Introduction

A body mass index (BMI) of ≥30 (or> 27 in those of Asian descent) kilograms per square meter constitutes the definition of obesity.[1] Obesity involves a complex interplay of genetic, sociocultural, environmental, and behavioral factors. In 1997, the World Health Organization (WHO) declared obesity a major global health issue along with undernutrition and climate change, the triad being termed "the Global Syndemic."[2] Today in the United States of America (USA), one-third of the adult population is obese, with the Centers for Disease Control and Prevention projecting that by 2050, 60% of men and 40% of women in the USA will be obese.[3] 

Obesity once again came into focus during the SARS-CoV-2 pandemic, when patients with obesity were found to have an increased need for mechanical ventilation and higher mortality.[4] Once thought to be an exclusive problem of the developed world, numerous studies have shown that developing countries now have the highest incidence of obesity. South-East Asians have a higher percentage of body fat, truncal/central obesity, and insulin resistance than their White counterparts, prompting the WHO to endorse a lower cut-off point for action against obesity at ≥27kg/m^2 in the Asian population.[5] The latest terminology introduced for obesity is ABCD-adiposity-based chronic disease, which shifts the focus to the chronic nature of obesity and its comorbidities, which require treatment in addition to the treatment of obesity itself.[6] 

It is well known that obesity is associated with a shortened life span and increased incidence of obstructive sleep apnea, osteoarthritis, gout, polycystic ovarian syndrome, metabolic syndrome, prediabetes, hypertension, stroke, non-alcoholic fatty liver disease, heart failure, and cancers of the colon, breast, endometrium, and gallbladder.[7] Therefore, the treatment of obesity is crucial, along with the early identification of complications. Although this article focuses on non-dieting approaches to treating obesity with medications, gastrointestinal devices, and bariatric surgery, it must be emphasized that diet and exercise are essential to good cardiometabolic health in obese patients.

Function

Obesity is a disease of prolonged positive energy balance. It has long been studied that the body actively defends adiposity as an adaptive survival mechanism; attempts to lose weight must be at least partially uncoupled from counter-regulatory or compensatory mechanisms to increase food intake. This can be achieved via medications and cognitive behavioral therapy. The hypothalamus is the center of the homeostatic pathways and functions as a master regulator of energy balance. Additionally, hedonistic counterregulatory/compensatory mechanisms involve the senses and specific areas of the brain, which are significantly different in their level of functioning between obese and lean people. The table below lists hormones, neurochemicals, and signals involved in this complex circuitry that governs food intake. Understanding these pathways is important as researchers continue to devise weight loss drugs that target these neurochemicals.[1][8]

Table

Table of neurochemicals, signals, and hormones involved in appetite and weight regulation: Y=Yes, N=No[8].

Issues of Concern

Even though lifestyle modification via diet, exercise, and behavioral therapy is considered the primary treatment of obesity, most people cannot achieve or maintain weight loss without the help of pharmacotherapy or surgery. Since 2013, numerous professional societies for Internal Medicine, Obesity, Endocrinology, and Cardiology have endorsed pharmacotherapy for patients with a BMI of ≥30 or ≥27 with obesity-related complications who have struggled to achieve their weight goals through diet and exercise. However, this guideline was promptly furthered in 2016 to endorse pharmacotherapy as a first-line treatment for weight loss in patients with severe obesity-related comorbidities, even without the criteria of failing lifestyle modification.[7] The Asia Pacific obesity guidelines endorse drug therapy for patients with a BMI of ≥25 or ≥23 with weight-related complications in Asian populations.[2]

Based on the 2007 FDA guidelines, any drug marketed for the treatment of obesity must produce a ≥5% weight reduction in at least 35% of the subjects studied in the trial with actual reduction of body fat measured by dual-energy absorptiometry, and simultaneously demonstrate cardiovascular safety with improvements in metabolic parameters, such as lipid profile and blood pressure. Additionally, all drugs must undergo pre-marketing testing to ensure that they do not increase the risk of cardiovascular disease. The weight lost at the 12-week mark is considered an indicator of response to a particular drug. If adherence to the drug can be ensured and weight loss of 5% is not achieved in 12 weeks, the dose of the drug can be increased, combined with another drug, stopped altogether, or a new drug can be started. Obesity must be considered a chronic condition requiring long-term treatment, as most patients who stop pharmacotherapy are prone to rebound weight gain. If lifestyle modification and drug therapy fail, bariatric surgery must be considered a sustainable weight loss option.[8][3][9]

I) Drugs of historical significance/withdrawn from the market for the treatment of obesity

Thyroid hormone, dinitrophenol, amphetamines, aminorex, phenylpropanolamine, and ephedra alkaloids were previously used for weight loss but were subsequently withdrawn by the FDA for this indication due to side effects associated with sympathetic overactivity. Fenfluramine and dexfenfluramine were banned due to their association with heart disease. Rimonabant, a cannabinoid receptor 1 antagonist/inverse agonist, was also banned as it was associated with depression and suicide. Sibutramine was associated with a high risk of cardiovascular disease and stroke. Lorcaserin was the latest drug to be withdrawn from the market by the FDA in February 2020 after the CAMELLIA-TIMI 61 trial showed that patients who were treated with lorcaserin long-term were at high risk of pancreatic, colorectal, and lung cancers.[9][1][7][10]

II) Drugs approved by the FDA for a short term, i.e., ≤12 weeks, for the treatment of obesity 

These drugs are amphetamine analogs that increase central adrenergic and dopaminergic activity to induce weight loss. Unfortunately, they have multiple potential side effects of sympathetic overactivity, including agitation, irritability, hallucinations, nausea, and vomiting. They are contraindicated in patients with hypertension and hyperthyroidism, as well as pregnant women. Amphetamine analog examples include phentermine (the most prescribed weight loss drug in the USA) at a dose of 15 to 37.5mg per day, diethylpropion 25 mg three times daily or 75mg extended-release daily, phendimetrazine 17.5mg to 70 mg two to three times a day, and benzphetamine 25mg to 50mg once to three times per day.[7][9][1][3]

III) Drugs approved by the FDA for the long-term treatment of obesity

The FDA approved 5 drugs for the long-term treatment of obesity in the general population, as listed below. All five drugs have been studied in detail through multiple trials to assess their efficacy, safety, and cardiometabolic benefits, as mandated by the FDA. Below is a detailed mechanism of action, year of FDA approval, important trials that have proven their benefits, approximate weight loss, dosing information, contraindications, precautions, adverse effects, and key facts related to each drug. 

1. Orlistat

• Mechanism of action: Gastric and pancreatic lipase inhibitor
• Year of FDA approval: 1999
• Important trials: XENDOS
• Approximate weight loss in % total body weight: 3
• Dosing:

  • Over the counter: Oral 60mg three times daily with meals
  • Prescription-strength: 120mg three times daily with meals
• Contraindications: Pregnancy, malabsorption syndrome, cholestasis
• Precautions: The patient should be on a multivitamin and fiber supplement
• Adverse Events: Flatus, fecal incontinence, steatorrhea, increased chances of renal oxalate stones
• Important facts: It is the only anti-obesity drug approved for adolescents [8][3][7][11][2]

 2. Liraglutide

• Mechanism of action: GLP-1 agonist: direct stimulation of pro-opiomelanocortin (POMC), amphetamine-regulated transcript, indirect inhibition of NPY, delays gastric emptying, promotes satiety
• Year of FDA approval: 2015
• Important trials: SCALE-Sleep apnea, SCALE-diabetes, SCALE-obesity and prediabetes, SCALE-maintenance, LEADER
• Approximate weight loss in % total body weight: 4 to 5.4
• Dosing: 0.6 mg subcutaneous (SQ) per day and up-titrate every week to 3mg SQ daily
• Contraindications: Pregnancy, multiple endocrine neoplasias (MEN)-2 syndrome, a personal/family history of medullary carcinoma of the thyroid, acute or chronic pancreatitis
• Precautions: Can cause concurrent hypoglycemia with insulin or insulin secretagogue
• Adverse Events: Nausea, vomiting, diarrhea, abdominal pain
• Important facts: Improves metabolic syndrome, hepatic steatosis, polycystic ovarian syndrome (PCOS), type 2 diabetes (T2DM), cardiovascular disease (CVD), and obstructive sleep apnea (OSA).[8][1][3][7][11][2]

3. Phentermine + Topiramate 

• Mechanism of action: Phentermine=noradrenergic: activates POMC neurons in arcuate nucleus + Topiramate=GABA Agonist, AMPA/Kainate glutamate antagonist
• Year of FDA approval: 2012
• Important trials: EQUATE, EQUIP, CONQUER, SEQUEL
• Approximate weight loss in % total body weight: 8.6 to 9.3
• Dosing: Phentermine immediate release with Topiramate sustained release: starting 3.75mg-23mg for 2 weeks and escalating to the recommended dose of 7.5mg-46mg. It can be further escalated to a maximum dose of 15mg-92mg daily
• Contraindications: Pregnancy, uncontrolled hypertension (HTN), CVD
• Precautions: Increased risk of kidney stones, an increase in heart rate, suicidal ideation, and abrupt withdrawal can trigger seizures 
• Adverse Events: Paraesthesia, dysgeusia, constipation, metabolic acidosis
• Important facts: It is the first combination treatment approved for obesity and the most effective in causing weight loss. It is a category X drug, increasing the chances of a cleft lip in the fetus. The Risk Evaluation and Mitigation Strategies (REMS) program recommends pregnancy tests before initiating the drug and monthly pregnancy tests while on the medication.[8][1][3][7][11][2]

4. Naltrexone + Bupropion

• Mechanism of action: Naltrexone=opioid antagonist: prevents beta-endorphin mediated negative feedback on alpha MSH + bupropion=inhibitor of DA and NE transporter: Stimulates POMC with increased release of alpha-MSH
• Year of FDA approval: 2014
• Important trials: COR-I, COR-II, COR-BMOD, COR-Diabetes, LIGHT
• Approximate weight loss in % total body weight: 3.3 to 4.8
• Dosing: Sustained release combination: 8-90 mg daily, up-titrated to 16mg-180mg twice daily
• Contraindications: Pregnancy, seizure disorder, anorexia or bulimia, alcohol withdrawal, age >75 years, use of monoamine oxidase inhibitors within 2 weeks of drug initiation
• Precautions: Monitor for suicidal ideation, an increase in heart rate
• Adverse Events: Nausea, vomiting, dizziness, dry mouth
• Important facts: Recommended for patients with obesity and a concurrent mood disorder.[8][1][3][7][11][2]

5. Semaglutide

• Mechanism of action: GLP-1 agonist with peripheral and central action
• Year of FDA approval: 2021
• Important trials: STEP-1 trial, which compared once-weekly SQ 2.4mg Semaglutide versus placebo in addition to lifestyle intervention (individual counseling every 4 weeks, 500 calorie deficit per day, and physical activity for 150 minutes per week) for 68 weeks. Interestingly, this trial excluded patients with a history of diabetes.
• Approximate weight loss: Overall, 14.9% weight reduction, which was statistically significant. Of the participants receiving Semaglutide, 86% achieved a weight loss of≥5%, 70% achieved a weight loss of≥10%, and 50% achieved a weight loss of at least 15%.
• Dosing: SQ 2.4mg weekly (in the trial, the drug was started at 0.25mg weekly and titrated up to the full dose by week 16)
• Contraindications: Pregnancy, MEN-2 syndrome, a personal/family history of medullary carcinoma of the thyroid, acute or chronic pancreatitis
• Adverse effects: Diarrhea, nausea, vomiting, cholelithiasis [4]

IV) The FDA has approved 2 drugs exclusively for patients with specific genetic conditions causing obesity. These are: 

1. Setmelanotide

• Mechanism of action: Melanocortin 4 receptor agonist acting on the hypothalamus downstream of the leptin signaling pathway; increases satiety and decreases food consumption.
• Year of FDA approval: November 2020
• Specific population: Patients with deficiencies in POMC, PCSK1, or LEPR genes (deemed pathogenic variants or variants of uncertain significance, confirmed on genetic testing), or patients with Bardet-Biedl syndrome
• Dosing: SQ 2mg daily (maximum dose 3mg daily)
• Contraindications: Patients with other causes of obesity, polygenic obesity, or benign variants of the genetic mutations
• Adverse effects: Hyperpigmentation, vomiting, nausea [2]

2. Metreleptin

• Mechanism of action: Stimulates POMC neurons and inhibits NPY neurons, thereby increasing energy expenditure and promoting satiety
• Year of FDA approval: 2014
• Specific population: Patients with congenital or acquired generalized lipodystrophy with leptin deficiency
• Adult dosing for weight ≥40kg: SQ 2.5mg daily for males and 5mg daily for females (maximum dose 10mg/day)
• Contraindications: Partial lipodystrophy, established metabolic diseases like type 2 diabetes with lipodystrophy, HIV related lipodystrophy
• Adverse effects: It can cause pancreatitis, generation of leptin-neutralizing antibodies, abdominal pain, and headache. Hence, it is monitored under the REMS program.[11][9][12]

V) Of note, certain medications FDA-approved for other indications (depression, seizure disorder, and type 2 diabetes) can cause weight loss as a side effect 

These include fluoxetine, zonisamide, pramlintide, lixisenatide, dulaglutide, empagliflozin, ertugliflozin, remogliflozin, sergliflozin, metformin, exenatide, canagliflozin, dapagliflozin, octreotide, mirabegron, tadalafil, or bupropion alone. These are not to be prescribed routinely to patients for the indication of weight loss.[3][11]

VI) The newest drug awaiting FDA approval for the indication of obesity:

1. Tirzepatide

• Mechanism of action: Commonly known as the "twincretin" due to its dual agonistic action on the incretins, Gastric Inhibitory Peptide (GIP) and GLP-1, which increase insulin response to oral glucose
• Important trials include the SURPASS trials, which have compared tirzepatide to placebo, metformin, semaglutide, dulaglutide, other oral anti-hyperglycemic agents, and Insulin in various combinations, as well as the SURMOUNT-1 trial.
• Controversies surrounding the drug and trials: Some studies have shown that GIP is, in fact, obesogenic, and there have been GIP antagonists developed to tackle obesity. GIP itself can contribute to hyperglycemia by stimulating glucagon and can inhibit the effect of GLP-1 on decreasing food intake. Hence, at least per laboratory data, using a GIP agonist is of limited utility. However, the trial investigators argue that GIP contributes more to the incretin effect than GLP-1, and GIP-induced weight loss is mediated through glucagon's anti-lipogenic and anorexic actions. Thus, having a dual agonist was more effective than a single agent. Another criticism is that the dose of GLP-1 agonists used in the SURPASS trials to show superiority is suboptimal compared to the dose currently being studied to treat obesity.
• Weight loss: With a weekly dose of 15 mg, tirzepatide has shown a 5.1kg weight reduction in Phase 1 trials and an 11.3kg weight reduction in Phase 2 trials. In the latest data published by Eli Lily, the SURPASS 2 trial comparing once-weekly SQ tirzepatide and a 1mg dose of SQ Semaglutide in addition to Metformin showed a weight reduction from baseline of 8.5% with the 5mg dose of Tirzepatide, 11% with the 10mg dose, and 13.1% with the 15mg dose which were all statistically significant over Semaglutide 1mg group.
• Dosing: SQ 5 to 15mg weekly. (In the SURPASS-2 trial, the drug was started at 2.5mg and titrated up 4 weekly to the desired dose)
• Adverse effects: Hypoglycemia with higher doses, nausea, diarrhea, vomiting [13][14]

Bariatric Surgeries for the Treatment of Obesity

Bariatric surgeries provide a greater and more sustained weight loss than drug therapy. Bariatric surgery can also lead to a longer life expectancy, as shown in a recent study.[15] However, it comes at the expense of irreversibility for some procedures and potential long-term complications. In addition, surgical therapy can prompt addiction transfer, the exchange of palatable food reinforcers with alternate addiction-causing agents, such as smoking, illicit drugs, and alcohol. Several procedures are specifically endorsed by the American Society for Metabolic and Bariatric Surgery and are FDA-approved devices that do not require an Institutional Review Board approval before intervention. However, other surgeries and devices do require IRB approval. Below is a comprehensive list of procedures, associated weight loss, and other considerations.

ASBMS=American Society for Metabolic and Bariatric Surgery, NA=not applicable, IRB=Institutional Review Board, Y=Yes, N=No, BMI in kilograms/square meter, ORC=Obesity related complication, GI=gastrointestinal

1. Roux-en-Y gastric bypass surgery (RNYGB)

• Description: The stomach is divided into the small proximal gastric pouch, anastomosed to an alimentary limb that drains the consumed food. The distal stomach remnant, liver, pancreas, duodenum, and part of the jejunum are anastomosed to the alimentary limb about 75 to 150cm from the gastrojejunostomy.
• ASBMS endorsed: Y, FDA approved: NA, ASBMS investigational: NA, IRB approval required: N, covered by insurance: Y
• Patient population: BMI ≥40 or ≥35 with 1 ORC
• Advantage/mechanism of weight loss: Food restriction, early satiety, increased anorexigenic gut hormones-GLP-1, CCK, PYY, and decreases ghrelin, thus termed 'metabolic surgery.' Sustained weight loss in long-term follow-up studies. Dramatically improves the T2DM part of the treatment algorithm for uncontrolled T2DM with a BMI of ≥35
• Approximate weight loss in % total body weight: 30 to 35, excess weight loss %: 59.7
• Adverse effects: Marginal ulcers, internal hernia, small bowel obstruction, vitamin and mineral deficiencies [1][6][7][9]

2. Sleeve gastrectomy (SG)

• Description: The stomach is converted to a tubular structure, "gastric sleeve," with most of the greater curvature resected to decrease its food-holding capacity. This procedure can also be done laparoscopically.
• ASBMS endorsed: Y, FDA approved: NA, ASBMS investigational: NA, IRB approval required: N, Covered by insurance: Y
• Patient population: BMI ≥40 or ≥35 with 1 ORC
• Advantage/Mechanism of weight loss: Food restriction, early satiety, decreased ghrelin, increases PYY and GLP-1. There is a lower risk of vitamin deficiency, and it can be converted to RNYGB at a later stage if needed. It is the most commonly performed bariatric surgery, according to the latest statistics.
• Approximate weight loss in % total body weight: 25 to 30, excess weight loss %: 55.5
• Adverse effects: Chronic obstructive symptoms, post-operative gastroesophageal reflux [1][6][7]

3. Laparoscopic adjustable gastric banding (LAGB)

• Description: An adjustable silicone band around the upper stomach is connected to a port in the subcutaneous tissue, which can be used to restrict the food-holding capacity of the stomach.
• ASBMS endorsed: Y, FDA approved: NA, ASBMS investigational: NA, IRB approval required: N, Covered by insurance: Y
• Patient population: BMI ≥40 or ≥35 with 1 ORC
• Advantage/Mechanism of weight loss: Food restriction, early satiety, the least invasive bariatric procedure, reversible, and an outpatient procedure
• Approximate weight loss in % total body weight: 20 to 25, excess weight loss %: 46.2
• Adverse effects: Band slippage, erosion, bowel obstruction, dilatation of the esophagus [1][6][7]

4. Biliopancreatic diversion with duodenal switch (BPD/DS)

• Description: This procedure involves a sleeve gastrectomy with pylorus attached to an alimentary limb. It also involves a biliopancreatic limb with distal anastomosis of the two limbs and a short common channel running just 50 to 100cm till the ileocaecal valve.
• ASBMS endorsed: Y, FDA approved: NA, ASBMS investigational: NA, IRB approval required: N, covered by insurance: Y
• Patient population: BMI ≥40 or ≥35 with 1 ORC
• Advantage/Mechanism of weight loss: Creates a degree of malabsorption of nutrients, decreases ghrelin.
• Approximate weight loss in % total body weight: 35 to 45, excess weight loss %: 63.6 
• Adverse effects: Protein malnutrition, anemia, diarrhea, stomach ulceration, duodenal dissection, the potential for internal hernias [1][6][7]

5. Single Anastomosis Duodeno-ileal bypass with Sleeve gastrectomy

• Description: A single end-to-side anastomosis between the gastric sleeve pouch with preserved pylorus and the distal ileum, with the division at the level of the duodenum.
• ASBMS endorsed: Y, FDA approved: NA, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Patient population: BMI ≥40 or ≥35 with 1 ORC
• Advantage/Mechanism of weight loss: Simpler than BPD/DS, strong metabolic effects
• Approximate weight loss in % total body weight: 35 to 45
• Adverse effects: Micronutrient deficiencies, duodenal dissection [6] 

6. Primary obesity surgery endoluminal (POSE procedure)

• Description: This endoscopic incisionless procedure creates full-thickness plications in the gastric fundus and body using anchors that effectively reduce gastric capacity.
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Advantage: Fewer adverse events compared to other bariatric procedures
• Approximate weight loss in % total body weight: 5
• Adverse effects: Abdominal pain, nausea, vomiting [6][16]

7. Endoscopic sleeve gastroplasty

• Description: This endoscopic total gastric thickness suturing system creates a tubular stomach pouch similar to sleeve gastrectomy but without any incisions or laparoscopy.
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Advantage: Fewer adverse events compared to other bariatric procedures
• Approximate weight loss in % total body weight: 16 to 20
• Adverse effects: No randomized controlled trials documenting the efficacy [6]

8. Laparoscopic greater curvature plication

• Description: As the name suggests, the gastric sleeve is created by greater curvature plication to itself. 
• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Advantage: Reversible, no devices or staplers involved
• Approximate weight loss in % total body weight: 15 to 25
• Disadvantages and adverse effects: Difficult to standardize the procedure, dilatation of the stomach [6][17]

9. One anastomosis gastric bypass

• Description: This procedure involves a single anastomosis between a tubular gastric pouch (involving the lesser curvature) and the ileum. The remnant stomach and pylorus continue into the duodenum; therefore, the alimentary limb and common channel are essentially the same.
• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Advantage: Considered a mini-gastric bypass procedure
• Approximate weight loss in % total body weight: 35 to 40
• Adverse effects: Potential for bile reflux [6][18]

10. Stomach intestinal pylorus sparing-one anastomosis duodenal switch

• Description: This procedure involves a single duodeno-ileostomy with duodenal dissection and transection.
• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, Covered by insurance: N 
• Patient population: Not specified; general criteria apply
• Advantage: Simpler than BPD/DS, strong metabolic effects
• Approximate weight loss in % total body weight: 35 to 45
• Adverse effects: Micronutrient deficiencies, duodenal dissection [6][19] 

Gastrointestinal Devices for the Treatment of Obesity

A) Intragastric balloons: 

Intragastric balloons can be used for patients with a BMI of 30 to 40 with 1 ORC. These are typically inserted endoscopically, and the balloon is inflated with 400 to 700cc of saline to reduce gastric capacity, promote satiety, and delay gastric emptying. Contraindications to their use include hiatal hernia, gastric mass, prior GI surgery, and esophageal motility disorder. Adverse effects include GI obstruction/perforation, abdominal pain, and bloating.

1. Orbera-1 balloon

• ASBMS endorsed: Y, FDA approved: Y-for 6 months use only, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Approximate weight loss in % total body weight: 10.2 [1][6][7][20]

2. Obalon-up to 3 balloons

• ASBMS endorsed: Y, FDA approved: Y-for 6 months use only, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Approximate weight loss in % total body weight: 6.6 [1][6][7][20]

3. ReShape-2 balloons

• ASBMS endorsed: Y, FDA approved: Y-for 6 months use only, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Approximate weight loss in % total body weight: 6.8 [1][6][7][21][20]

4. Spatz

• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, covered by insurance: N
• Excess weight loss %: 45 to 49 [6][22][23] 

 5. Ellipse

• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, covered by insurance: N
• Excess weight loss %: 32 [6][24]

B) Maestro Rechargeable system-Vagal blockade

• Description: Leads are attached to the anterior and posterior vagal trunks laparoscopically, which cause intermittent vagal blockade to induce a sense of satiety
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, Covered by insurance: N
• Patient population: BMI 35 to 45 with 1 ORC
• Approximate weight loss in % total body weight: 8 to 9
• Contraindications: Cirrhosis, portal hypertension, hiatal hernia, patients with other implanted devices like permanent pacemakers, and intracardiac defibrillators
• Adverse effects: Nausea, vomiting, reflux, pain at the regurgitation site [1][6][7]

C) Aspire Assist

• Description: Directly removes ingested food from the stomach via a port
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, Covered by insurance: N
• Patient population: BMI 35 to 55, having failed other treatment modalities 
• Approximate weight loss in % total body weight: 12 to 14
• Contraindications: Ulcers, bleeding, gastric masses, eating disorders, cirrhosis
• Adverse effects: Pain, electrolyte disorders, irritation, infection [1][6][7] 

D) Transpyloric Bulb Shuttle

• Description: This is a double-bulb system inserted endoscopically that slows gastric emptying across the pylorus to induce satiety
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, Covered by insurance: N
• Patient population: Not specified; general criteria apply
• Approximate weight loss in % total body weight: 14
• Adverse effects: Gastric ulcers [6] 

E) Gelesis100 (Hydrogel)

• Description: A superabsorbent hydrogel in a swallowed capsule that absorbs water to expand and fill up the stomach to induce satiety 
• ASBMS endorsed: N, FDA approved: Y, ASBMS investigational: NA, IRB approval required: N, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Approximate weight loss in % total body weight: 6
• Adverse effects: Minor GI side effects [6][25]

F) Endoscopic gastrointestinal bypass devices

• Description: This is a barrier device inserted endoscopically, which extends from the proximal duodenum to the jejunum, effectively simulating a duodenojejunal bypass and promoting rapid weight loss
• ASBMS endorsed: N, FDA approved: N, ASBMS investigational: Y, IRB approval required: Y, covered by insurance: N
• Patient population: Not specified; general criteria apply
• Approximate weight loss in % total body weight: 40
• Contraindications and adverse effects: High rate of early removal of the device[6][7]

Other investigational procedures include the following: Bariatric arterial embolization, endoscopic ablation of duodenal mucosa, transoral gastroplasty, articular circular endoscopic stapler, endoscopic sclerotherapy, transoral endoscopic restrictive implant system, mucosal resurfacing, and gastric botulinum toxin A injection. These procedures are not ASBMS-endorsed or FDA-approved and remain investigational procedures, requiring IRB approval and not covered by insurance.[6][7][26][27]

The role of combination therapy: Multiple studies have shown that combining two or more drugs or combining drug therapy with surgery/devices has an additive action on weight loss. Some combinations are designed to counteract counterregulatory mechanisms that hinder weight loss. However, some of them are not yet ASBMS or FDA approved.

Some combination therapies that have been studied include:

• Pramlintide+phentermine
• Amylin+bupropion-naltrexone
• GLP-1 agonists+glucagon
• GLP-1+PYY
• GLP-1+PYY+oxyntomodulin
• Exenatide+dapagliflozin
• Canagliflozin+phentermine
• Repeat intragastric balloon treatment
• RNYGB+endoscopic enhancement
• Intragastric balloon+liraglutide
• Endobarrier device+liraglutide
• GLP1+GIP+glucagon triple agonist
• Setmelanotide+liraglutide
• Cagrilintide+ semaglutide
• Pramlintide+metreleptin+calcitonin receptor agonist [8][11][28][29][30]

Clinical Significance

Obesity due to caloric excess can be driven by a "food addiction," similar to substance abuse, causing a persistent desire to overeat despite the consequences of excess food intake.[8] It is primarily for this reason that non-dieting approaches (such as cognitive behavioral therapy, pharmacotherapy, and bariatric surgery and devices) are essential to treat obesity. Many patients enroll and fail comprehensive diet and lifestyle programs primarily because weight loss maintenance requires participation for extended periods of time, which is costly and produces slow results.[1] 

Generally, weight loss is curvilinear and reaches a plateau in 3 to 6 months, after which lifestyle interventions need to be continued to further the weight loss, else weight gain is imminent due to compensatory mechanisms that take over.[7] Thus, consistent and sustained weight loss achieved through pharmacotherapy and bariatric surgery plays a vital role in patients' weight loss journeys and should be considered early in the treatment course.

Other Issues

New Drugs/Therapies Being Developed to Tackle Obesity

These are not yet FDA-approved drugs, but they target parts of the hedonistic and homeostatic pathways in the peripheral and central nervous systems to induce weight loss. They include tesofensine-a serotonin-noradrenaline-dopamine reuptake inhibitor, RNA inhibitor against RIP140, CDDO-imidazolide, antibodies against ghrelin, high dose systemic PYY antagonists, cetilistat-a gastric and pancreatic lipase inhibitor, beloranib-MetAP2 inhibitor, KD026-microsomal transfer protein inhibitor in the intestine, fecal microbiota transplant, bile acid receptors-TGR5, FXR, GSK1521498-selective mu-opioid receptor antagonist, PRX-07034-a 5-HT6 antagonist, SNAP-94847-MCH-1 antagonist, oxyntomodulin-a glucagon + GLP 1 agonist, ghrelin antagonist and vaccines, GIP receptor antagonist, monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH)-appetite suppression-degradation of endocannabinoids anandamide, 2-arachidonic acid glycerol, a long-acting amylin analog, an FGF21 analog, licogliflozin-SGLT1 inhibitor, PYY 3-36 analog, oxytocin receptor agonist and a Type 4 FGF receptor antagonist.[9][8][11][13][31][2]

Caution About Dietary Supplements and Unproven Treatments for Weight Loss

Some over-the-counter supplements advertised for weight loss are not FDA-approved and have not undergone rigorous testing and review to prove their efficacy or safety. These contain substances like green tea, caffeine, yohimbine, bitter orange, guar gum, glucomannan, pyruvate, chromium, and calcium. In addition, techniques like liposuction are typically sought for their aesthetic value but do not improve metabolic parameters or change insulin sensitivity and cannot reduce ectopic fat deposits, which influence cardiovascular outcomes.[7]

Enhancing Healthcare Team Outcomes

A motivated patient, along with an interprofessional team comprising physicians, bariatric surgeons, gastroenterologists, nurses, pharmacists, physical and exercise therapists, dietitians, and psychiatrists, is the key to achieving and maintaining sustainable weight loss. Non-dieting approaches to treating obesity with drug therapy, gastrointestinal devices, and bariatric surgery should be offered early to patients, along with lifestyle modification. With interprofessional care coordination and counseling, patients will have a greater chance of achieving therapeutic success. [Level 5]

Patients and providers must consider obesity a chronic disease that requires ongoing treatment. Primary care physicians must obtain a detailed history, physical examination, and run basic laboratory tests to rule out other treatable causes of obesity, such as hypothyroidism and Cushing's syndrome. Family and friends must also motivate patients through their weight loss journeys, as these can sometimes be long and arduous.

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Disclosure: Ekta Tirthani declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Quartuccio declares no relevant financial relationships with ineligible companies.