Old and new anti-obesity drugs

Abstract

Obesity is a pandemic problem that correlates with a cluster of metabolic factors leading to poor cardiovascular outcomes, morbidity, and an increased risk of overall mortality. It is necessary to approach obesity with a comprehensive treatment plan, which may involve lifestyle modifications (diet, exercise, and behavioral therapy) and pharmacological interventions. This article provides an overview of the mechanisms of action, efficacy, and safety of available long-term anti-obesity drugs and introduces other potential agents under investigation.

Introduction

The growing prevalence of metabolic disorders is a pressing worldwide health issue. The most prevalent metabolic disorders are diabetes, obesity, and metabolic syndrome [1]. Obesity is a complex chronic disease characterized by excessive body fat and defined as a Body Mass Index(BMI) of ≥ 30 kg/m2 [2]. It is projected to affect nearly one-half of the world’s population by 2035 [3]. In 2021, the total annual number of deaths attributed to the risk factor of obesity, as reported by the Global Burden of Diseases study, was 3.71 million individuals across all age groups and both sexes [4]. A systematic review study, found a significant prevalence of overweight/obesity among both adults and individuals under-18 populations in Iran, from January 2005 through Jan 2014, with the prevalence of overweight/obesity ranging from 27.0 to 38.5 and 12.6–25.9, respectively, among adults. In individuals under-18 the range of overweight and obesity prevalence was 5.0–13.5, and 3.2–11.9, respectively [5]. Projected numbers of high BMI adults and children are expected to rise substantially from 2020 to 2035. The prevalence of children with high BMI is projected to increase from 34% in 2020 to 55% in 2035 [3]. Egypt, Libya, the United States of America, Saudi Arabia, Turkey, and Iraq are estimated to have the highest adult obesity rates (≥ 30%) among adults with a BMI ≥ 30 kg/m2 [6]. In this article, we discuss old and new pharmacologic treatments for obesity.

Mechanism of obesity

The hypothalamus plays a crucial role in regulating appetite and energy balance. It integrates various peripheral signals including hormonal and nutritional information, to regulate appetite and energy expenditure. Key hypothalamic neuropeptides, including melanin-concentrating hormone (MCH), orexins, alpha-melanocyte stimulating hormone (α-MSH), agouti-related protein (AgRP), neuropeptide Y (NPY), and oxytocin, are involved in the regulation of appetite. Adiposity signals through leptin, insulin, and gut peptides such as peptide YY (PYY), pancreatic polypeptide (PP), oxyntomodulin (OXM), and glucagon-like peptide-1 receptor (GLP-1R) act on the arcuate nucleus via proopiomelanocortin/cocaine and amphetamine-regulated transcript (POMC/CART) neurons, ultimately leading to reduced appetite by affecting the satiety center. Additionally, they indirectly act on the satiety center through an inhibitory effect on NPY, resulting in reduced appetite. NPY/AgRP neurons stimulate the hunger center via ghrelin, a peptide secreted from the stomach, and inhibit the satiety center, resulting in increased appetite by blocking POMC/CART neurons and melanocortin receptors 3 and 4 (MC3/4R) [7–9]. Obesity is a chronic disease, emphasizing the importance of primary, secondary, and tertiary prevention in managing obesity. The classification of obesity and indications for medication prescription are summarized in Table 1 [10].

Table 1.

Classification of obesity and an indication of intervention

BMI(kg/m2)	Disease stage	Phases of chronic disease prevention	Suggested treatment based on clinical judgments
25–29.9 23–24.9 in certain ethnicities	Overweight Stage 0	Secondary ( no complications)	Lifestyle modification: -Limitation of calorie -Physical activity -Behavioral therapy pharmacotherapy: Consider if there are risk factors and weight gain trajectory in BMI 27–29.9
≥ 30 ≥ 25 in certain ethnicities 30–34.9 (class I) 35–39.9(class II) ≥40 (class III)	Obesity Stage 0	Secondary ( no complications)	Lifestyle modification: -Limitation of calorie -Physical activity -Behavioral therapy Pharmacotherapy: -Consider after lifestyle modification fails to prevent progressive weight gain in BMI 27–29.9 -Strongly consider if there are risk factors and weight gain trajectory in BMI 30–34.9 Bariatric surgery: If pharmacotherapy fail(BMI ≥ 40)
≥ 25 ≥ 23 in certain ethnicities	Obesity Stage 1 (≥ 1 mild to moderate complications)	Tertiary	Lifestyle modification: -Limitation of calorie -Physical activity -Behavioral therapy Pharmacotherapy: Consider after lifestyle modification fails to achieve a therapeutic goal or initiate concurrent with lifestyle modification (BMI ≥ 27) Bariatric surgery: Consider if pharmacotherapy fails and there are risk factors in BMI 30–34.9
≥ 25 ≥ 23 in certain ethnicities	Obesity Stage 2 (≥ 1 severe complications)	Tertiary	Lifestyle modification: -Limitation of calorie -Physical activity -Behavioral therapy Pharmacotherapy: Add to lifestyle modification(BMI ≥ 27) Bariatric surgery: Consider in BMI ≥ 35

Obesity-related complications include metabolic syndrome. Prediabetes, type2 diabetes, hypertension, dyslipidemia, cardiovascular disease, nonalcoholic fatty liver disease, polycystic ovarian syndrome, female infertility, male hypogonadism, obstructive sleep apnea, asthma, reactive airway disease, osteoarthritis, urinary stress incontinence, gastroesophageal reflux disease, depression

Weight loss treatment

Treatments for obesity include behavior modification, dietary therapy, exercise, pharmacotherapy, liposuction, and, surgery. Primary prevention of obesity focuses on preventing the development of overweight and obesity. Secondary prevention aims to prevent future weight gain and the development of weight-related complications in patients with overweight and obesity. Tertiary prevention aims to treat weight-related complications and prevent disease progression through weight loss therapy. Pharmacotherapy and bariatric surgery should be considered for patients who do not achieve adequate weight loss with traditional therapy and do not have definite contraindications for drug therapy. BMI ≥ 27 kg/m2 with obesity-related diseases and BMI ≥ 30 kg/m2 without comorbidity are indications for pharmacotherapy. A BMI ≥ 40 kg/m2 with or without obesity-related complications, or a BMI ≥ 35 kg/m2 (or BMI ≥ 30 kg/m2 for laparoscopic adjustable gastric banding) with at least one obesity-related complication is an indication for bariatric surgery. Patients with a BMI of ≥ 35 kg/m2 and at least one severe obesity-related complication, including Type 2 diabetes mellitus(T2DM), hypertension, obstructive sleep apnea syndrome(OSAS), obesity hypoventilation syndrome, Pickwickian syndrome, pseudotumor cerebri, gastroesophageal reflux disease, nonalcoholic fatty liver disease or steatohepatitis, severe urinary incontinence, asthma, venous stasis disease, debilitating arthritis, or significantly impaired quality of life (QOL) may also be considered for surgical intervention. Patients with a BMI of 30 to 34.9 kg/m2 with diabetes or metabolic syndrome may also be considered for bariatric surgery. However, current evidence is limited by the number of patients studied and the lack of long-term data demonstrating benefits. Measurement of weight loss is based on mean weight loss (kg), percentage weight loss, percentage of individuals losing ≥ 5% or ≥ 10% of baseline weight, maintenance of weight loss during the study, and absolute weight loss (i.e., over placebo) [11]. There is a list of non-approved drugs and extracts that may promote weight loss but have unacceptable side effect profiles. These include sheep thyroid extract, amphetamine, diuretics, laxatives, fenfluramine/phentermine, and sibutramine [12]. Phentermine is a sympathomimetic approved for obesity treatment in 1959 for short-term use only. It stimulates the release of norepinephrine and to a lesser extent serotonin (5-hydroxytryptamine [5HT]) dopamine. Weight loss with phentermine is approximately 5% at 8 to 12 weeks and is typically administered at 15 mg to 37.5 mg orally three times daily with meals as a short-term adjunct (a few weeks) to behavioral weight loss approaches. A lower 8-mg dose for longer-term use is available, but durability has not been reported. The clinical effect of phentermine is to decrease appetite, and it appears to work better in individuals who start with greater hunger and less cognitive restraint on their eating behavior [13]. Side effects of phentermine can include pulmonary hypertension, valvular heart disease, increased heart rate or blood pressure, insomnia, restlessness, dry mouth, diarrhea, constipation, and changes in sexual drive [14]. The U.S. Food and Drug Administration(FDA) approved anti-obesity drugs for long-term use include orlistat (Xenical, Alli in 1999), phentermine/topiramate (Qsymia in 2012), naltrexone/bupropion(Contrave in 2014), and Liraglutide (Saxenda in 2014) Table 2 [12]. Other FDA-approved drugs include semaglutide (Wegovy in 2021), setmelanotide (Imcivree in 2020), and tirzepatide(Mounjaro-zepbound in 2023) [15]. Current anti-obesity drugs act through several potential mechanisms including increased energy expenditure, appetite suppression, inhibition of digestive enzymes, or disruption of absorption at the level of the intestinal tract of fat or sugar from food. The mechanisms of anti-obesity drugs are summarized in Fig. 1. Both Glucagon-like peptide-1(GLP-1) and GLP-2 released from gut enteroendocrine cells (EECs) control meal-related glycemic excursions through the enhancement of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, maximizing nutrient absorption while limiting weight gain. Their quantities are minimal during fasting or between meals, maintaining low basal levels, and circulating levels of these peptides rise promptly within minutes of food ingestion [16]. The effect of GLP-1 on various organs is summarized in Fig. 2.

Table 2.

FDA-Approved anti-obesity drugs for long-term

Generic name	Brand name	FDA approval time	Mechanism of action	Dose	Weight loss (Kg)	Major side effects
Orlistat	Xenical, Alli	1999	Lipase inhibitor	120 mg	5.8–6.7	Steatorrhea Flatulence
Phentermine/topiramate	Qsymia	2012	Stimulator of synaptic noradrenaline dopamine and serotonin release + augmenting the activity of gamma aminobutyrate	3.75/23 mg 7.5/46 mg	8.1–10.2	Dry mouth Dizziness Paresthesia Constipation Insomnia
Naltrexone/Bupropion	Contrave	2014	Opioid receptor antagonist and reuptake inhibitor of dopamine and noradrenaline	32/360 mg	9.3	Nausea Vomiting Headache Dizziness Constipation Dry mouth
Liraglutide	Saxenda	2014	GLP1 receptor agonist	3 mg	8.4 ± 7.3	Nausea Hypoglycemia Diarrhea Constipation Vomiting Pancreatitis
Semaglutide	Wegovy	2021	GLP1 receptor agonist	2.4 mg	9.7–16.8	Nausea Hypoglycemia Diarrhea Constipation Vomiting Pancreatitis
Setmelanotide	Imcivree	2020	melanocortin-4 receptor agonist	2.5–3 mg	13.9–51 (0.6 kg/w)	Skin pigmentation Nausea Vomiting Diarrhea Headache
Tirzepatide	Mounjaro-zepbound	2023	Dual GIP and GLP-1 receptor agonist	5–15 mg	16.1–23.6	Nausea Vomiting Diarrhea Headache Pancreatitis

GLP-1, Glucagon-like peptide-1; GIP, glucose-dependent insulinotropic polypeptide

Fig. 1.

Anti-obesity drugs mechanism. GLP-1, Glucagon-like peptide-1

Fig. 2.

Glucagon-like peptide-1(GLP-1) effect on other organs

Lorcaserin (Belviq)

Lorcaserin acts as a selective 5-hydroxytryptamine 2 C (5-HT- 2 C) agonist on POMC neurons, which in turn causes the release of alpha-MSH. Further, alpha-MSH acts on melanocortin 4 receptors (MC4R) in the paraventricular nucleus in the hypothalamus, leading to a decrease in appetite [17]. The FDA approved lorcaserin as an anti-obesity drug in 2012, but in February 2020, the FDA requested the voluntary withdrawal of Belviq from the U.S. market due to an increased risk of cancer. In January 2020, the FDA announced a possible risk of cancer associated with lorcaserin based on preliminary data analysis. The FDA is not recommending special screening for patients who have taken lorcaserin but recommends standard cancer screening for all patients [18].

Orlistat

Orlistat inhibits pancreatic lipase and thereby reduces the absorption of fatty acids in the intestines, causing an energy deficit of approximately 300 kcal/day. This results in moderate fat malabsorption. Excretion of about 30% of ingested triglycerides, which is close to the maximum plateau value, occurs at a dose of 360 mg/day (120 mg three times daily with meals) [14]. A systematic review and meta-analysis of 22 studies with an average age of 48 years and an average BMI of 36.7 kg/m2, in which73% of participants were women, found that there was a weight loss of 2.75 kg(3.31–2.20 kg) with orlistat [19].

Phentermine/topiramate (Qsymia)

Phentermine acts to reduce appetite by increasing norepinephrine in the hypothalamus. Topiramate may reduce appetite through its effect on GABA receptors [20]. In the CONQUER trials 2,487 overweight or obese patients aged 18 years or older (BMI ≥ 27 and ≤ 45 kg/m²) with at least two weight-related comorbidities were evaluated. These comorbidities included hypertension (elevated blood pressure ≥ 140/90 mmHg, or ≥ 130/85 mmHg for diabetics or requiring ≥ 2 antihypertensive medications), high cholesterol (triglycerides > 200–400 mg/dL or receiving treatment with ≥ 2 lipid-lowering agents), diabetes(elevated fasting blood glucose > 100 mg/dL or diabetes), and waist circumference ≥ 102 cm in men or ≥ 88 cm in women. In the Qsymia groups, 66% of patients completed the trial compared to 57% in the placebo group. At the start of the study, the average weight and BMI of patients were 227 pounds and 36.6 kg/m², respectively. The effect of Qsymia on cardiovascular morbidity and mortality has not been established. Qsymia is not indicated for the treatment of hypertension, type 2 diabetes mellitus, stroke, or heart disease. The overall percent weight loss from baseline, ITT-LOCF analysis, showed a 9.8% weight loss for patients taking the top dose (15 mg/92 mg) of Qsymia and 7.8% for patients who took the recommended dose (7.5 mg/46 mg), compared to 1.2% in the placebo group (P < 0.0001). 84% of patients responded to Qsymia in the 7.5 mg/46 mg cohort, defined as achieving at least 3% weight loss at 12 weeks. Qsymia is contraindicated in pregnancy, glaucoma, hyperthyroidism, patients receiving or within 14 days of treatment with monoamine oxidase inhibitors (MAOIs), patients with hypersensitivity or idiosyncrasy to sympathomimetic amines, topiramate, or any inactive ingredients in Qsymia. At 56 weeks, the change in body weight was − 1.4 kg for placebo, −8.1 kg for Qsymia(7.5 mg/46 mg), and − 10.2 kg for Qsymia (15 mg/92 mg). 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%) with phentermine 7.5 mg plus topiramate 46.0 mg, and 687 (70%) with phentermine 15.0 mg plus topiramate 92.0 mg. For ≥ 10% weight loss, the corresponding numbers were 72 (7%), 182 (37%), and 467 (48%) [21].

Tesofensine (NS2330)

A triple monoamine re-uptake inhibitor with an affinity for dopamine, serotonin, and norepinephrine transporters [22]. Tesofensine reduced food intake in rats, resulting in a sustained decrease in body weight. It has dual-action properties that increases energy expenditure and effectively reduce body weight in high-fat-fed rats [23, 24]. Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p < 0.0001). The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia [25]. However, the findings need to be ascertained in phase 3 trials [22].

Bupropion-naltrexone (Contrave)

The naltrexone slow-release (SR)/bupropion SR combination, marketed as Contrave, is a µ-opioid receptor antagonist combined with a norepinephrine and dopamine receptor inhibitor. Bupropion has neuronal effects associated with reduced energy intake and increased energy expenditure, and naltrexone potentiates this effect such that the effects of the combination are greater than those with bupropion alone [26]. Bupropion activates proopiomelanocortin (POMC) neurons, increasing the production of POMC, which can be cleaved into α-MSH and β-endorphin. The α-MSH powerfully inhibits food intake. In contrast, it was hypothesized that β-endorphin, acting through the µ-opioid receptor, inhibits the activity of POMC neurons [27, 28]. Thus, inhibiting the action of β-endorphin with naltrexone has the effect of increasing POMC activity [29]. This is the mechanism for the enhanced activation of POMC neurons seen when bupropion is combined with naltrexone [30]. Contrave was evaluated in four randomized, double-blind, placebo-controlled, phase III trials with study durations of 56 weeks: Contrave Obesity Research-I(COR-I) [31], COR-II [32], COR-BMOD [33], and COR diabetes [34]. These trials included approximately 4,500 overweight or obese adults (BMI range 27–45 kg/m2) with and without significant weight-related conditions. Contrave significantly induced greater % weight loss from 4 weeks versus placebo that is sustained for the longer term (56 weeks), weight reductions of ≥ 5%, ≥ 10%, and ≥ 15% in significantly more patients versus placebo, induced significantly greater improvements versus placebo in cardiometabolic risk factors resulting from 56 weeks of treatment, induced significant improvements in QOL measures associated with weight loss versus placebo, induced significantly greater weight loss and improvements in cardiovascular risk factors and glycemic control versus placebo in patients with type 2 diabetes. 42% of patients treated with Contrave lost at least 5% of their body weight compared with 17% of patients treated with placebo [31–34]. The approved administration of Contrave for long-term use is one tablet (8 mg naltrexone/90 mg bupropion) in week 1 and gradually increased dose to the maximum daily dose of 4 tablets (32 mg naltrexone/360 mg bupropion). The adverse effects of Contrave include nausea, vomiting, constipation, headache, dizziness, insomnia, and a transient increase in blood pressure (1 to 2 mmHg on average) during the initial 12 weeks of treatment. Heart rate may also be increased. Contrave is contraindicated in patients with uncontrolled hypertension, seizures, eating disorders, use of other bupropion-containing products, chronic opioid use, use within 14 days of MAO inhibitor, pregnancy, and use with caution in breastfeeding [35].

Liraglutide (Saxenda)

Glucagon-like peptide-1(GLP1) receptor agonist’s proposed brand name for obesity is Saxenda. In addition to stimulating insulin release and inhibiting glucagon secretion, slows gastric emptying and increases satiety after eating. The dose for obesity will be 3.0 mg, in contrast to 1.2 or 1.8 mg for diabetes. In the largest trial involving 3731 patients, After 56 weeks, the liraglutide group had lost an average of 8.0 kg, compared with 2.8 kg with placebo. The proportion losing at least 5% of their body weight was 63% versus 27% in the placebo group, while 33% versus 11% lost more than 10%. Overall, approximately 92% lost weight on liraglutide, compared with 65% on placebo. The liraglutide group also had greater reductions in HbA_1c, plasma glucose, systolic and diastolic blood pressure, and improvement in all measures of fasting lipids along with other metabolic parameters. They also scored higher on scales for overall physical and mental health [36]. The most reported side effects are gastrointestinal (GI), including nausea, vomiting, and diarrhea. Other side effects are injection site reactions and erythema [37]. There is an increased risk of fatal hemorrhagic and necrotizing pancreatitis using any GLP-1 analog. GLP-1RAs should be discontinued if a patient has a history of pancreatitis or develops pancreatitis [38]. All GLP-1 receptor agonists are contraindicated in patients with hypersensitivity to the drug [39]. GLP-1 receptor agonists should be avoided in gastroparesis or inflammatory bowel disorders [40]. Based on the current evidence, discontinuing GLP-1RAs during pregnancy is recommended. Limited data on the excretion of GLP-1 agonists in human breast milk is available. Therefore, caution is recommended when considering GLP-1RA during lactation [41]. In rodent studies, liraglutide was associated with benign and malignant thyroid C-cell tumors. It is unclear whether any effect is present in humans (humans have fewer C-cells) and expression of the GLP-1 receptor in human C-cells is very low. Nevertheless, liraglutide is not recommended for use in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasm 2 A or 2B ( MEN2A or 2B) [42].

Semaglutide (Wegovy)

The approval of Semaglutide2.4 mg, administered once-weekly subcutaneously, as an anti-obesity medication was based on data from 4 trials of the STEP (Semaglutide treatment effect in people with obesity) phase IIIa clinical program, which involved > 4,500 people [43, 44]. The STEP clinical program was a comprehensive, randomized, double-blind, placebo-controlled study that lasted for 68 weeks, with 7 weeks of follow-up without treatment for safety assessments. The program compared 2.4 mg semaglutide with a placebo as an adjunct to lifestyle interventions (500 kcal/day deficit relative to the estimated total energy expenditure, plus 150 min/week of physical activity) (except for STEP 3) in people with obesity or overweight (and T2DM in STEP 2). The primary endpoints of the study were the percentage change in body weight and the proportion of participants who achieved a ≥ 5% weight loss from baseline to week 68 without weight regain (i.e. at randomization; week 20 in STEP 4). The study included participants aged ≥ 18 years old have a history of at least one failed attempt to lose body weight. Except in STEP 2, adults in the STEP clinical program had a BMI ≥ 30 kg/m² or ≥ 27 kg/m² with the presence of weight-related complications: dyslipidemia, obstructive sleep apnea syndrome, hypertension, or cardiovascular disease. Participants in STEP 2 were also required to be diagnosed with T2DM (HbA1c 7–10% [53–86 mmol/mol]) ≥ 180 days before screening. The phase III STEP clinical program has demonstrated the efficacy of 2.4 mg semaglutide in achieving clinically meaningful and durable weight loss, providing more weight loss than other available agents for obesity. Additionally, the treatment improves the overall health and quality of life for individuals with obesity or overweight (with or without T2DM) [45]. In STEP 7, enrolled adults with overweight or obese, with or without T2DM, received a weekly subcutaneous injection of either semaglutide 2.4 mg or placebo for 44 weeks, in addition to diet and physical activity interventions. The study population consisted of individuals ≥ 18 years old, BMI ≥ 30 kg/m² or ≥ 27 kg/m² with the presence of ≥ 1 weight-related comorbidity or HbA1C ≤ 6.5% in the population without T2DM and BMI ≥ 27 kg/m² or ≤ 3 oral agent anti-diabetic drugs (and no insulin) or HbA1C = 7–10% in the population with T2DM.The study found that semaglutide 2.4 mg resulted in a significant and greater percentage of weight loss compared with placebo, with an estimated mean percentage change of −12.1% versus − 3.6% from baseline to week 44 (p < 0.0001). Additionally, the proportion of participants who lost ≥ 5% of their body weight was higher in the semaglutide 2.4 mg group(85%) than in the placebo group (31%), with an odds ratio of 13.1 (95% CI 7.4–23.1; p < 0.0001) [46]. The study found that semaglutide significantly improved symptoms and physical limitations in patients with heart failure with preserved ejection fraction and a BMI ≥ 30 kg/m² as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations), with a mean increase of 16.6 points with semaglutide compared to 8.7 points with placebo. Additionally, semaglutide resulted in a greater reduction in body weight, with a mean percentage change of − 13.3% with semaglutide compared to − 2.6% with placebo (estimated difference, − 10.7% points; P < 0.001). Serious adverse events occurred in 35 participants (13.3%) in the semaglutide group compared to 71 (26.7%) in the placebo group (P < 0.001); with a significant difference driven by a lower number of cardiac disorder events in the semaglutide group (7 [2.7%] versus 30 [11.3%] in the placebo group; P < 0.001) [47]. In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, designed to evaluate the efficacy and safety of 2.4 mg semaglutide in patients ≥ 45 years old with preexisting cardiovascular disease and a BMI ≥ 27 kg/m² but no history of diabetes, the trial randomly assigned 17,604 patients to receive semaglutide or placebo to determine whether semaglutide is superior to placebo in reducing cardiovascular events. A primary cardiovascular endpoint event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 6.5% in the semaglutide group and 8.0% in the placebo group (hazard ratio, 0.80; P < 0.001). Death from cardiovascular causes, the first confirmatory secondary endpoint, was slightly lower in the semaglutide group with 223 patients (2.5%) experiencing this outcome compared to the placebo group where 262 patients (3.0%) experienced it (hazard ratio of 0.85; 95% CI, 0.71 to 1.01).The hazard ratio for the heart failure composite endpoint was 0.82 (95% CI, 0.71 to 0.96), and for death from any cause was 0.81 (95% CI, 0.71 to 0.93) [48]. In the double-blind, parallel-group, randomized, placebo-controlled trial, adolescents (12 to < 18 years of age) with obesity (a BMI ≥ 95th percentile) or with overweight (a BMI ≥ 85th percentile) and ≥ 1 weight-related coexisting condition were enrolled. The study randomized participants to receive semaglutide 2.4 mg or placebo along with lifestyle modification for 68 weeks. The study found that treatment with semaglutide resulted in a statistically significant reduction in BMI from baseline to week 68, with a mean change in BMI of − 16.1% with semaglutide compared to 0.6% with placebo, representing a significant difference of − 16.7% points. At week 68, the semaglutide group showed a significant improvement in weight loss and cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) compared to the placebo group, with 73% of participants achieving a weight loss ≥ 5% compared to 18% in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P < 0.001). Reductions in body weight and improvement were greater with semaglutide than with placebo. The study found that semaglutide was associated with a higher incidence of gastrointestinal adverse events (62%) compared to placebo (42%), with a higher rate of cholelithiasis (4% versus 0%). Serious adverse events were reported in 11% of participants in the semaglutide group and 9% of participants in the placebo group [49]. The side effects and contraindications of semaglutide are similar to those of liraglutide but a recent retrospective cohort study of 16,827 patients revealed a higher risk of nonarteritic anterior ischemic optic neuropathy (NAION) in patients prescribed semaglutide compared with patients prescribed non-glucagon-like peptide receptor agonist medications for diabetes or obesity [50].

Setmelanotide (Imcivree)

A synthetic cyclic peptide that binds to the human MC4R with high affinity, has demonstrated significant reductions of approximately 10% in body weight. Thus, setmelanotide is the first drug approved by the Food and Drug Administration (FDA) for the treatment of severe obesity of genetic origin [51]. In a study of 376 patients, 328 (87.2%) received setmelanotide for a mean follow-up of 52 weeks. Weight loss with setmelanotide was significant (Median − 3.52; 95% CI −3.98, −3.05; p = 0.01), with an average proportion of −6.91% weight loss during treatment. Changes in BMI showed − 10.55 kg/m² in patients over 18 years and − 0.61 kg/m² in patients under 18 years (BMI score). However, the drug was associated with a higher risk of skin hyperpigmentation (odds ratio[OR]of 0.69; p = 0.08) [52].

Tirzepatide(Mounjaro-zepbound)

Tirzepatide (Mounjaro) is the first dual Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1receptor (GLP-1 R)agonist for the treatment of T2DM, obesity, and nonalcoholic steatohepatitis [53]. Tirzepatide was approved by the FDA in 2022 for the treatment of T2DM. It demonstrates a binding affinity to the GIPR comparable to that of native GIP itself while displaying a lower binding affinity to the GLP-1R in comparison to native GLP-1 [54]. Two research programs were conducted: the SURPASS trials for T2DM efficacy and the SURMOUNT trials for weight reduction. In the SURMOUNT-1 trial targeting non-diabetic patients with obesity, tirzepatide achieved an impressive 22.5% reduction in body weight after 72 weeks, surpassing other drugs [55]. This significant weight loss which was accompanied by a favorable safety profile and improvements in secondary outcomes, including a delay in the onset of T2DM, reduced risk of decline in estimated glomerular filtration rate or renal death, and enhancements in quality of life measures. These positive outcomes contribute to the potential reduction of obesity-related morbidity and mortality [56]. The study, SURMOUNT-1, (Supported by Eli Lilly) assigned 2539 adults with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² and ≥ 1weight-related complication, except diabetes, to receive once-weekly, subcutaneous tirzepatide or placebo for 72 weeks. The 5 mg, 10 mg, or 15 mg dose of tirzepatide, resuled in mean percentage change in weight − 15.0%, −19.5%, −20.9%, respectively, with a corresponding weight reduction of 16.11 kg, 22.2 kg and, 23.6 kg. In contrast, the placebo group had a mean percentage change in weight of −3.1% and a weight reduction of 2.4 kg (P < 0.001 for all comparisons with placebo). The percentage of individuals with a weight reduction of ≥ 5% was 85%, 89%, and 91% with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% with placebo; 50% and 57% of participants in the 10-mg and 15-mg groups had a reduction in body weight of ≥ 20%, as compared with 3% in the placebo group (P < 0.001 for all comparisons with placebo). At week 72, more participants in the tirzepatide groups had reductions in body weight of ≥ 10%, ≥ 15%, and ≥ 20% from baseline than participants in the placebo group (P < 0.001) [55]. In phase 3, a double-blind, randomized, placebo-controlled trial (Supported by Eli Lilly; SURMOUNT-2) was conducted in 7countries. Adults (aged ≥ 18 years) with a BMI ≥ 27 kg/m² and glycated hemoglobin (HbA_1c) of 7–10% (53–86 mmol/mol) were randomly assigned (1:1:1), to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. Least-squares mean change in body weight at week 72 with tirzepatide 10 mg and 15 mg was − 12.8% and − 14.7%, respectively, and − 3.2% with placebo, resulting in estimated treatment differences versus placebo of −9.6% percentage points (95% CI −11.1 to −8.1) with tirzepatide 10 mg and − 11.6% percentage points (−13.0 to −10.1) with tirzepatide 15 mg (all p < 0.0001). More participants treated with tirzepatide versus placebo met body weight reduction thresholds of ≥ 5% (79–83% versus 32%) [57]. In a double-blind, placebo-controlled trial(Supported by Eli Lilly; SURMOUNT-3) randomized (1:1) adults with BMI ≥ 30 or ≥ 27 kg/m² and ≥ 1 obesity-related complication (except diabetes), who achieved ≥ 5.0% weight reduction after a 12-week intensive lifestyle modification, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72weeks. 579 (71.8%) who achieved ≥ 5% weight reduction at the end of the period. Mean body weight and BMI in these 579 participants decreased from 109.5 kg to 38.6 kg/m², respectively, at the screening to 101.9 kg and 35.9 kg/m², respectively, at randomization, representing an average 6.9% reduction in body weight after the 12-week intensive lifestyle modification [58]. In Phase 3, a randomized withdrawal clinical trial (SURMOUNT-4), included adults with a BMI ≥ 30 kg/m² or ≥ 27 kg/m² and a weight-related complication, excluding diabetes. Participants received a once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. Who experienced a mean weight reduction of 20.9%.The mean percent weight change from week 36 to week 88 was − 5.5% with tirzepatide versus 14.0% with placebo (difference, − 19.4% [95% CI, − 21.2% to − 17.7%]; P < 0.001). Overall, 89.5% participants receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < 0.001). The overall mean weight reduction from weeks 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo [59].

Network meta-analysis

A meta-analysis of 28 randomized clinical trials comparing US FDA-approved weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) versus placebo for weight loss and adverse events was conducted. The trials included 29,018 patients, with a median age of 46 years, 74% women, and a median baseline body weight of 100.5 kg. The results showed that all active agents were associated with significant excess weight loss compared to the placebo at one year. Moreover, phentermine-topiramate, 15 mg/92 mg once daily, was associated with significant excess weight loss compared with all active agents and had the highest probability of achieving at least 5% and 10% weight loss. All agents were associated with higher proportions of patients achieving at least 5% and 10% weight loss compared with placebo. Overall, the excess weight loss compared with placebo was 2.6 kg with orlistat, 3.2 kg with lorcaserin, 5.0 kg with naltrexone-bupropion, 8.8 kg with phentermine-topiramate, and 5.2 kg with liraglutide [14]. A systematic review and network meta-analysis of 483 full-text articles compared GLP-1RAs and placebo for weight loss. The study included 76 trials involving 15 GLP-1RA drugs and 39,246 participants. Cagrisema (semaglutide with cagrilintide) had a mean difference of − 14.03 kg (− 17.05 to − 11.00), and was identified as the most effective GLP-1RA drug in lowering body weight. Other GLP-1RAs showed significant weight loss effects compared to the placebo.Tirzepatide(− 2.85(− 3.70to − 2.01)),orforglipron(− 2.01(− 3.22to − 0.91)),semaglutide(− 1.28(− 1.73 to − 0.83)), and liraglutide(− 0.81(− 1.26 to − 0.36)) effectively lowered BMI levels compared with placebo. Moreover, tirzepatide(− 6.77 cm(− 8.97 to − 4.57)), semaglutide(− 3.74 cm(− 5.25 to − 2.24)) and liraglutide(− 2.30 cm(− 3.78 to − 0.82)) were shown to be effective in reducing waist circumference. However, some GLP-1RAs showed higher odds ratios of discontinuation due to adverse events compared to the placebo. The most reported adverse reactions were gastrointestinal events, with cagrisema, lixisenatide, orforglipron, semaglutide, liraglutide, exenatide, and dulaglutide causing the most vomiting [60]. A network meta-analysis evaluates the efficacy and safety of tirzepatide compared to GLP1R agonists and other FDA-approved weight loss drugs in the treatment of overweight and obesity. 31 randomized controlled trials, involving more than 35,000 patients show that tirzepatide 15 mg had the highest efficacy compared with placebo for achieving ≥ 15% weight loss, ranking in the top glycemic profile, lipid parameters, and blood pressure. But tirzepatide and GLP1R agonist compared to placebo had significant increases in gastrointestinal adverse effects [61]. During the weight loss phase changes in diet selection, decreased appetite, and changes in gut hormone levels are known to play a significant role [62]. In the last 20 years, the emergence of pharmacological treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. Three gastrointestinal hormones that can play a role in the therapeutic goal of obesity medication include glucagon, GIP, and GLP-1 [63]. Therefore, it is unsurprising that the discovery and development of gastrointestinal hormone co-agonists as a pharmacological therapy has transformed the treatment of obesity. This drug class is the most efficacious compared to the limited number of other available obesity medications [64]. The remarkable weight loss and glucose-lowering results achieved by the dual peptides paved the way for triple GIP/GLP-1/glucagon receptor three agonists with the hope that the new combinatorial approaches provide further synergistic metabolic effects [63]. Glucagon is a peptide hormone processed by prohormone convertase 2. It is mostly produced in the pancreatic α-cells in response to fasting or hypoglycemia, but some production occurs in the small intestine [65]. Most glucagon receptors are found on hepatocytes, but they are also present in the central nervous system, kidney, gastrointestinal tract, and pancreas [66]. The functions of glucagon include the induction of hepatic gluconeogenesis and glycogenolysis, the inhibition of hepatic glycogenesis, stimulation of lipolysis and increased ketogenesis [67]. Glucagon promotes satiety and increases energy expenditure in humans. Interestingly, it also stimulates insulin secretion from β-cells, but with much lower potency than GLP-1 with the mechanism potentially due to the weak binding of glucagon at the GLP-1 receptor site [65]. Therefore, despite its hyperglycemic effects, glucagon triggers lipid catabolism and energy expenditure and reduces food intake. These characteristics support the use of glucagon in combination with other gastrointestinal hormones that have opposite glucose-lowering effects for the treatment of obesity and T2DM [68]. GIP is a 42 amino-acid protein secreted from K cells in the mucosa of the proximal duodenum and jejunum in response to eating and has a marked postprandial increase in secretion [69]. It acts on G-protein-coupled receptors mostly expressed in pancreatic β-cells but is also found in adipose tissue, stomach, and bone [70]. GIP has further effects beyond insulin secretion by stimulating lipogenesis in adipose tissue and reducing lipolysis [71].The brain GIP receptor signaling pathways play a key role in the regulation of energy balance [72]. Despite the above preclinical evidence, there is no significant effect on appetite, energy intake, or energy expenditure following a GIP acute infusion over a short period. However, Mathiesen et al. [73] have speculated that long-term GIP receptor agonists result in significant GIP receptor downregulation and effectively lead to GIP receptor antagonism with the effect of reduced food intake. Further studies are needed to clarify the effects of GIP pharmacology on feeding behavior.GLP-1 is a peptide hormone secreted by intestinal enteroendocrine L-cells, specific neurons of the solitary tract in the brainstem, and some α-cells in the pancreas [74]. Its main roles are the stimulation of insulin release [75], suppression of glucagon secretion [16], delay of gastric emptying, and reduction in food intake [76]. GLP-1 inhibits food intake and promotes satiety in healthy individuals and those with obesity and diabetes [77]. Prospects for the next generation of obesity treatments focus on Fibroblast growth factor 21 (FGF21), ghrelin antagonism, GLP-1/glucagon coagonists, GLP-1/GIP/glucagon triple agonists, growth differentiation factor 15(GDF15), melaninconcentrating antagonists, and amylin-based therapies including pramlintide, cagrilintide, cagrilintid plus semaglutide [78]. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as GIP, glucagon, and amylin) are under investigation to enhance the weight loss and cardiometabolic benefits of GLP-1 RA [79]. Pharmacotherapies under investigation based on a combination of GLP1 with other gut hormones are shown in Fig. 3 [80]. Retatrutide is a single peptide conjugated to a fatty di-acid moiety and has an agonist effect on the GIP, GLP-1, and glucagon receptors. A phase 2, multicenter, randomized, double-blind, placebo-controlled trial in the United States assessed the efficacy and safety of retatrutide in 338 adults aged 18–75 years without diabetes but with obesity or overweight plus ≥ 1 weight-related condition for 48 weeks. Participants received a retatrutide dose of 4 mg or higher, followed by gradual dose escalation every 4 weeks for up to 12 weeks. The least-squares mean percentage change in weight at 48 weeks (secondary endpoint) was − 8.7% in the 1-mg group, − 16.3% in the 4-mg group with an initial dose of 2 mg, − 17.8% in the 4-mg group with an initial dose of 4 mg, − 21.7% in the 8-mg group with an initial dose of 2 mg, − 23.9% in the 8-mg group with an initial dose of 4 mg, and − 24.2% in the 12-mg group with an initial dose of 2 mg, as compared with − 2.1% in the placebo group. At 48 weeks, 64 to 100% of participants in the retatrutide groups had body-weight reductions of 5% or more, as compared with 27% of the participants in the placebo group. Higher percentages of participants had reductions in body weight of 10% or more and 15% or more with retatrutide (all doses) than with placebo. Gastrointestinal adverse events occurred substantially more often with retatrutide than with placebo; these events were usually mild to moderate in severity and were more common at higher doses of retatrutide [81].

Fig. 3.

Pharmacotherapies under investigation based on a combination of GLP1 with other gut hormones. GLP-1, Glucagon-like peptide-1; GIP, glucose-dependent insulinotropic polypeptide; PYY, peptide YY; GLP1R, Glucagon-like peptide-1 receptor

Conclusion

Obesity is a pandemic global problem. Management of obesity includes lifestyle modification, pharmacotherapy, bariatric surgery, and cognitive behavioral strategies. The success rate of lifestyle modification in weight loss is low. Pharmacotherapy plays an important role in achieving clinically significant weight loss and preventing weight-related comorbid conditions. In the last 20 years, the emergence of promising treatments for obesity based on gastrointestinal hormones has transformed the therapeutic landscape. In summary, intensive lifestyle intervention (ILI) results in a 5% weight loss. ILI and older anti-obesity medications including naltrexone/bupropion, phentermine/topiramate, and liraglutide lead to greater weight loss compared to ILI. Semaglutide 2.4 mg, Tirzepatide 15 mg, and cagrilintide/semaglutide combination result in greater weight loss compared to older anti-obesity medications. Bariatric and metabolic surgical interventions are effective treatments for weight loss, which also result in significant improvement in obesity-related morbidities such as Type 2 diabetes. Retatrutide as a triple receptor agonist has shown higher weight loss than surgical treatments and is under investigation in obesity clinical trials. New anti-obesity drugs with different mechanisms are under investigation and will be introduced in the near future.

Author contributions

SD wrote the manuscript under the direction of SH. Data collection was done by SH and SD. All authors reviewed, edited, and approved the final manuscript.

Funding

No funding was received.

Data availability

Not applicable.

Declarations

Ethical statement

There was no need for ethics approval.

Competing interests

The authors declare that they have no competing interests.