Obesity is a chronic disease, and its prevalence has increased worldwide (1). According to the World Health Organization (WHO), there were approximately 1.9 billion overweight adults in 2016, of which 650 million were obese (2, 3). Genetic, environmental, and behavioral interactions have been linked to obesity; thus, the consumption of high-calorie foods associated with sedentary lifestyles increases the number of obese people in the world (4). Therefore, obesity can lead to a high risk of cardiovascular diseases, type 2 diabetes mellitus (DM2), hypertension, and some types of cancer. In addition, other diseases, such as dyslipidemia and even depression, are associated with obesity (5, 6).

Despite the increase in weight management approaches, the pandemic of obesity is still rising. However, strategies to control this phenomenon have primarily focused on physical exercise, behavioral factors, surgery (including bariatric surgery), and pharmaceutical interventions (7).

Pharmacological strategies have been fundamental for reducing the obesity pandemic (8). In this context, the group of glucagon-like peptide 1 receptor agonists (GLP-1RA), which mimic the natural hormone glucagon-like peptide 1 (GLP-1), has been mainly used for the treatment of DM2 (9). In addition, studies have shown that these drugs can have pleiotropic effects such as blood pressure lowering, weight reduction, endothelial protection, and insulin sensitivity (Figure 1). For instance, semaglutide and liraglutide, two GLP-1RA agonist drugs, have been associated with weight loss and body weight maintenance (10–12).

The present review aims to elucidate and describe the molecular mechanisms of the GLP-1RA drugs, semaglutide and liraglutide, and their effectiveness and potential as a therapeutic option against obesity.

The scientific papers search was performed in Google Scholar and PubMed databases. The following individual and combined search terms were used: “GLP-1,” “Semaglutide and Liraglutide,” “molecular mechanism,” “lipid metabolism,” “insulin metabolism,” “glucose homeostasis,” “energy expenditure” “obesity treatment,” “type 2 diabetes mellitus,” “side effects,” “clinical trials,” “treatment option,” “fatty liver disease,” “hypertension,” “neurodegenerative diseases,” “cardiovascular diseases,” “therapeutic options.” Only articles published in the last 10 years are included, although older pivotal studies were added.

The metabolic effect of semaglutide and liraglutide in obese people is remarkable. The main mechanism of action of these GLP-1RA is the stimulation of the GLP-1R that triggers the activation of several metabolic pathways involved in insulin secretion, lipid metabolism, energy expenditure, pro-survival and anti-apoptotic cellular signaling, and oxidative stress prevention, in several tissues like the pancreas, central nervous system, heart, muscle, kidneys, gut, among others (15). The wide distribution of the GLP-1R has allowed the study of semaglutide and liraglutide pharmacological protocols to improve metabolic diseases in several experimental models (26, 40, 48–50). The assessment of these GLP-1RA could elucidate the role of these drugs in the cellular signaling process of obese-related diseases, which could support the development of new pharmacological approaches. For instance, the combination of GLP-1RA and enzyme inhibitors of proinflammatory, lipogenesis, pro-apoptotic, and pro-oxidative stress processes could be evaluated in metabolic diseases. Although, rigorous safety and efficacy-controlled trials must be carried out, like those performed to assess the effect of semaglutide and liraglutide in obese or DM2 individuals.

Clinical trials have evaluated the effectiveness of GLP-1RA drugs, semaglutide, and liraglutide, in treating obesity. The Semaglutide Treatment Effect in People with Obesity (STEP) program evaluated the once-weekly administration of 2.4 mg subcutaneous semaglutide in people with obesity or overweight. In the STEP 1 trial, 1961 participants underwent dietary and exercise interventions. In this trial, 69 to 79% of the participants lost weight with an average weight reduction of ≥10% after 68 weeks of treatment compared with placebo group (12–17%) (51). Additionally, the STEP trials evaluated patients with obesity and DM2; the results supported the recommended dose of 2.4 mg of semaglutide per week for weight loss in individuals with obesity, with or without DM2 (52).

Similarly, in the Peptide Innovation for Early Diabetes Treatment (PIONEER) clinical trial, oral semaglutide was tested in patients with DM2. Results showed that oral semaglutide has a significantly higher efficacy compared to placebo and other DPP4 inhibitor drugs (53). Moreover, the results from the PIONEER clinical trials suggested that oral semaglutide effectively reduced HbA1c and body weight, showing responsiveness in diverse age groups with a diagnosis of DM2 (54).

The efficiency of liraglutide was evaluated in the clinical trial called SCALE (Satiety and Clinical Adiposity: Evidence for liraglutide), where it was determined that a dosage of 3.0 mg induced an 8% weight loss equivalent to 8.4 kg of the initial weight in over 56 weeks. In comparison, the placebo group experienced a decrease of 2.6% equivalent to 2.8 kg. Participants also improved weight-related comorbidities through lifestyle and diet adjustments (55).

Azuri et al. showed that semaglutide had a better performance than liraglutide in terms of weight loss (12.4% [95% CI: 11.5–13.4%] vs. 5.4% [95% CI: 5–5.8%]). Moreover, this study reported that semaglutide had a lower economic spend than liraglutide for obesity management (56). This highlights the potential use of semaglutide due to its low cost and superior performance.

The posology of semaglutide and liraglutide also showed differences in body weight reduction. In obese individuals without diabetes mellitus, a once-weekly subcutaneous semaglutide (2.4 mg) dose had a significant body weight change compared with a once-daily subcutaneous liraglutide (3.0 mg) dose after 68 weeks. Participants under the semaglutide treatment showed a 15% weight loss than baseline, while liraglutide recipients experienced a 6% weight loss (57). Therefore, semaglutide also has an advantage due to the smaller number of doses and greater weight loss.

A meta-analysis revealed that a 2.4 mg dose of semaglutide led to a reduction of 12.4 kg of body weight, while doses of 3.0 mg of liraglutide, 1.0 mg of semaglutide, and 1.8 mg of liraglutide led to reductions in body weight of 5.2 kg, 3.7 kg, and 1.8 kg, respectively. The evaluation of these doses was performed in various periods, ranging from 20 weeks to 68 weeks. The most effective treatment involved a weekly dose of 2.4 mg semaglutide for 68 weeks. Moreover, for the dose of 2.4 mg semaglutide, the decrease in glycated hemoglobin was the highest (1.48% reduction with 2.4 mg semaglutide dose) compared with the other doses (58). Once again, semaglutide demonstrates a higher performance compared with liraglutide, although individual medical status must be assessed before the prescription of this treatment to prevent side effects.

Another important component of the treatment with GLP-1RA is the inclusion of lifestyle interventions, including exercise and a low-calorie diet (1, 59). This factor is significant for weight loss sustaining, given that after subcutaneous semaglutide (2.4 mg) treatment suspension, studies have shown that there may be a weight regain worsening cardiometabolic parameters (60). This highlights that GLP-1RA treatment must be continuous, along with a healthy lifestyle. Therefore, monitoring after several years of semaglutide or liraglutide withdrawal should be performed to verify metabolic status and weight. For instance, the outcomes of semaglutide and liraglutide in patients with DM2 have shown a cardiovascular risk factors reduction and an improvement in glucose levels and nutritional status (22, 58, 61–63).

The safety profile of GLP-1RA drugs generally indicates a low incidence of side effects, although it depends on the dose and the administration mode. For instance, oral semaglutide (14 mg) exhibited more side effects (such as vomiting or gastrointestinal issues) than subcutaneous liraglutide (1.2 mg); however, these side effects were no different from those observed with subcutaneous semaglutide treatment (64). Moreover, the use of semaglutide has been related to the increased risk of cholelithiasis (65).

The effectiveness of these GLP-1RA drugs, especially semaglutide, is associated with an improvement in other diseases like cardiovascular diseases (22, 50). Studies suggest that DM2 accompanied by insulin resistance may contribute to memory impairment and the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (66). Furthermore, these GLP-1RA medications have also been related to a reduction of neuroinflammation, probably due to its possible role in neuronal insulin signaling pathway restoration (49, 67, 68). Hence, semaglutide and liraglutide could also have the potential to ameliorate neurodegeneration processes observed in pathologies like Alzheimer’s and Parkinson’s diseases, although further research is needed (48, 69). Moreover, clinical trials have reported a reduction of the inflammatory C-reactive protein (70), which could indicate that this drug may also regulate the immune system, although this approach requires further assessment. Therefore, given the association with improved nutritional status under semaglutide treatment, this GLP-1RA could be explored in other obesity-related conditions, including fatty liver disease, dyslipidemia, hypertension, and potentially even cancer.

Obesity is a current public health issue that must be addressed to avoid and prevent several underlying pathologies like cardiovascular diseases, fatty liver disease, DM2, hypertension, and cancer. Therefore, lifestyle and pharmacological options must be evaluated to improve or prevent those obesity underlying pathologies. Between the pharmacological options, the GLP-1RA, originally approved for the treatment of DM2, have been demonstrated to be useful for body weight reduction in obese individuals. The main molecular mechanisms of GLP-1RA in obesity reduction include the increased production of insulin by the cAMP/PKA pathway in pancreatic β-cells, along with an augmented translocation of GLUT-4 in the cellular membrane for improved glucose homeostasis, and energy expenditure by lipolytic cycle stimulation. The GLP-1RA with better outcomes in clinical trials is semaglutide since this drug can reduce up to 15% of the baseline weight after a 2.4 mg subcutaneous weekly dose. Moreover, semaglutide has shown a reduction of cardiovascular risk factors and inflammatory proteins observed in obese individuals. Therefore, semaglutide could improve other obesity-related pathologies like cardiovascular, hypertension, or fatty liver diseases.

RT-T: Conceptualization, Writing – original draft, Writing – review & editing. VR-P: Conceptualization, Writing – original draft, Writing – review & editing. SC-U: Writing – original draft, Writing – review & editing. PG-R: Writing – original draft, Writing – review & editing, Writing – original draft. EP-C: Writing – original draft, Writing – review & editing. RZ-V: Writing – original draft, Writing – review & editing. DS-R: Conceptualization, Resources, Writing – original draft, Writing – review & editing. AZ: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing.