Understanding the Mechanism of Action and Clinical Implications of Anti-Obesity Drugs Recently Approved in Korea

The Korean Ministry of Food and Drug Safety has approved three anti-obesity drugs for long-term management in the past decade. In addition, since 2019, bariatric surgery has been financially supported by National Health Insurance Service in Korea. In this review, the mechanisms of action and the clinical implications of the recently approved anti-obesity drugs, lorcaserin, naltrexone/bupropion, and liraglutide are explained. Lorcaserin stimulates proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons and inhibits neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, which results in the activation of melanocortin 3/4 receptors. Naltrexone/bupropion stimulates POMC neurons through bupropion; this stimulation is augmented by blocking the autoinhibitory mechanism of POMC with naltrexone. The hypophagic effect of liraglutide is mediated through the direct activation of POMC/CART neurons and the indirect suppression of NPY/AgRP neurons through γ-aminobutyric acid-dependent signaling, with adjunctive suppression of the mesolimbic dopamine reward system. In addition to liraglutide, another glucagon-like peptide-1 receptor agonist, semaglutide, is expected to be added to the list of anti-obesity drugs in the near future. In patients with obesity and high cardiovascular risk, lorcaserin was considered neutral and liraglutide was considered favorable, whereas inconclusive results were obtained for naltrexone/bupropion.


INTRODUCTION
There are five methods of obesity treatment: diet, exercise, behavior modification, drugs, and surgery. These treatment modalities can be divided into two categories, active and passive, based on the perspective of the patient. The active methods, including diet, exercise, and behavior modification, must be done by the patients themselves, whereas the passive methods of pharmacotherapy and bariatric surgery are performed by medical personnel.
A sufficient reduction in food intake and a radical increase in daily activity can reduce excess body weight and then maintain normal body weight in almost all patients with obesity. However, it is well established, through clinical experience and many previous clinical trials, 1) that the standard active treatments are not strong enough to induce clinically significant weight loss. Very few patients with obesity can resist hunger and select low-energy-density foods when facing the excess availability of high-energy-density foods. Moreover, very few patients with obesity can maintain an active daily life given the present social prevalence of sedentary lifestyles. Thus, obesity specialists are constantly seeking passive methods of weight reduction.
Over the past decade, there have been major changes in the global treatment of obesity, and in Korea. Between 1964 and 2009, 25 antiobesity drugs, most of which were monoamine neurotransmitter reuptake inhibitors or releasers, were withdrawn after marketing in several countries or worldwide due to cardiotoxicity or potential for drug abuse/dependency. 2) Consequently, in 2009, orlistat was the only antiobesity drug approved for long-term treatment in Korea. However, Korean Ministry of Food and Drug Safety has approved three more antiobesity drugs for long-term management in the past decade and another drug is under consideration for approval. The currently prescribed anti-obesity drugs are listed in Table 1, along with their status in the controlled substances schedule, by the US Drug Enforcement Administration. 3) In addition, since 2019, bariatric surgery has been supported financially by the National Health Insurance Service.
In this review paper, the mechanisms of action and the clinical implications of the recently approved anti-obesity drugs, lorcaserin, naltrexone/bupropion, and liraglutide, will be described.

MECHANISM OF ACTION OF CENTRALLY ACTING ANTI-OBESITY DRUGS
In the previous era of anti-obesity drugs, it was unclear how the centrally acting anti-obesity drugs suppressed appetite; however, the mechanism of action of orlistat, a gastric/pancreatic lipase inhibitor that inhibits the absorption of dietary fat in the small intestine, was well characterized. However, the appetite-suppressing mechanisms of lorcaserin, naltrexone/bupropion, and liraglutide are easy to understand. Before the mechanism of action of anti-obesity drugs is described, a brief overview of the mechanism of energy homeostasis in the brain will be provided.

Energy Homeostasis and the Arcuate Nucleus
For the maintenance of energy homeostasis, it is essential to sense the peripheral signals related to the amount and accessibility of energy.
The signals can be divided into two groups: the relatively stable signals that describe the amount of overall stored energy in the body; and the rapidly changing signals that describe the sudden energy consumption, the recent food intake, food availability, and anticipated energy consumption. These peripheral signals of body energy status are considered to be transferred to a specific region of the brain through the humoral and neural pathways and are integrated there. The signaling routes for the control of obesity have been described in detail previously. 4) The neurons in the arcuate nucleus of the hypothalamus, which control food intake and energy expenditure, can be grouped into two major populations: orexigenic neurons, which express neuropeptide Y (NPY) and/or agouti-related peptide (AgRP); and anorexigenic neurons, which express proopiomelanocortin (POMC) and/or cocaineand amphetamine-regulated transcript (CART). These two neuron populations gather and integrate the peripheral signals related to the current energy status of body, the presence of food, and the amount of food intake, and they activate the feeding center or transmit signs of satiety, which stop feeding behavior and suppress feeding actions for a certain period of time. Downstream of the POMC/CART neurons, the activation of melanocortin (MC) 3 and 4 receptors by α-melanocyte stimulating hormone occurs ( Figure 1).

Serotonergic Satiety in Brain
Serotonin (5-hydroxytryptophan, 5-HT) is a monoamine neurotransmitter that is been well conserved across species throughout evolution. 5) The 5-HT system and receptors are quite varied and the 5-HT receptors have been grouped into seven families, 5-HT1 to 5-HT7, which include 14 known subtypes. 5) 5-HT is involved in diverse physiology, including cognition, mood, sexual behavior, and feeding behavior. 5) Although 5-HT has been conserved well throughout evolution,

Interaction of Serotonin Satiety System with POMC/CART Neurons and NPY/AgRP Neurons
The anorexic effects of the serotonin receptor agonist (RA), fenfluramine, which was widely administered to patients with obesity in the early 1990s, were known to be mediated through the central melano-  hyperpolarize NPY neurons, whereas 5-HT1B receptor antagonists prevented the hyperpolarization induced by 5-HT1B RAs. 13) These findings suggested that 5-HT may directly inhibit NPY/AgRP neuron activity through the inhibitory 5-HT1B receptor.

Gut to Brain
Preproglucagon, coded by the proglucagon gene, is processed to glucagon-like peptide-1 (GLP-1), and is secreted from intestinal endocrine L-cells, which are located mainly in the distal ileum and colon, and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. 14,15) Although there are many GLP-1 binding sites in the brain, the half-life of endogenous GLP-1 secreted from the gut is too short to reach the brain owing to the rapid degradation; therefore, some GLP-1 RAs may reach the brain through the humoral pathway, cross the blood-brain barrier (BBB), and attach to GLP-1 binding sites in the brain. GLP-1 RAs that reach the inside of brain may act like brain-derived endogenous GLP-1.
GLP-1 can activate the hepatic vagal nerve and the vagal afferent fibers of nodose ganglion neurons. 16,17) In rats with subdiaphragmatic vagal deafferentation, the hypophagic effect of intraperitoneally injected GLP-1 was suppressed in the early stage (until 1 hour) of low-dose administration, whereas the hypophagic effect was observed in the later stages (≥2 hours) or by a high-dose administration. 18) Similarly, the hypophagic effect of liraglutide was sustained in rats with subdiaphragmatic vagal deafferentation. 19) According to these findings, putatively, the neural pathway through the vagus nerve is responsible for a large part of the influence of endogenous gut-derived GLP-1 on the brain, whereas peripherally administered long-acting GLP-1 RAs act directly on brain GLP-1 RAs through the humoral pathway.

Mechanisms of Action of Lorcaserin and Liraglutide
Considering the energy homeostasis mechanism described above, the action mechanism of lorcaserin, a  Values are presented as number or mean±standard deviation. The mean weight loss was calculated for the full analysis set, which comprised all randomized individuals exposed to trial drug with at least one post-randomization weight assessment. *The participants were patients with obesity and diabetes. † Treatment was combined with behavior modification. However, there are no GLP-1 receptors on NPY/AgRP neurons, and the inhibitory signal of liraglutide on orexigenic NPY neurons is transmitted via γ-aminobutyric acid (GABA)-dependent signaling. 19) In addition, the activation of GLP-1 receptors suppressed the reward system activity of mesolimbic dopamine neurons to highly palatable food intake, which may be a mechanism through which liraglutide demonstrates its hypophagic effect. 21) GLP-1 can induce direct thermogenesis. It was demonstrated that GLP-1 increased thermogenesis in rats, mediated by the lower brainstem and the sympathoadrenal system, with a larger increase observed from intravenous administration than from intracerebroventricular administration. 22) The thermogenic effect of GLP-1 is induced by the increase in interscapular brown adipose tissue activity, which depends on adrenergic signaling. 23) However, the increase in resting energy expenditure was not significant in patients with type 2 diabetes mellitus (T2DM). 24) In conclusion, the hypophagic effect of liraglutide depends on the direct activation of POMC/CART neurons and the indirect suppression of NPY/AgRP neurons through GABA-dependent signaling, and the suppression of mesolimbic dopamine reward system (Figure 1).

Combination of Naltrexone/Bupropion
The fixed dose drug combination of sustained-release (SR) naltrexone 32 mg and SR bupropion 360 mg (NB) is one of the approved antiobesity drugs for long-term treatment in Korea.
In the arcuate nucleus, dopamine receptor activation suppresses NPY neurons and stimulates POMC neurons, most likely through D2 receptors. 33,34) The intraperitoneal co-administration of a selective dopamine reuptake inhibitor with a selective norepinephrine reuptake inhibitor showed additive effects on negative energy balance in mice. 35) Although bupropion, a norepinephrine-dopamine reuptake inhibitor, is unique among anti-depressants owing to its association with weight loss due to its mechanism of action, the extent of weight reduction from bupropion is minimal in patients with obesity. In a randomized placebo-controlled trial, 24-week administration of SR bupropion 300 and 400 mg/d were associated with mean weight loss of 5.7% and 7.7%, respectively, compared with that of 4.0% in the placebo group. 36)  Values are presented as number or mean±standard deviation. The mean weight loss was calculated for the full analysis set, which comprised all randomized individuals exposed to trial drug with at least one post-randomization weight assessment. BMI, body mass index; FE, fast (2-weekly) dose escalation. *The participants were patients with obesity who lost ≥5% of their initial body weight during a variable-length (4-12 weeks) low-energy diet run-in period. † The participants were patients with obesity and diabetes (BMI ≥27 kg/m 2 with hemoglobin A1c 7.9%−10.0%).
Naltrexone, an opioid receptor antagonist used in the treatment of opioid or alcohol dependence, resulted in the dose-related suppression of eating and drinking in rats. 37) Consequently, naltrexone was administered to patients with obesity in several clinical trials in the 1980s to induce weight loss in humans, but the results were unsuccessful. 38,39) Although the weight loss effects of bupropion and naltrexone in humans were not satisfactory, in vivo electrophysiology studies by Greenway et al. 40) demonstrated that bupropion stimulated POMC neurons and the combination of bupropion and naltrexone showed greater effects on POMC neurons. Animal studies, preclinical, and clinical trials of NB showed that this combination had a greater weight loss effect compared with previous results for the monotherapy of each drug. [40][41][42][43][44] In conclusion, the mechanism of action of NB is the stimulation of POMC neurons with bupropion, with this stimulation augmented by blocking of the autoinhibitory mechanism of POMC by nal trexone (Figure 1). The weight loss results of clinical trials of NB are summarized in Table 2. [41][42][43][44]

GLP-1 RECEPTOR AGONISTS FOR THE TREATMENT OF OBESITY: LIRAGLUTIDE AND SEMAGLUTIDE
Presently, six GLP-1 RAs are used worldwide for the treatment of and long-acting (albiglutide, dulaglutide, exenatide long-acting release, liraglutide, and semaglutide). The main mechanism of the glucose-lowering effect is somewhat different between the two groups.
The short-acting GLP-1 RAs inhibit gastric emptying and mainly lower postprandial glucose levels, whereas the long-acting drugs stimulate postprandial insulin secretion and suppress fasting glucagon secretion, which can affect both fasting and postprandial blood glucose levels. 45,46) Endogenous GLP-1, liraglutide, and lixisenatide can cross the BBB and reach the hypothalamus. 19,47,48) However, there is no evidence that other GLP-1 RAs cross the BBB. The molecular size and structure of albiglutide and dulaglutide are completely different from endogenous GLP-1; therefore, it is difficult for them to cross BBB and act on the hypothalamic neurons through the humoral pathway.
Of the six GLP-1 RAs, only liraglutide and semaglutide were researched for long-term weight management; liraglutide is currently available in Korea. There have been several large phase 2 and 3 clinical trials for these drugs in the treatment of obesity and the participants and mean weight loss results are summarized in Table 3. [28][29][30][31][32] As shown in the clinical trials, the weight reduction effect of liraglutide was modest (mean weight loss from -5.7% to -8.0%) and that of semaglutide

CARDIOVASCULAR SAFETY OF ANTI-OBESITY DRUGS
Diabetes is diagnosed from an elevated blood glucose level and nonenzymatic glycation products; thus, the tight control of blood glucose should be the core of the prevention of cardiovascular disease, which is the most common cause of mortality, disability, and financial burden. However, intensive glycemic control was shown to fail in the reduction of macrovascular episodes, even though it reduced microvascular events in well-known large clinical observational or interventional studies. 57) It is certain that obesity increases cardiovascular risk and that weight reduction can ameliorate risk. However, similar to the glycemic control achieved with anti-diabetic drugs, there is little evidence on whether the weight reduction induced by anti-obesity drugs can decrease or postpone cardiovascular events in patients with obesity. Conversely, several anti-obesity drugs, including fenfluramine and sibutramine, were banned from market owing to their deleterious effects on the cardiovascular system. 2) Based on these historical events, newly developed anti-obesity drugs should have proven safety and/or efficacy on cardiovascular events in addition to its weight loss effect.
In the past several years, three clinical trials of the cardiovascular safety of anti-obesity drugs have been performed: the CAMELLIA-TIMI 61 58) trial of lorcaserin, the study by Nissen et al. 59) of NB, and the LEADER trial of liraglutide in patients with T2DM. 60) The results of the trials are summarized in   Values are presented as number (%), median (interquartile range), or mean±standard deviation, unless otherwise stated. HR, hazard ratio; NB, naltrexone 32 mg+bupropion 360 mg; AE, adverse event; MACE, major cardiovascular events (a composite of cardiovascular death, myocardial infarction, and stroke); NA, not applicable; CI, confidence interval. *The participants were people with obesity and pre-existing cardiovascular disease or with an increased cardiovascular risk. † The participants were patients with type 2 diabetes and high cardiovascular risk. ‡ Glycated hemoglobin level in patients with diabetes, median (interquartile range). § 99.7% CI.