Exploring the off-Label use of liraglutide in the treatment of obesity: a review

Exploring the off-Label use of liraglutide in the treatment of obesity: a review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Exploring the off-Label use of liraglutide in the treatment of obesity: a review Carla Bruna Amorim Braga, João Paulo Viana Araújo Segundo, Carlos Alberto Alves Dias Filho This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6631957/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Apr, 2026 Read the published version in Molecular and Cellular Biochemistry → Version 1 posted 7 You are reading this latest preprint version Abstract Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, has been used off-label for the treatment of obesity due to its considerable weight-reducing effects. This integrative review evaluated experimental studies in humans in order to explore the pharmacological mechanisms, metabolic effects, and the various clinical responses involved in the use of this drug. The research was conducted in the PubMed database, considering articles written in English and published in the last 10 years, with 9 studies included.The studies demonstrated that liraglutide is effective for weight loss and acts through gastric emptying, modulation of satiety, and influences on brain regions. Additionally, genetic polymorphisms may interfere with the clinical response. Regarding metabolic effects, improvements in glycemia and hepatic steatosis were observed, as well as possible anti-inflammatory action and improvement in blood pressure and lipid profile.The efficacy of liraglutide does not depend on variables such as BMI (Body Mass Index) or age; however, alcohol consumption and proper adherence to treatment may influence clinical outcomes. The main adverse effects, such as nausea and constipation, were well tolerated. Therefore, liraglutide can be considered a promising alternative in the management of obesity, especially in populations with multiple metabolic risk factors. Liraglutide Obesity treatment GLP-1 analog Weight loss Metabolic effects Off-label use 1 Introduction Obesity is defined as a multifactorial disease characterized by caloric intake that is incompatible with energy expenditure, resulting in an accumulation of body fat [ 7 ]. According to the World Health Organization (WHO), around 650 million adults were obese in 2016, and it is estimated that by the year 2030, one billion people will be affected. In this context, several mechanisms are associated with the development of this condition, including genetic, pharmacological, psychological, neuro-hormonal, and environmental factors [ 10 ]. Additionally, clinical conditions involving increased blood pressure, insulin resistance, and lipid profile alterations are directly related to obesity, potentially leading to cardiovascular damage and impairing patients’ quality of life, which demands comprehensive therapeutic strategies [ 17 ]. Given this, glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent a class of medications increasingly considered as an off-label option for the treatment of obesity. However, their original indication was approved for the treatment of type 2 diabetes mellitus (T2DM). The action of these drugs occurs by mimicking GLP-1, an incretin hormone responsible for stimulating insulin secretion and inhibiting glucagon release, as well as slowing gastric emptying and inducing satiety [ 3 ]. Among this therapeutic class, liraglutide has been associated with significant weight loss and improvements in metabolic profile. In 2010, this drug was approved by the FDA (Food and Drug Administration) to assist in the treatment of T2DM. By 2014, it was considered an option for chronic weight management in adults, and in 2020 it was validated for the treatment of obesity in patients aged 12 and older. For adults, a dose of 3 mg/day is recommended for weight loss, administered subcutaneously in the abdomen, thigh, or upper arm [ 2 ]. However, in the context of obesity treatment, there are still gaps in the scientific literature regarding the exact mechanism behind the weight loss and how individual variables — such as sex, age, ethnicity, and BMI — influence the treatment with liraglutide. Beyond weight loss, other potential benefits of this medication also require further study. Therefore, this literature review aims to explore the effects of liraglutide in the treatment of obesity, with emphasis on pharmacological aspects, varying clinical responses, and possible additional effects of the drug. By analyzing and discussing recent findings, the goal is to contribute to a more detailed understanding of liraglutide in obesity management and to promote safe, personalized, and evidence-based use of this medication in clinical practice. 2 Methods A review was conducted to summarize the available findings from experimental studies. The search was carried out in the PubMed database to identify relevant articles. The following descriptors were used in the search: ("Obesity" OR "Overweight" OR "Obesity, Abdominal") AND ("Glucagon-Like Peptide-1 Receptor" OR "Glucagon-Like Peptide-1" OR "Liraglutide" OR "Off-Label Use") AND ("Weight Loss" OR "Diet Therapy" OR "Exercise Therapy" OR "Behavior Therapy" OR "Pharmacologic Therapy" OR "Placebo"). The exclusion criteria included: articles that did not address the off-label use of Liraglutide in the treatment of obesity, review articles, case reports, meta-analyses, editorials, letters to the editor, studies written in languages other than English, and duplicate articles. For the characterization of the included studies, the inclusion criteria were: experimental data in humans, individuals over 18 years of age, studies that evaluated the association between Liraglutide and obesity, and studies that assessed weight loss with the use of Liraglutide and/or the mechanisms involved. 3 Results Based on the systematization and combination of these terms, 271 full-text and open-access articles published in the last 10 years were identified. In a second selection phase, aiming to assess their relevance to the current research, 25 articles were selected based on their titles, and 12 articles were considered relevant after reading the abstracts. In the end, after a full reading of the selected articles, 9 studies comprised the final sample of the present review. Table 1 presents the studies that investigated the effects of liraglutide in the treatment of obesity. The following items were analyzed: study objective, study type, sample size, duration, and main findings. Table 1 Characterization of studies and main findings related to liraglutide in the treatment of obesity. Study (Year) Objective Study Type Sample Duration Main Findings Maselli et al. (2022) [ 14 ] To investigate the impact of genotypes related to GLP-1 on weight loss and effects of liraglutide Randomized clinical trial 136 16 weeks - Gastric emptying delay at weeks 5 and 16- GLP1R rs6923761 AG/AA genotype: lower % body fat- TCF7L2 rs7903146 CC genotype: greater weight loss- Nausea associated with greater weight loss Sannaa et al. (2023) [ 18 ] To assess gastric emptying and its association with weight loss and genetic variants Case-control study 136 16 weeks - Greater delay in GET T1/2 at week 5 tended toward greater weight loss- GLP1R and TCF7L2 were not significant predictors Papamargaritis et al. (2024) [ 15 ] To assess the safety, adverse effects, and metabolic impact of long-term liraglutide use Case-control study 392 104 weeks - Sustained reduction in HbA1c- 42% experienced gastrointestinal side effects; only 1.9% discontinued- Mild improvement in triglycerides- Reduced need for new antihypertensive medications Faar et al. (2019) [ 8 ] To evaluate the effect of liraglutide on brain areas involved in satiety and metabolic parameters Case-control study 20 5 weeks - Increased OFC activation (adjusted for BMI)- Decreased blood glucose and improved lipid profile- Reduction in SBP (–5.9) and DBP (–3.3) mmHg Coppin et al. (2023) [ 4 ] To assess whether liraglutide alters food pleasure and activation of brain reward areas Randomized clinical trial 73 16 weeks - No impact on food pleasure- Similar activation of vmPFC and amygdala between groups Santini et al. (2023) [ 19 ] To assess the impact of liraglutide on hepatic steatosis, inflammation, and body composition Cohort study 136 10 months - Reduction in hepatic steatosis, NAFLD, and hsCRP- No change in cholesterol, LDL, HDL- Constipation common, no impact on weight loss- Women lost more fat mass Haase et al. (2021) [ 12 ] To investigate gastrointestinal symptoms during liraglutide treatment and their relation to weight loss Cohort study 277 12 months - Frequent constipation, no impact on weight loss- Reduction in DBP (–5.4 mmHg)- Similar effect in bariatric and non-bariatric patients Kolotkin et al. (2018) [ 13 ] To evaluate the impact of liraglutide-induced weight loss on quality of life Case-control study 2254 160 weeks - Improved quality of life (QoLRS)- Mental aspects improved only with ≥ 15% weight loss Park et al. (2021) [ 16 ] To assess factors influencing response to liraglutide in weight loss Cohort study 169 180 days - Alcohol consumption reduced weight loss- Age, BMI, HbA1c, and sex had no effect on the outcome Legend : GET T1/2 = gastric emptying half-time, OFC = right orbitofrontal cortex, SBP = systolic blood pressure, DBP = diastolic blood pressure, vmPFC = ventromedial prefrontal cortex, NAFLD = non-alcoholic fatty liver disease score, hsCRP = high-sensitivity C-reactive protein. 4 Discussion 4.1 Efficacy of liraglutide in reducing body weight The impact of liraglutide on weight reduction throughout treatment was extensively addressed in the studies analyzed. Despite variations in treatment duration and participant profiles, the studies agree on the medication’s effectiveness. Some authors observed weight loss occurring within the first weeks of treatment. Maselli et al. (2022) reported substantial weight loss after 5 and 16 weeks of treatment, with reductions of 3.8 kg and 5.8 kg, respectively. Similar results were found by Sannaa et al. (2022), who reported losses of over 1 kg in 5 weeks and more than 4 kg in 16 weeks. Farr et al. (2019) confirmed that after 5 weeks of dose escalation, weight loss was significantly greater in patients treated with liraglutide compared to the placebo group [ 14 ]. Similarly, Coppin et al. (2023) recorded an average loss of 8.96% of body weight after 16 weeks of treatment [ 4 ]. Park et al. (2019) further supported this view by analyzing weight trends over different periods, reporting average losses of 3.2 kg in 30 days, 4.5 kg in 60 days, 6.3 kg in 90 days, and 7.8 kg in 180 days, reinforcing the continuous effectiveness of liraglutide over time [ 16 ]. These findings suggest a progressive reduction in body weight and a consistent effect of the medication during the initial weeks of treatment. Longer-term studies, such as those by Santini et al. (2023) and Haase et al. (2021), reinforce this trend. Santini et al. demonstrated that after 10 months of liraglutide use, weight loss ranged from 10.0 to 14.1 kg, with 96% of patients losing at least 5% of their body weight and 61% losing more than 10% [ 19 ]. Similarly, Haase et al. reported an average weight loss of 4.1 kg after 7 months of treatment; between 7–12 months, the loss increased to 5.1 kg, and patients who continued treatment for 12 months achieved an average reduction of 7.5 kg [ 12 ]. However, the analysis by Papamargaritis et al. (2024) brings an important point regarding the long-term maintenance of weight loss. The authors found that during the first 52 weeks of liraglutide treatment, 25.4% of participants lost more than 15% of their body weight, 44.8% lost more than 10%, and 63.2% lost more than 5%, with an average weight reduction of 8.1 kg during the first year. However, by the end of 104 weeks, only 11.4% of those participants had lost more than 15% of their initial body weight, 24.2% had lost more than 10%, and 47% had lost more than 5%, resulting in an average weight loss of just 5.2 kg compared to baseline [ 15 ]. These data reveal some degree of weight regain in the second year of liraglutide use, suggesting that continued treatment and patient adherence may influence the sustainability of the results. The study by Kolotkin et al. (2018) shows weight loss after three years of liraglutide use, reporting that 10.9% of patients lost at least 15% of their initial body weight, 13.8% lost between 10% and 14.9%, and 24.7% had reductions between 5% and 9.9% [ 13 ]. However, there were no periodic analyses of weight loss, which raises questions about weight regain during the treatment period, as data were collected only at the end of the three years. Therefore, there is a need for extended studies with periodic assessments to clarify the long-term use of liraglutide. Table 2 Relationship between weight loss and treatment period with liraglutide in the studies analyzed. Study Evaluation Period Average Weight Loss Maselli et al. (2022) [ 14 ] 5 weeks -3.8 kg Maselli et al. (2022) [ 14 ] 16 weeks -5.8 kg Sannaa et al. (2022) [ 19 ] 5 weeks > 1 kg Sannaa et al. (2022) [ 19 ] 16 weeks > 4 kg Santini et al. (2023) [ 19 ] 10 months -10.0 to -14.1 kg Haase et al. (2021) [ 12 ] 7 months -4.1 kg Haase et al. (2021) [ 12 ] > 7 months -5.1 kg Haase et al. (2021) [ 12 ] 12 months -7.5 kg Coppin et al. (2023) [ 4 ] 16 weeks -8.96% of body weight Farr et al. (2019) [ 8 ] 5 weeks -2.50% of body weight Papamargaritis et al. (2024) [ 15 ] 52 weeks 25.4% lost ≥ 15%, 44.8% lost ≥ 10%, and 63.2% lost ≥ 5% of initial body weight On average − 8,1 kg Papamargaritis et al. (2024) [ 15 ] 104 weeks 11.4% lost ≥ 15%, 24.2% lost ≥ 10%, and 47% lost ≥ 5% of body weight On average − 5.2 kg (indication of regain) Kolotkin et al. (2018) [ 13 ] 3 years 10.9% lost ≥ 15%; 13.8% lost 10–14.9%; 24.7% lost 5–9.9% Park et al. (2019) [ 16 ] 30 days -3.2 kg Park et al. (2019) [ 16 ] 60 days -4.5 kg Park et al. (2019) [ 16 ] 90 days -6.3 kg Park et al. (2019) [ 16 ] 180 days -7.8 kg 4.2 Influence of individual variables on the response to liraglutide Some authors have reported that individual characteristics may influence the outcomes of obesity treatment with liraglutide. In a Swiss population, Santini et al. (2023) observed differences in weight loss between men and women undergoing liraglutide treatment, with women achieving a greater reduction in fat mass compared to men. This difference may be attributed to hormonal and metabolic variations between the sexes. However, there were no significant differences in weight loss when considering participants' BMI values or age [ 19 ]. Similarly, Park et al. (2021) demonstrated that, in a Korean population, the response to liraglutide was consistent regardless of age, baseline BMI, or HbA1c levels; however, they did not find any sex-related differences. Additionally, the authors noted that patients who consumed alcohol during liraglutide treatment experienced less weight loss compared to those who did not drink alcohol [ 16 ]. Finally, Haase et al. (2021) observed that both bariatric and non-bariatric patients experienced similar weight loss responses after 7 months of therapy. These findings suggest that while weight loss outcomes may vary based on sex, ethnicity, and lifestyle habits, they appear to be independent of age, initial BMI, and previous bariatric surgery [ 12 ]. Despite these potential influences, liraglutide remains effective across a variety of metabolic profiles. 4.3 Multifactorial processes that contribute to weight loss. Although the authors agree on the efficacy of liraglutide in promoting weight loss, different mechanisms have been proposed. Maselli et al. (2022) reported that liraglutide promotes weight loss by delaying gastric emptying of solids at 5 and 16 weeks. However, there was a reduced effect on gastric emptying half-time (GET T1/2) at 16 weeks compared to 5 weeks, suggesting that continuous activation of GLP-1 receptors by the drug may lead to tolerance. Additionally, the study pointed to increased fasting gastric volume and enhanced satiety at 16 weeks as factors contributing to weight loss [ 14 ]. These findings are supported by Sannaa et al. (2023), who found that a greater delay in GET T1/2 from baseline at 5 weeks tended to result in greater weight loss at 16 weeks [ 19 ]. Other key factors in weight loss include genetic variations in GLP1R and TCF7L2. The GLP1R gene encodes the GLP-1 receptor, which is expressed in the intestine, brainstem, and to a lesser extent in the endocrine pancreas [ 6 ]. The TCF7L2 (transcription factor 7-like 2) gene may influence pancreatic β-cell proliferation and act on intestinal endocrine cells, affecting GLP-1 production [ 5 ]. Maselli et al. (2022) proposed that the GLP1R rs6923761 AG/AA genotype was associated with a lower percentage of body fat in response to liraglutide. Furthermore, individuals with the TCF7L2 rs7903146 CC genotype experienced greater weight reduction at 16 weeks compared to those with the CT/TT genotypes [ 14 ]. These findings suggest that polymorphisms may influence liraglutide's effect on body composition and weight loss. However, Sannaa et al. (2023) noted that variations in the TCF7L2 and GLP1R genotypes were not significant predictors of weight loss [ 19 ]. Faar et al. (2019) sought to evaluate liraglutide’s effects on brain activity. The study showed that after five weeks of treatment, there were no apparent changes in brain activation related to food reward when participant anthropometric data (weight and BMI) were not considered. However, increased activation in the right orbitofrontal cortex (OFC)—a region associated with pleasure and motivation for food—was observed after five weeks when those variables were taken into account [ 8 ]. These findings indicate that brain response to liraglutide is not uniform and may vary based on individual characteristics, possibly contributing to a compensatory neural mechanism that stabilizes long-term weight loss (therapeutic plateau). When analyzing neural responses to milkshake consumption versus a taste control stimulus, Coppin et al. (2023) reported activation in the ventromedial prefrontal cortex (vmPFC) and amygdala—regions involved in reward processing [ 1 ]. However, the liraglutide group did not show significant changes compared to the placebo group. Additionally, the study found no evidence that liraglutide affects the hedonic perception of food, suggesting that weight loss may occur through mechanisms other than changes in food-related pleasure [ 4 ]. Adverse effects of liraglutide have also been discussed as contributing to reduced appetite and weight loss [ 9 , 11 ]. Maselli et al. (2022) identified nausea as a common side effect, and individuals experiencing it showed greater weight loss [ 14 ]. In contrast, Haase et al. (2021) and Santini et al. (2023) highlighted constipation as another frequent side effect but found no significant impact on weight loss among those affected [ 12 , 19 ]. This suggests that most patients lose weight regardless of clinically relevant adverse effects. Papamargaritis D. et al. (2024) observed that 42% of participants on liraglutide reported gastrointestinal side effects such as nausea, constipation, and diarrhea. However, symptoms were mild, and only five individuals (1.9%) discontinued treatment due to adverse events [ 15 ]. Therefore, despite being common, side effects are generally well tolerated, reinforcing the viability of this treatment. 4.4 Integrated assessment of other effects of liraglutide Papamargaritis et al. (2024) demonstrated that patients using liraglutide achieved sustained reductions in glycated hemoglobin (HbA1c) levels at 52 and 104 weeks compared to the control group [ 15 ]. Faar et al. (2019) and Santini et al. (2023) support these findings, as their studies showed consistent decreases in glycemic values in patients using the medication [ 8 , 19 ]. These results reinforce the effectiveness of liraglutide in controlling patients’ glycemic profiles. Santini et al. (2023) evidenced a significant reduction in the prevalence of hepatic steatosis and in the liver fibrosis score (NAFLD score) after 10 months of treatment with liraglutide. Furthermore, the authors identified improvements in hsCRP (high-sensitivity C-reactive protein) levels [ 19 ], which indicates a potential anti-inflammatory effect of the medication. These findings are relevant in populations with obesity and insulin resistance, in which liver alterations associated with chronic inflammation are frequent. There are controversies regarding the effects of liraglutide on the lipid profile. Santini et al. (2023) did not observe significant changes in total cholesterol, LDL, or HDL levels after the use of the medication, whereas Faar et al. (2019) reported improvement in all lipid parameters during treatment [ 19 ]. Papamargaritis et al. (2024) observed only slight changes in lipids, with a tendency for improvement only in triglyceride levels in the intervention group [ 15 ]. These divergences may result from differences in study methodologies, especially in terms of follow-up duration, individual participant profiles, or concurrent use of medications that affect lipid levels, such as hypolipidemic agents. Authors also diverged regarding the influence of liraglutide on blood pressure. Haase et al. (2021) reported a reduction in diastolic blood pressure (DBP) at various treatment periods, with the greatest reduction observed in patients who maintained the use of the medication for ≥ 12 months, showing an average decrease of − 5.4 mmHg. Although there was a trend toward reduced systolic blood pressure (SBP) in this group, the change was not statistically significant [ 12 ]. On the other hand, Faar et al. (2019) noted an average SBP reduction of − 5.9 mmHg and DBP of − 3.3 mmHg after 5 weeks of use [ 8 ]. In contrast, Papamargaritis et al. (2024) observed no significant differences in absolute SBP and DBP values between the placebo and intervention groups at 52 and 104 weeks. However, they noted that the intervention group required fewer additions of new antihypertensive drugs, suggesting a potential indirect benefit of the drug on blood pressure control [ 15 ]. Nevertheless, it is important to consider that improved blood pressure levels may be secondary to weight loss, making it difficult to confirm a direct antihypertensive effect of the drug. Kolotkin et al. (2018), through the IWQOL-Lite questionnaire (Impact of Weight on Quality of Life – Lite), demonstrated that liraglutide improved the quality of life in individuals with overweight or obesity over a period of 3 years. Although patients showed improvements in quality of life regardless of treatment received, participants using liraglutide experienced greater improvements, particularly in physical functioning, self-esteem, sexual life, public distress, and work performance. However, there were no significant differences between the groups in terms of bodily pain, social functioning, and emotional domains. Benefits in mental aspects were observed only in participants who achieved ≥ 15% weight loss, reinforcing the importance of more substantial weight reduction for positive psychological impacts. Despite the superiority of liraglutide, diet and physical activity also proved effective in promoting significant improvements in quality of life, highlighting the importance of combined approaches [ 13 ]. 5 Conclusion Based on the studies selected for this review, liraglutide showed considerable efficacy for weight loss, especially in the short and medium term. The main mechanisms identified for weight reduction include delayed gastric emptying, influence on satiety, and genetic polymorphisms. In addition, its use was also associated with benefits in metabolic profile, such as glycemic control, reduction of hepatic steatosis, modulation of inflammatory response, and possible influence on blood pressure and lipid values. However, variables such as sex, alcohol consumption, genetics, and adherence to prolonged treatment influenced the response to the drug. Thus, liraglutide presents itself as a promising medication, especially in populations with multiple metabolic risk factors, as in addition to the demonstrated benefits, its side effects are generally well tolerated, making it a good option for patients with obesity, metabolic syndrome, and type 2 diabetes. Nonetheless, some gaps are still identified regarding the understanding of liraglutide’s effects in obesity treatment. Moreover, there are points to be clarified regarding its action on the lipid and blood pressure profiles, as well as the influence of central and genetic mechanisms on the treatment response. These limitations may arise from the diversity in study design, different population samples, variable follow-up periods, drug interactions, and difficulty in isolating the drug’s direct effects on weight loss. In addition, most of the analyzed studies assessed these effects in the short and medium term, which limits the understanding of long-term weight maintenance, including the plateau effect or weight regain over time. Finally, further studies are needed, especially those with longer follow-up periods and longitudinal randomized trials involving patients of different ethnicities or those with other comorbidities, in order to determine who benefits most from liraglutide. Moreover, animal studies could help elucidate the main pathways of liraglutide’s action. Therefore, it is essential to understand the mechanisms of action and predictors involved in the therapeutic response to ensure safe and personalized use, maximizing the drug’s benefits. Declarations Author Contribution All authors contributed to the conception and design of the study. Material preparation, data collection, and analysis were performed by Carla Bruna Amorim Braga, João Paulo Viana Araújo Segundo, and Carlos Alberto Alves Dias Filho. The first draft of the manuscript was written by Carla Bruna Amorim Braga and João Paulo Viana Araújo Segundo, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgement The authors would like to thank AFYA Faculdade de Ciências Médicas de Santa Inês for the technical and institutional support provided during the development of this study. 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Effects of liraglutide on gastrointestinal functions and weight in obesity: A randomized clinical and pharmacogenomic trial. Obesity (Silver Spring, Md.), 30(8), 1608–1620. https://doi.org/10.1002/oby.23481 Papamargaritis, D., Al-Najim, W., Lim, J. Z. M., Crane, J., Bodicoat, D. H., Barber, S., Lean, M., McGowan, B., O'Shea, D., Webb, D. R., Wilding, J. P. H., le Roux, C. W., & Davies, M. J. (2024). Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial. The Lancet regional health. Europe, 39, 100853. https://doi.org/10.1016/j.lanepe.2024.100853 Park, J. S., Kwon, J., Choi, H. J., & Lee, C. (2021). Clinical effectiveness of liraglutide on weight loss in South Koreans: First real-world retrospective data on Saxenda in Asia. Medicine, 100(2), e23780. https://doi.org/10.1097/MD.0000000000023780 Popoviciu, M. S., Păduraru, L., Yahya, G., Metwally, K., & Cavalu, S. (2023). Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. International journal of molecular sciences, 24(13), 10449. https://doi.org/10.3390/ijms241310449 Sannaa, W., Dilmaghani, S., BouSaba, J., Maselli, D., Atieh, J., Eckert, D., Taylor, A. L., Harmsen, W. S., Acosta, A., & Camilleri, M. (2023). Factors associated with successful weight loss after liraglutide treatment for obesity. Diabetes, obesity & metabolism, 25(2), 377–386. https://doi.org/10.1111/dom.14880 Santini, S., Vionnet, N., Pasquier, J., Gonzalez-Rodriguez, E., Fraga, M., Pitteloud, N., & Favre, L. (2023). Marked weight loss on liraglutide 3.0 mg: Real-life experience of a Swiss cohort with obesity. Obesity (Silver Spring, Md.), 31(1), 74–82. https://doi.org/10.1002/oby.23596 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Apr, 2026 Read the published version in Molecular and Cellular Biochemistry → Version 1 posted Editorial decision: Revision requested 04 Aug, 2025 Reviews received at journal 05 Jul, 2025 Reviewers agreed at journal 05 Jul, 2025 Reviewers invited by journal 16 Jun, 2025 Editor assigned by journal 07 Jun, 2025 Submission checks completed at journal 10 May, 2025 First submitted to journal 09 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6631957","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":454622996,"identity":"23822828-1de8-412a-81b1-06e8d16cf137","order_by":0,"name":"Carla Bruna Amorim Braga","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYHACxgOMDTC2AYMciDrwgIAeFC3GYJEE4rUwMCSC2fi08LeffXDg5457idvZTyc+rijYlj4/7PBDoC12croN2LVInEk3ONh7pjhxZ0/uZsMzBrdzN95OMwBqSTY2O4BdiwFDGsMB3raExA0HcrdJNoC0zE4AaTmQuA2XFv5nDAf/grScfwvWkm44O/0Dfi0SaQyHwbbcgNiSIC+dg98WiRvPGA7Lnkkw3nDj7WZDoBbDDdI5BQcSDHD7hb8/jfHh2x0JshvO52582PDntrz87PTNHz5U2Mnh0oLFqQcgwUICkG8gRfUoGAWjYBSMBAAAFmhtCMS0DKIAAAAASUVORK5CYII=","orcid":"","institution":"AFYA Faculdade de Ciências Médicas de Santa Inês","correspondingAuthor":true,"prefix":"","firstName":"Carla","middleName":"Bruna Amorim","lastName":"Braga","suffix":""},{"id":454622997,"identity":"ae0f7c57-d2f2-47ee-bd90-b97f18edf149","order_by":1,"name":"João Paulo Viana Araújo Segundo","email":"","orcid":"","institution":"AFYA Faculdade de Ciências Médicas de Santa Inês","correspondingAuthor":false,"prefix":"","firstName":"João","middleName":"Paulo Viana Araújo","lastName":"Segundo","suffix":""},{"id":454622998,"identity":"8c3545be-5a1f-4d9b-afab-22f86a756800","order_by":2,"name":"Carlos Alberto Alves Dias Filho","email":"","orcid":"","institution":"AFYA Faculdade de Ciências Médicas de Santa Inês","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Alberto Alves Dias","lastName":"Filho","suffix":""}],"badges":[],"createdAt":"2025-05-10 02:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6631957/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6631957/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11010-026-05560-8","type":"published","date":"2026-04-30T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":108437603,"identity":"123edc71-b549-4b9d-be89-8de9e3356e28","added_by":"auto","created_at":"2026-05-04 16:00:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":261700,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6631957/v1/1fa2207a-79e7-41ab-9e26-bf0b6211a01d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exploring the off-Label use of liraglutide in the treatment of obesity: a review","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eObesity is defined as a multifactorial disease characterized by caloric intake that is incompatible with energy expenditure, resulting in an accumulation of body fat [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. According to the World Health Organization (WHO), around 650\u0026nbsp;million adults were obese in 2016, and it is estimated that by the year 2030, one billion people will be affected. In this context, several mechanisms are associated with the development of this condition, including genetic, pharmacological, psychological, neuro-hormonal, and environmental factors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Additionally, clinical conditions involving increased blood pressure, insulin resistance, and lipid profile alterations are directly related to obesity, potentially leading to cardiovascular damage and impairing patients\u0026rsquo; quality of life, which demands comprehensive therapeutic strategies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven this, glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent a class of medications increasingly considered as an off-label option for the treatment of obesity. However, their original indication was approved for the treatment of type 2 diabetes mellitus (T2DM). The action of these drugs occurs by mimicking GLP-1, an incretin hormone responsible for stimulating insulin secretion and inhibiting glucagon release, as well as slowing gastric emptying and inducing satiety [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAmong this therapeutic class, liraglutide has been associated with significant weight loss and improvements in metabolic profile. In 2010, this drug was approved by the FDA (Food and Drug Administration) to assist in the treatment of T2DM. By 2014, it was considered an option for chronic weight management in adults, and in 2020 it was validated for the treatment of obesity in patients aged 12 and older. For adults, a dose of 3 mg/day is recommended for weight loss, administered subcutaneously in the abdomen, thigh, or upper arm [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, in the context of obesity treatment, there are still gaps in the scientific literature regarding the exact mechanism behind the weight loss and how individual variables \u0026mdash; such as sex, age, ethnicity, and BMI \u0026mdash; influence the treatment with liraglutide. Beyond weight loss, other potential benefits of this medication also require further study. Therefore, this literature review aims to explore the effects of liraglutide in the treatment of obesity, with emphasis on pharmacological aspects, varying clinical responses, and possible additional effects of the drug. By analyzing and discussing recent findings, the goal is to contribute to a more detailed understanding of liraglutide in obesity management and to promote safe, personalized, and evidence-based use of this medication in clinical practice.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cp\u003eA review was conducted to summarize the available findings from experimental studies. The search was carried out in the PubMed database to identify relevant articles. The following descriptors were used in the search: (\"Obesity\" OR \"Overweight\" OR \"Obesity, Abdominal\") AND (\"Glucagon-Like Peptide-1 Receptor\" OR \"Glucagon-Like Peptide-1\" OR \"Liraglutide\" OR \"Off-Label Use\") AND (\"Weight Loss\" OR \"Diet Therapy\" OR \"Exercise Therapy\" OR \"Behavior Therapy\" OR \"Pharmacologic Therapy\" OR \"Placebo\").\u003c/p\u003e \u003cp\u003eThe exclusion criteria included: articles that did not address the off-label use of Liraglutide in the treatment of obesity, review articles, case reports, meta-analyses, editorials, letters to the editor, studies written in languages other than English, and duplicate articles. For the characterization of the included studies, the inclusion criteria were: experimental data in humans, individuals over 18 years of age, studies that evaluated the association between Liraglutide and obesity, and studies that assessed weight loss with the use of Liraglutide and/or the mechanisms involved.\u003c/p\u003e"},{"header":"3 Results","content":"\u003cp\u003eBased on the systematization and combination of these terms, 271 full-text and open-access articles published in the last 10 years were identified. In a second selection phase, aiming to assess their relevance to the current research, 25 articles were selected based on their titles, and 12 articles were considered relevant after reading the abstracts. In the end, after a full reading of the selected articles, 9 studies comprised the final sample of the present review.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the studies that investigated the effects of liraglutide in the treatment of obesity. The following items were analyzed: study objective, study type, sample size, duration, and main findings.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacterization of studies and main findings related to liraglutide in the treatment of obesity.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eObjective\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy Type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDuration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMain Findings\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaselli et al. (2022)\u003c/b\u003e [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo investigate the impact of genotypes related to GLP-1 on weight loss and effects of liraglutide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRandomized clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Gastric emptying delay at weeks 5 and 16- GLP1R rs6923761 AG/AA genotype: lower % body fat- TCF7L2 rs7903146 CC genotype: greater weight loss- Nausea associated with greater weight loss\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSannaa et al. (2023)\u003c/b\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo assess gastric emptying and its association with weight loss and genetic variants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase-control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Greater delay in GET T1/2 at week 5 tended toward greater weight loss- GLP1R and TCF7L2 were not significant predictors\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePapamargaritis et al. (2024)\u003c/b\u003e [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo assess the safety, adverse effects, and metabolic impact of long-term liraglutide use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase-control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e104 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Sustained reduction in HbA1c- 42% experienced gastrointestinal side effects; only 1.9% discontinued- Mild improvement in triglycerides- Reduced need for new antihypertensive medications\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFaar et al. (2019)\u003c/b\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo evaluate the effect of liraglutide on brain areas involved in satiety and metabolic parameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase-control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Increased OFC activation (adjusted for BMI)- Decreased blood glucose and improved lipid profile- Reduction in SBP (\u0026ndash;5.9) and DBP (\u0026ndash;3.3) mmHg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCoppin et al. (2023)\u003c/b\u003e [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo assess whether liraglutide alters food pleasure and activation of brain reward areas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRandomized clinical trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- No impact on food pleasure- Similar activation of vmPFC and amygdala between groups\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSantini et al. (2023)\u003c/b\u003e [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo assess the impact of liraglutide on hepatic steatosis, inflammation, and body composition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Reduction in hepatic steatosis, NAFLD, and hsCRP- No change in cholesterol, LDL, HDL- Constipation common, no impact on weight loss- Women lost more fat mass\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHaase et al. (2021)\u003c/b\u003e [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo investigate gastrointestinal symptoms during liraglutide treatment and their relation to weight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e277\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Frequent constipation, no impact on weight loss- Reduction in DBP (\u0026ndash;5.4 mmHg)- Similar effect in bariatric and non-bariatric patients\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKolotkin et al. (2018)\u003c/b\u003e [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo evaluate the impact of liraglutide-induced weight loss on quality of life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase-control study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e160 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Improved quality of life (QoLRS)- Mental aspects improved only with \u0026ge;\u0026thinsp;15% weight loss\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePark et al. (2021)\u003c/b\u003e [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTo assess factors influencing response to liraglutide in weight loss\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e180 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e- Alcohol consumption reduced weight loss- Age, BMI, HbA1c, and sex had no effect on the outcome\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eLegend\u003c/b\u003e:\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eGET T1/2\u003c/b\u003e\u0026thinsp;=\u0026thinsp;gastric emptying half-time, \u003cb\u003eOFC\u003c/b\u003e\u0026thinsp;=\u0026thinsp;right orbitofrontal cortex, \u003cb\u003eSBP\u003c/b\u003e\u0026thinsp;=\u0026thinsp;systolic blood pressure, \u003cb\u003eDBP\u003c/b\u003e\u0026thinsp;=\u0026thinsp;diastolic blood pressure, \u003cb\u003evmPFC\u003c/b\u003e\u0026thinsp;=\u0026thinsp;ventromedial prefrontal cortex, \u003cb\u003eNAFLD\u003c/b\u003e\u0026thinsp;=\u0026thinsp;non-alcoholic fatty liver disease score, \u003cb\u003ehsCRP\u003c/b\u003e\u0026thinsp;=\u0026thinsp;high-sensitivity C-reactive protein.\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Efficacy of liraglutide in reducing body weight\u003c/h2\u003e \u003cp\u003eThe impact of liraglutide on weight reduction throughout treatment was extensively addressed in the studies analyzed. Despite variations in treatment duration and participant profiles, the studies agree on the medication\u0026rsquo;s effectiveness.\u003c/p\u003e \u003cp\u003eSome authors observed weight loss occurring within the first weeks of treatment. Maselli et al. (2022) reported substantial weight loss after 5 and 16 weeks of treatment, with reductions of 3.8 kg and 5.8 kg, respectively. Similar results were found by Sannaa et al. (2022), who reported losses of over 1 kg in 5 weeks and more than 4 kg in 16 weeks. Farr et al. (2019) confirmed that after 5 weeks of dose escalation, weight loss was significantly greater in patients treated with liraglutide compared to the placebo group [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Similarly, Coppin et al. (2023) recorded an average loss of 8.96% of body weight after 16 weeks of treatment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Park et al. (2019) further supported this view by analyzing weight trends over different periods, reporting average losses of 3.2 kg in 30 days, 4.5 kg in 60 days, 6.3 kg in 90 days, and 7.8 kg in 180 days, reinforcing the continuous effectiveness of liraglutide over time [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These findings suggest a progressive reduction in body weight and a consistent effect of the medication during the initial weeks of treatment.\u003c/p\u003e \u003cp\u003eLonger-term studies, such as those by Santini et al. (2023) and Haase et al. (2021), reinforce this trend. Santini et al. demonstrated that after 10 months of liraglutide use, weight loss ranged from 10.0 to 14.1 kg, with 96% of patients losing at least 5% of their body weight and 61% losing more than 10% [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, Haase et al. reported an average weight loss of 4.1 kg after 7 months of treatment; between 7\u0026ndash;12 months, the loss increased to 5.1 kg, and patients who continued treatment for 12 months achieved an average reduction of 7.5 kg [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the analysis by Papamargaritis et al. (2024) brings an important point regarding the long-term maintenance of weight loss. The authors found that during the first 52 weeks of liraglutide treatment, 25.4% of participants lost more than 15% of their body weight, 44.8% lost more than 10%, and 63.2% lost more than 5%, with an average weight reduction of 8.1 kg during the first year. However, by the end of 104 weeks, only 11.4% of those participants had lost more than 15% of their initial body weight, 24.2% had lost more than 10%, and 47% had lost more than 5%, resulting in an average weight loss of just 5.2 kg compared to baseline [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These data reveal some degree of weight regain in the second year of liraglutide use, suggesting that continued treatment and patient adherence may influence the sustainability of the results.\u003c/p\u003e \u003cp\u003eThe study by Kolotkin et al. (2018) shows weight loss after three years of liraglutide use, reporting that 10.9% of patients lost at least 15% of their initial body weight, 13.8% lost between 10% and 14.9%, and 24.7% had reductions between 5% and 9.9% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, there were no periodic analyses of weight loss, which raises questions about weight regain during the treatment period, as data were collected only at the end of the three years. Therefore, there is a need for extended studies with periodic assessments to clarify the long-term use of liraglutide.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between weight loss and treatment period with liraglutide in the studies analyzed.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvaluation Period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAverage Weight Loss\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaselli et al. (2022) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-3.8 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaselli et al. (2022) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-5.8 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSannaa et al. (2022) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSannaa et al. (2022) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSantini et al. (2023) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-10.0 to -14.1 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaase et al. (2021) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4.1 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaase et al. (2021) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;7 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-5.1 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaase et al. (2021) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.5 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoppin et al. (2023) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-8.96% of body weight\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFarr et al. (2019) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-2.50% of body weight\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapamargaritis et al. (2024) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.4% lost\u0026thinsp;\u0026ge;\u0026thinsp;15%,\u003c/p\u003e \u003cp\u003e44.8% lost\u0026thinsp;\u0026ge;\u0026thinsp;10%,\u003c/p\u003e \u003cp\u003eand 63.2% lost\u0026thinsp;\u0026ge;\u0026thinsp;5% of initial body weight\u003c/p\u003e \u003cp\u003eOn average \u0026minus;\u0026thinsp;8,1 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapamargaritis et al. (2024) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.4% lost\u0026thinsp;\u0026ge;\u0026thinsp;15%,\u003c/p\u003e \u003cp\u003e24.2% lost\u0026thinsp;\u0026ge;\u0026thinsp;10%,\u003c/p\u003e \u003cp\u003eand 47% lost\u0026thinsp;\u0026ge;\u0026thinsp;5% of body weight\u003c/p\u003e \u003cp\u003eOn average \u0026minus;\u0026thinsp;5.2 kg (indication of regain)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKolotkin et al. (2018) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.9% lost\u0026thinsp;\u0026ge;\u0026thinsp;15%;\u003c/p\u003e \u003cp\u003e13.8% lost 10\u0026ndash;14.9%;\u003c/p\u003e \u003cp\u003e24.7% lost 5\u0026ndash;9.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePark et al. (2019) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-3.2 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePark et al. (2019) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4.5 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePark et al. (2019) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-6.3 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePark et al. (2019) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e180 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-7.8 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Influence of individual variables on the response to liraglutide\u003c/h2\u003e \u003cp\u003eSome authors have reported that individual characteristics may influence the outcomes of obesity treatment with liraglutide. In a Swiss population, Santini et al. (2023) observed differences in weight loss between men and women undergoing liraglutide treatment, with women achieving a greater reduction in fat mass compared to men. This difference may be attributed to hormonal and metabolic variations between the sexes. However, there were no significant differences in weight loss when considering participants' BMI values or age [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSimilarly, Park et al. (2021) demonstrated that, in a Korean population, the response to liraglutide was consistent regardless of age, baseline BMI, or HbA1c levels; however, they did not find any sex-related differences. Additionally, the authors noted that patients who consumed alcohol during liraglutide treatment experienced less weight loss compared to those who did not drink alcohol [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFinally, Haase et al. (2021) observed that both bariatric and non-bariatric patients experienced similar weight loss responses after 7 months of therapy. These findings suggest that while weight loss outcomes may vary based on sex, ethnicity, and lifestyle habits, they appear to be independent of age, initial BMI, and previous bariatric surgery [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite these potential influences, liraglutide remains effective across a variety of metabolic profiles.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Multifactorial processes that contribute to weight loss.\u003c/h2\u003e \u003cp\u003eAlthough the authors agree on the efficacy of liraglutide in promoting weight loss, different mechanisms have been proposed. Maselli et al. (2022) reported that liraglutide promotes weight loss by delaying gastric emptying of solids at 5 and 16 weeks. However, there was a reduced effect on gastric emptying half-time (GET T1/2) at 16 weeks compared to 5 weeks, suggesting that continuous activation of GLP-1 receptors by the drug may lead to tolerance. Additionally, the study pointed to increased fasting gastric volume and enhanced satiety at 16 weeks as factors contributing to weight loss [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings are supported by Sannaa et al. (2023), who found that a greater delay in GET T1/2 from baseline at 5 weeks tended to result in greater weight loss at 16 weeks [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther key factors in weight loss include genetic variations in GLP1R and TCF7L2. The GLP1R gene encodes the GLP-1 receptor, which is expressed in the intestine, brainstem, and to a lesser extent in the endocrine pancreas [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The TCF7L2 (transcription factor 7-like 2) gene may influence pancreatic β-cell proliferation and act on intestinal endocrine cells, affecting GLP-1 production [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Maselli et al. (2022) proposed that the GLP1R rs6923761 AG/AA genotype was associated with a lower percentage of body fat in response to liraglutide. Furthermore, individuals with the TCF7L2 rs7903146 CC genotype experienced greater weight reduction at 16 weeks compared to those with the CT/TT genotypes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings suggest that polymorphisms may influence liraglutide's effect on body composition and weight loss. However, Sannaa et al. (2023) noted that variations in the TCF7L2 and GLP1R genotypes were not significant predictors of weight loss [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFaar et al. (2019) sought to evaluate liraglutide\u0026rsquo;s effects on brain activity. The study showed that after five weeks of treatment, there were no apparent changes in brain activation related to food reward when participant anthropometric data (weight and BMI) were not considered. However, increased activation in the right orbitofrontal cortex (OFC)\u0026mdash;a region associated with pleasure and motivation for food\u0026mdash;was observed after five weeks when those variables were taken into account [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These findings indicate that brain response to liraglutide is not uniform and may vary based on individual characteristics, possibly contributing to a compensatory neural mechanism that stabilizes long-term weight loss (therapeutic plateau).\u003c/p\u003e \u003cp\u003eWhen analyzing neural responses to milkshake consumption versus a taste control stimulus, Coppin et al. (2023) reported activation in the ventromedial prefrontal cortex (vmPFC) and amygdala\u0026mdash;regions involved in reward processing [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, the liraglutide group did not show significant changes compared to the placebo group. Additionally, the study found no evidence that liraglutide affects the hedonic perception of food, suggesting that weight loss may occur through mechanisms other than changes in food-related pleasure [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdverse effects of liraglutide have also been discussed as contributing to reduced appetite and weight loss [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Maselli et al. (2022) identified nausea as a common side effect, and individuals experiencing it showed greater weight loss [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In contrast, Haase et al. (2021) and Santini et al. (2023) highlighted constipation as another frequent side effect but found no significant impact on weight loss among those affected [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This suggests that most patients lose weight regardless of clinically relevant adverse effects.\u003c/p\u003e \u003cp\u003ePapamargaritis D. et al. (2024) observed that 42% of participants on liraglutide reported gastrointestinal side effects such as nausea, constipation, and diarrhea. However, symptoms were mild, and only five individuals (1.9%) discontinued treatment due to adverse events [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, despite being common, side effects are generally well tolerated, reinforcing the viability of this treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Integrated assessment of other effects of liraglutide\u003c/h2\u003e \u003cp\u003ePapamargaritis et al. (2024) demonstrated that patients using liraglutide achieved sustained reductions in glycated hemoglobin (HbA1c) levels at 52 and 104 weeks compared to the control group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Faar et al. (2019) and Santini et al. (2023) support these findings, as their studies showed consistent decreases in glycemic values in patients using the medication [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These results reinforce the effectiveness of liraglutide in controlling patients\u0026rsquo; glycemic profiles.\u003c/p\u003e \u003cp\u003eSantini et al. (2023) evidenced a significant reduction in the prevalence of hepatic steatosis and in the liver fibrosis score (NAFLD score) after 10 months of treatment with liraglutide. Furthermore, the authors identified improvements in hsCRP (high-sensitivity C-reactive protein) levels [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which indicates a potential anti-inflammatory effect of the medication. These findings are relevant in populations with obesity and insulin resistance, in which liver alterations associated with chronic inflammation are frequent.\u003c/p\u003e \u003cp\u003eThere are controversies regarding the effects of liraglutide on the lipid profile. Santini et al. (2023) did not observe significant changes in total cholesterol, LDL, or HDL levels after the use of the medication, whereas Faar et al. (2019) reported improvement in all lipid parameters during treatment [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Papamargaritis et al. (2024) observed only slight changes in lipids, with a tendency for improvement only in triglyceride levels in the intervention group [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These divergences may result from differences in study methodologies, especially in terms of follow-up duration, individual participant profiles, or concurrent use of medications that affect lipid levels, such as hypolipidemic agents.\u003c/p\u003e \u003cp\u003eAuthors also diverged regarding the influence of liraglutide on blood pressure. Haase et al. (2021) reported a reduction in diastolic blood pressure (DBP) at various treatment periods, with the greatest reduction observed in patients who maintained the use of the medication for \u0026ge;\u0026thinsp;12 months, showing an average decrease of \u0026minus;\u0026thinsp;5.4 mmHg. Although there was a trend toward reduced systolic blood pressure (SBP) in this group, the change was not statistically significant [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. On the other hand, Faar et al. (2019) noted an average SBP reduction of \u0026minus;\u0026thinsp;5.9 mmHg and DBP of \u0026minus;\u0026thinsp;3.3 mmHg after 5 weeks of use [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In contrast, Papamargaritis et al. (2024) observed no significant differences in absolute SBP and DBP values between the placebo and intervention groups at 52 and 104 weeks. However, they noted that the intervention group required fewer additions of new antihypertensive drugs, suggesting a potential indirect benefit of the drug on blood pressure control [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Nevertheless, it is important to consider that improved blood pressure levels may be secondary to weight loss, making it difficult to confirm a direct antihypertensive effect of the drug.\u003c/p\u003e \u003cp\u003eKolotkin et al. (2018), through the IWQOL-Lite questionnaire (Impact of Weight on Quality of Life \u0026ndash; Lite), demonstrated that liraglutide improved the quality of life in individuals with overweight or obesity over a period of 3 years. Although patients showed improvements in quality of life regardless of treatment received, participants using liraglutide experienced greater improvements, particularly in physical functioning, self-esteem, sexual life, public distress, and work performance. However, there were no significant differences between the groups in terms of bodily pain, social functioning, and emotional domains. Benefits in mental aspects were observed only in participants who achieved\u0026thinsp;\u0026ge;\u0026thinsp;15% weight loss, reinforcing the importance of more substantial weight reduction for positive psychological impacts. Despite the superiority of liraglutide, diet and physical activity also proved effective in promoting significant improvements in quality of life, highlighting the importance of combined approaches [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eBased on the studies selected for this review, liraglutide showed considerable efficacy for weight loss, especially in the short and medium term. The main mechanisms identified for weight reduction include delayed gastric emptying, influence on satiety, and genetic polymorphisms.\u003c/p\u003e \u003cp\u003eIn addition, its use was also associated with benefits in metabolic profile, such as glycemic control, reduction of hepatic steatosis, modulation of inflammatory response, and possible influence on blood pressure and lipid values. However, variables such as sex, alcohol consumption, genetics, and adherence to prolonged treatment influenced the response to the drug. Thus, liraglutide presents itself as a promising medication, especially in populations with multiple metabolic risk factors, as in addition to the demonstrated benefits, its side effects are generally well tolerated, making it a good option for patients with obesity, metabolic syndrome, and type 2 diabetes.\u003c/p\u003e \u003cp\u003eNonetheless, some gaps are still identified regarding the understanding of liraglutide\u0026rsquo;s effects in obesity treatment. Moreover, there are points to be clarified regarding its action on the lipid and blood pressure profiles, as well as the influence of central and genetic mechanisms on the treatment response. These limitations may arise from the diversity in study design, different population samples, variable follow-up periods, drug interactions, and difficulty in isolating the drug\u0026rsquo;s direct effects on weight loss. In addition, most of the analyzed studies assessed these effects in the short and medium term, which limits the understanding of long-term weight maintenance, including the plateau effect or weight regain over time.\u003c/p\u003e \u003cp\u003eFinally, further studies are needed, especially those with longer follow-up periods and longitudinal randomized trials involving patients of different ethnicities or those with other comorbidities, in order to determine who benefits most from liraglutide. Moreover, animal studies could help elucidate the main pathways of liraglutide\u0026rsquo;s action. Therefore, it is essential to understand the mechanisms of action and predictors involved in the therapeutic response to ensure safe and personalized use, maximizing the drug\u0026rsquo;s benefits.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the conception and design of the study. Material preparation, data collection, and analysis were performed by Carla Bruna Amorim Braga, Jo\u0026atilde;o Paulo Viana Ara\u0026uacute;jo Segundo, and Carlos Alberto Alves Dias Filho. The first draft of the manuscript was written by Carla Bruna Amorim Braga and Jo\u0026atilde;o Paulo Viana Ara\u0026uacute;jo Segundo, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank AFYA Faculdade de Ci\u0026ecirc;ncias M\u0026eacute;dicas de Santa In\u0026ecirc;s for the technical and institutional support provided during the development of this study. We also extend our gratitude to colleagues and collaborators who contributed with constructive suggestions throughout the research. A special thanks to our families, whose emotional support and constant encouragement were essential to the completion of this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBaxter, M. G., \u0026amp; Murray, E. A. (2002). The amygdala and reward. Nature reviews. Neuroscience, 3(7), 563\u0026ndash;573. https://doi.org/10.1038/nrn875\u003c/li\u003e\n\u003cli\u003eCerillo, J. L., \u0026amp; Parmar, M. (2024). Liraglutide. In StatPearls. StatPearls Publishing.\u003c/li\u003e\n\u003cli\u003eCollins, L., \u0026amp; Costello, R. A. (2024). Glucagon-Like Peptide-1 Receptor Agonists. In StatPearls. StatPearls Publishing.\u003c/li\u003e\n\u003cli\u003eCoppin, G., Mu\u0026ntilde;oz Tord, D., Pool, E. R., Locatelli, L., Achaibou, A., Erdemli, A., Le\u0026oacute;n P\u0026eacute;rez, L., Wuensch, L., Cereghetti, D., Golay, A., Sander, D., \u0026amp; Pataky, Z. (2023). A randomized controlled trial investigating the effect of liraglutide on self-reported liking and neural responses to food stimuli in participants with obesity. International journal of obesity (2005), 47(12), 1224\u0026ndash;1231. https://doi.org/10.1038/s41366-023-01370-w \u003c/li\u003e\n\u003cli\u003eDel Bosque-Plata, L., Hern\u0026aacute;ndez-Cort\u0026eacute;s, E. P., \u0026amp; Gragnoli, C. (2022). The broad pathogenetic role of TCF7L2 in human diseases beyond type 2 diabetes. Journal of cellular physiology, 237(1), 301\u0026ndash;312. https://doi.org/10.1002/jcp.30581\u003c/li\u003e\n\u003cli\u003eDrucker D. J. (2022). GLP-1 physiology informs the pharmacotherapy of obesity. Molecular metabolism, 57, 101351. https://doi.org/10.1016/j.molmet.2021.101351\u003c/li\u003e\n\u003cli\u003eFaccioli, N., Poitou, C., Cl\u0026eacute;ment, K., \u0026amp; Dubern, B. (2023). Current Treatments for Patients with Genetic Obesity. Journal of clinical research in pediatric endocrinology, 15(2), 108\u0026ndash;119. https://doi.org/10.4274/jcrpe.galenos.2023.2023-3-2 \u003c/li\u003e\n\u003cli\u003eFarr, O. M., Upadhyay, J., Rutagengwa, C., DiPrisco, B., Ranta, Z., Adra, A., Bapatla, N., Douglas, V. P., Douglas, K. A. A., Nolen-Doerr, E., Mathew, H., \u0026amp; Mantzoros, C. S. (2019). 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J., Mezquita-Raya, P., Carretero-G\u0026oacute;mez, J., Castro, A., Cebri\u0026aacute;n-Cuenca, A., de Torres-S\u0026aacute;nchez, A., Garc\u0026iacute;a-de-Lucas, M. D., N\u0026uacute;\u0026ntilde;ez, J., Obaya, J. C., Soler, M. J., G\u0026oacute;rriz, J. L., \u0026amp; Rubio-Herrera, M. \u0026Aacute;. (2022). Clinical Recommendations to Manage Gastrointestinal Adverse Events in Patients Treated with Glp-1 Receptor Agonists: A Multidisciplinary Expert Consensus. Journal of clinical medicine, 12(1), 145. https://doi.org/10.3390/jcm12010145 \u003c/li\u003e\n\u003cli\u003eHaase, C. L., Serratore Achenbach, M. G., Lucrezi, G., Jeswani, N., Maurer, S., \u0026amp; Egermann, U. (2021). Use of Liraglutide 3.0 mg for Weight Management in a Real-World Setting in Switzerland. Obesity facts, 14(5), 568\u0026ndash;576. https://doi.org/10.1159/000518325 \u003c/li\u003e\n\u003cli\u003eKolotkin, R. L., Gabriel Smolarz, B., Meincke, H. H., \u0026amp; Fujioka, K. (2018). 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Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial. The Lancet regional health. Europe, 39, 100853. https://doi.org/10.1016/j.lanepe.2024.100853 \u003c/li\u003e\n\u003cli\u003ePark, J. S., Kwon, J., Choi, H. J., \u0026amp; Lee, C. (2021). Clinical effectiveness of liraglutide on weight loss in South Koreans: First real-world retrospective data on Saxenda in Asia. Medicine, 100(2), e23780. https://doi.org/10.1097/MD.0000000000023780 \u003c/li\u003e\n\u003cli\u003ePopoviciu, M. S., Păduraru, L., Yahya, G., Metwally, K., \u0026amp; Cavalu, S. (2023). Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. International journal of molecular sciences, 24(13), 10449. https://doi.org/10.3390/ijms241310449 \u003c/li\u003e\n\u003cli\u003eSannaa, W., Dilmaghani, S., BouSaba, J., Maselli, D., Atieh, J., Eckert, D., Taylor, A. L., Harmsen, W. S., Acosta, A., \u0026amp; Camilleri, M. (2023). Factors associated with successful weight loss after liraglutide treatment for obesity. Diabetes, obesity \u0026amp; metabolism, 25(2), 377\u0026ndash;386. https://doi.org/10.1111/dom.14880 \u003c/li\u003e\n\u003cli\u003eSantini, S., Vionnet, N., Pasquier, J., Gonzalez-Rodriguez, E., Fraga, M., Pitteloud, N., \u0026amp; Favre, L. (2023). Marked weight loss on liraglutide 3.0 mg: Real-life experience of a Swiss cohort with obesity. Obesity (Silver Spring, Md.), 31(1), 74\u0026ndash;82. https://doi.org/10.1002/oby.23596\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-and-cellular-biochemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcbi","sideBox":"Learn more about [Molecular and Cellular Biochemistry](https://www.springer.com/journal/11010)","snPcode":"11010","submissionUrl":"https://submission.nature.com/new-submission/11010/3","title":"Molecular and Cellular Biochemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Liraglutide, Obesity treatment, GLP-1 analog, Weight loss, Metabolic effects, Off-label use","lastPublishedDoi":"10.21203/rs.3.rs-6631957/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6631957/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLiraglutide, a glucagon-like peptide-1 (GLP-1) analog, has been used off-label for the treatment of obesity due to its considerable weight-reducing effects. This integrative review evaluated experimental studies in humans in order to explore the pharmacological mechanisms, metabolic effects, and the various clinical responses involved in the use of this drug. The research was conducted in the PubMed database, considering articles written in English and published in the last 10 years, with 9 studies included.The studies demonstrated that liraglutide is effective for weight loss and acts through gastric emptying, modulation of satiety, and influences on brain regions. Additionally, genetic polymorphisms may interfere with the clinical response. Regarding metabolic effects, improvements in glycemia and hepatic steatosis were observed, as well as possible anti-inflammatory action and improvement in blood pressure and lipid profile.The efficacy of liraglutide does not depend on variables such as BMI (Body Mass Index) or age; however, alcohol consumption and proper adherence to treatment may influence clinical outcomes. The main adverse effects, such as nausea and constipation, were well tolerated. Therefore, liraglutide can be considered a promising alternative in the management of obesity, especially in populations with multiple metabolic risk factors.\u003c/p\u003e","manuscriptTitle":"Exploring the off-Label use of liraglutide in the treatment of obesity: a review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 03:47:23","doi":"10.21203/rs.3.rs-6631957/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-04T07:42:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-05T10:45:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"173480412329656144065204295549910179388","date":"2025-07-05T10:16:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-16T13:57:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-08T03:27:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-10T08:25:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular and Cellular Biochemistry","date":"2025-05-10T02:20:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-and-cellular-biochemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcbi","sideBox":"Learn more about [Molecular and Cellular Biochemistry](https://www.springer.com/journal/11010)","snPcode":"11010","submissionUrl":"https://submission.nature.com/new-submission/11010/3","title":"Molecular and Cellular Biochemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0bd8f3bf-0d1f-470d-9b7a-895fd3762e56","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T15:59:40+00:00","versionOfRecord":{"articleIdentity":"rs-6631957","link":"https://doi.org/10.1007/s11010-026-05560-8","journal":{"identity":"molecular-and-cellular-biochemistry","isVorOnly":false,"title":"Molecular and Cellular Biochemistry"},"publishedOn":"2026-04-30 15:57:09","publishedOnDateReadable":"April 30th, 2026"},"versionCreatedAt":"2025-05-13 03:47:23","video":"","vorDoi":"10.1007/s11010-026-05560-8","vorDoiUrl":"https://doi.org/10.1007/s11010-026-05560-8","workflowStages":[]},"version":"v1","identity":"rs-6631957","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6631957","identity":"rs-6631957","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}