAs causing anxiety have been reported [46], despite its potential antidepressant effects [41-43]. In fact, complex symptoms including anxiety, sleep difficulties, and depression alleviation may be explained by the GLP-1 RA-related potential change of GABAergic neurotransmission [47,48]. Yet, a recent systematic review analysis of individuals with Type-2 diabetes mellitus identified a dearth of evidence that raised the possibility that GLP-1RA users may experience ambiguous side effects or perhaps see an increase in depression incidence [49].

More than half (73.4%) of GLP-RA users in this study stopped using the drug. Personal issues accounted for 45.8% of the causes, followed by costs (21.9%) and medication schedule (20.0%). In a cross-sectional study that evaluated the reasons for discontinuation of GLP-1 Receptor Agonists (GLP-1RAs) among patients with type 2 diabetes mellitus, while excluding cost as a factor, it was found that gastrointestinal symptoms, specifically vomiting and nausea were the predominant reasons for discontinuation reported by both patients and physicians [24].  A recent retrospective cohort study found that the percentage of people who stopped taking GLP-1 agonists was 26.2%, 30.8%, and 36.5% at 3, 6, and 12 months, respectively [50]. Compared to individuals with diabetes mellitus or both conditions combined, obese patients were more likely to discontinue treatment after a year [50].

Regarding GLP-RA effectiveness, 63.6% of research participants did not reach their set weight loss goals. The average weight reduction was 6 kg, 46.6% of individuals lost less than 10 kg, 22.4% lost between 10 and less than 20 kg, and only 13.8% of the participants lost 20 kg or more. As might be expected, those who used the drug for more than six months were substantially more likely to lose twenty kg or more (24.3%, p < 0.001). In a follow-up analysis including 175 patients, those who took GLP-1RAs for three months lost 6.7 kg of weight; those who continued using them for a full year lost 12.3 kg [51]. Additionally, a benefit-harm balance analysis showed that the significant factors influencing the net benefit of weight loss were patient preferences, risk aversion and willingness to accept risks. Even a 5% weight loss may be net beneficial for those who are more eager in decreasing weight and less concerned about the potential risks [52].

The significant prevalence of nausea as a side effect is likely contributing to the high rate of discontinuation, with 73.4% of patients stopping the medication. The distress associated with nausea can lead to negative perceptions of the treatment, prompting individuals to reassess the benefits versus the discomfort they experience. Additionally, the study showed that a substantial number of patients (63.6%) did not reach their weight loss goals, which may have further exacerbated feelings of frustration and disappointment, leading them to stop the medication. Given that nausea can be a challenging side effect to manage, it is crucial for healthcare providers to address this issue directly with patients.

Limitations

Self-Reported Data: The reliance on self-reported side effects and reasons for discontinuation may lead to inaccuracies, as patients might underreport or overreport their experiences.

Sample Size and Demographics: Although 354 patients were included in the study, most of them were Saudi nationals and female, which may limit the applicability of the results to other populations or genders.

Short Follow-Up Period: Participants used GLP-1 receptor agonists for varying lengths of time, thus it’s possible that long-term effects or side effects from prolonged use were not fully captured in the study.

Conclusion

This study highlights the significant side effects and reasons for discontinuation of GLP-1 receptor agonists (liraglutide and semaglutide) among patients seeking weight loss. With 80.2% of participants reporting adverse symptoms, particularly nausea, the high discontinuation rate of 73.4% raises concerns about the efficacy and patient experience with these medications. According to the results, in order to improve patient adherence, healthcare professionals should anticipate possible side effects and establish reasonable goals for weight loss. Further research is necessary to explore long-term effects and to assess the impact of these medications on weight loss.

Conflict of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Consent to Participate

Informed consent was obtained from each participant prior to specimen collection.

Financial Disclosure

This research did not receive any grants from funding agencies in the public, commercial or not-for-profit sectors.

Data Availability

Data is available for the journal. Informed consents were not necessary for this paper.

Author’s Contribution

The authors contributed equally.

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