The prevalence of obesity continues to increase worldwide, and Korea is no exception to this trend [1,2]. Obesity is associated with a variety of diseases, including type 2 diabetes, metabolic syndrome, renal impairment, cancer, and cardiovascular disease. Thus, obesity increases medical costs and imposes a burden on public health [3,4]. According to the 2021 Obesity Fact Sheet published by the Korean Society for the Study of Obesity (KSSO), 36.3% of adults over 20 years of age were obese when obesity was defined as a body mass index (BMI) of 25 kg/m² or more. The prevalence of obesity has consistently increased over the past 11 years, and a particularly sharp increase has been observed in men (46.2%) [5]. In addition, the risk of type 2 diabetes, other cardiovascular diseases, and cancer has increased in obese Korean patients, similar to the trends reported in other countries [5]. Therefore, the prevention of obesity through systematic management and active treatment of obese patients is important in the management of other related comorbidities.

The KSSO's 2020 Guidelines for the Management of Obesity recommend diet, exercise, and behavioral therapy as basic treatment methods for obesity, as well as pharmacological treatment and surgery in certain scenarios [6]. In patients with a BMI ≥25 kg/m², pharmacological treatment should be considered when nonpharmacological treatments, such as diet, exercise, and behavioral therapy, fail to contribute to weight loss. If a patient does not lose more than 5% of his or her baseline weight within 3 months of initiating pharmacological treatment, it is recommended to either change or discontinue the drug [6]. The obesity drugs available in Korea include orlistat, a combination of naltrexone extended-release (ER) with bupropion ER, liraglutide, and a phentermine-topiramate ER combination. Among them, liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is an injection with proven effects on weight loss. It is currently used as an important treatment for obesity in Korea. Therefore, this review was conducted to analyze the results of various clinical studies on the mechanism of action and weight loss effects of liraglutide and to summarize its side effects.

In Korea, Xenical (Roche, Basel, Switzerland), a lipase inhibitor with the generic name of orlistat, was prescribed as a full-fledged antiobesity drug in the 2000s. Although Xenical was a high-selling obesity treatment at the time of its launch, its weight loss effect was not higher than placebo treatment (2.8%). Compliance with Xenical was poor due to frequent side effects, such as fatty stools, abdominal distension, flatus, and defecation incontinence. The naltrexone ER-bupropion ER combination, which appeared next, also showed no significant weight loss compared to placebo (3.2% to 5.2% per year), and patients often did not achieve the desired weight loss. In addition, this combination was not actively used for antiobesity treatment due to its side effects on the digestive system, such as nausea/vomiting, and various neurological side effects, such as dizziness and anxiety. Saxenda, a GLP-1 RA derivative with liraglutide as an active ingredient, was developed by Novo Nordisk (Bagsværd, Denmark). Saxenda was developed by varying the dose of Victoza, another brand-name diabetes drug containing liraglutide [7]. In a long-term clinical study, weight loss due to treatment with 0.3 mg of liraglutide was reported to be 5.4% to 6.0%, which was superior to that achieved using existing antiobesity drugs [8]. A real-world data analysis also reported that liraglutide had a greater effect on weight loss than orlistat [9].

GLP-1 is an incretin peptide hormone that is rapidly secreted from the small intestine when food is absorbed [10,11]. GLP-1 receptors are in various organs; in particular, GLP-1 receptors in the pancreas act in a glucose-dependent manner to stimulate insulin secretion and inhibit glucagon secretion [12,13]. In addition, GLP-1 stimulates anorexigenic neurons and inhibits orexigenic neurons, thereby increasing satiety, delaying gastric emptying, and decreasing appetite [14]. It also regulates food intake through direct effects on vagal afferent neurons in the digestive system [15]. GLP-1 RA-induced weight loss occurs through various mechanisms. In fact, postprandial GLP-1 levels rise after bariatric surgery (also known as metabolic surgery), which can improve glucose metabolism and affect weight loss [16].

GLP-1 has a very short half-life of 1.5 minutes when administered intravenously and 1.5 hours when administered subcutaneously [17]. To extend the half-life of GLP-1 RAs, liraglutide was acylated to prevent degradation by reversible binding to serum albumin, making it possible to administer a single subcutaneous dose daily [17]. Therefore, liraglutide is classified as a GLP-1 derivative with more than 90% sequence similarity to the human GLP-1 [18]. Liraglutide (Saxenda, 3.0 mg) is currently approved for the treatment of obesity in many countries, including Korea, and has a 97% sequence similarity to human GLP-1. The plasma concentration of liraglutide peaks 11 hours after subcutaneous administration and has a half-life of 13 hours [18].

The most common side effects of liraglutide are gastrointestinal, such as nausea, vomiting, diarrhea, constipation, digestive disorders, abdominal pain, bloating, gastroesophageal reflux, dry mouth, and gastritis [31]. In addition, redness at the injection site, fatigue, lethargy, dizziness, and sleep disturbances have also been reported [31]. Liraglutide is also known to increase the levels of amylase and lipase and increase the risk of the development of gallstones [6]. Furthermore, 16% to 39% of patients treated with liraglutide complained of these side effects, whereas 4% to 14% of patients treated with placebo reported these adverse reactions [8,19]. Most of them were mild or transient at the start of treatment, and the likelihood of discontinuing the drug owing to side effects was reported to be low [8,19–21,23,24,32,33]. However, it should be explained to patients receiving liraglutide that nausea, vomiting, diarrhea, constipation, and digestive disorders may occur at the initial stage of drug administration and during the dose-escalation phase [8,19]. If vomiting is severe, sufficient fluid intake is recommended to prevent dehydration and renal dysfunction due to dehydration.

In a postmarketing survey, acute pancreatitis was observed in patients receiving liraglutide, and throughout the SCALE program, pancreatitis was observed in 0.3% of patients who received liraglutide versus 0.1% in the placebo group [31]. However, the risk of pancreatitis due to liraglutide administration was reported to be very low when 3,720 person-years were analyzed for all doses of liraglutide [31]. Gallbladder-related side effects, including acute cholecystitis, were more common in the liraglutide group than in the placebo group in the SCALE trials (cholelithiasis, 2.2% in the liraglutide group vs. 0.8% in the placebo group; cholecystitis, 0.8% in the liraglutide group vs. 0.4% in the placebo group) [8,19–21,23,24]. Based on this, the KSSO Guidelines for the Management of Obesity recommend that patients with a history of pancreatitis or currently suffering from pancreatitis must avoid liraglutide administration, and the occurrence of cholelithiasis should be monitored [6]. In fact, gallbladder disease and cholecystitis can occur in patients rapidly losing weight by any means, and this risk increases with greater weight loss. The incidence of gallbladder disease and cholecystitis in patients with sudden weight loss unrelated to liraglutide is known to vary substantially from 4.4% to 11.0% [34]. Since liraglutide is an antiobesity drug based on a drug that regulates blood glucose levels, it is important to observe the effect of liraglutide administration on blood glucose levels. In the SCALE Insulin trial, hypoglycemia was less common in the liraglutide group than in the placebo group: 742.3 cases per 100 patient-years in the liraglutide-treated group and 937.9 cases per 100 patient-years in the placebo group, using the American Diabetes Association's definition of hypoglycemia [25].

Liraglutide is contraindicated in pregnant women and in patients with medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2, or a family history of those conditions. Although the evidence for the development of neoplastic tumors in obese patients treated with liraglutide is limited, a causal relationship between the occurrence of neoplastic tumors and liraglutide has not yet been established [35].

Liraglutide, a GLP-RA that is administered subcutaneously once a day, has shown significant effects on weight loss compared to the placebo group in various clinical studies. In addition to its effect on weight loss, liraglutide improved various cardiometabolic risk factors, such as lowering blood pressure, dyslipidemia, and blood glucose levels, which are closely related to obesity. In various clinical studies, serious side effects that require discontinuation of liraglutide administration did not occur, but digestive system side effects, such as nausea, vomiting, and other digestive disorders, were noted frequently. Although a clear causal relationship has not yet been established, liraglutide requires attention, as cholelithiasis and pancreatitis have been reported.

Therefore, when prescribing liraglutide, it is necessary to have a detailed discussion with patients about the expected clinical effects and side effects of the drug. This can lead to successful treatment of obesity. In the future, if the administration interval of the drug is increased or an oral dosage form becomes possible, patients' adherence to the medication is expected to increase. Eventually, liraglutide can be expected to show significant effects on weight loss in patients.