Understanding the pathophysiologic pathways that underlie obesity and options for treatment

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© 2021 Boehringer Ingelheim. Published by Informa UK Limited, trading as Taylor & Francis Group.

Figure 1. Hormonal and neural pathways regulating food intake [17]. AgRP: agouti-related peptide, α-MSH: α-melanocyte-stimulating hormone, GHsR: GH secretagogue receptor, INSR: insulin receptor, LEPR: leptin receptor, MC4R: melanocortin receptor type 4, NPY: neuropeptide Y, POMC: pro-opiomelanocortin, PYY: peptide YY, Y1R: Y1 receptor, Y2R: Y2 receptor.

From Apovian CM, Aronne LJ, Bessesen DH Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–362, licensed under Creative Commons CC-BY-NC-ND.

Table 1. Causes of obesity [17]

Primary causes	Examples
Genetic
Monogenic	MC4 receptor mutations Leptin deficiency POMC deficiency
Secondary causes	Examples
Hypothalamic	Brain injury Brain tumor Cranial irradiation Syndromes: Froehlich Prader-Willi Bardet-Biedl Cohen Alström
Endocrine	Hypothyroidism Cushing’s syndrome Growth hormone deficiency Pseudohypoparathyroidism
Psychological	Stressors Depression Eating disorder
Environmental/behavioral	Sedentary lifestyle Insomnia Endocrine disruptors Stress
	Emotional eating High-calorie diet Limited access to nutritious food
Drug-induced	See Table 2

MC: melanocortin, POMC: pro-opiomelanocortin.

Table 2. Medications for people with multiple comorbidities and how they affect body weight [39]

	Weight gain	Weight neutral	Weight loss
Antidiabetes	Insulin Thiazolidinediones Sulfonylureas Meglitinides	α-Glucosidase inhibitors Bromocriptine Colesevelam DPP-4 inhibitors	GLP-1 receptor agonists Metformin Amylin analogues (Pramlintide) SGLT2 inhibitors
Antihypertensive	α-Adrenergic blockers β-Adrenergic blockers (atenolol, metoprolol, nadolol, propranolol) (dyslipidemia, insulin resistance, ↓metabolic rate by up to 10%)	ACE inhibitors ARBs (provide renal protection) β-Adrenergic blockers (carvedilol, nebivolol) CCBs Thiazides (dyslipidemia, insulin resistance)
Antidepressant	TCAs (amitriptyline, doxepin, imipramine, nortriptyline) MAOIs Mirtazapine SSRI (paroxetine) Lithium	SSRIs (fluoxetine, sertraline)	Bupropion (↓appetite and food cravings)
Antiseizure	Gabapentin Pregabalin Valproic acid Vigabatrin	Amotrigine Levetiracetam Phenytoin Lamotrigine	Topiramate Zonisamide
Antipsychotic	Clozapine Olanzapine	Aripiprazole Ziprasidone
Contraceptive	Medroxyprogesterone	Copper IUD
Migraine therapy	β-adrenergic blocker (propranolol)	Botulinum toxin Calcium channel blockers	Topiramate
Hormone therapy	Corticosteroids

ACE: angiotensin-converting enzyme, ARB: angiotensin receptor blocker, CCB: calcium channel blocker, DPP-4: dipeptidyl peptidase-4, GLP-1: glucagon-like peptide-1, IUD: intrauterine device, MAOI: monoamine oxidase inhibitor, SGLT2: sodium glucose co-transporter 2, SSRI: selective serotonin receptor inhibitor, TCA: tricyclic antidepressant.

Table 3. Approved pharmacotherapies for obesity^*ठ[16]

Drug	Mechanism of action	Administration	Contraindication	Warnings	Common AEs
Phentermine (8 mg [short acting], 15 mg, 30 mg capsule, 37.5 mg tablet)	Sympathomimetic amine	15 mg or 37.5 mg orally once daily; 8 mg orally 2–3 times daily; can start with a quarter or half of a 37.5 mg tablet once daily and titrate upward to a maximum dosage of 37.5 mg	CVD, uncontrolled hypertension, agitated states, history of drug use, hyperthyroidism, glaucoma, or MAOI use within 14 days	Rare cases of primary pulmonary hypertension or serious regurgitant cardiac valvular disease	Increase in HR and/or BP, dizziness, dry mouth, constipation, insomnia and irritability
Orlistat (60 mg OTC, 120 mg)	Pancreatic and gastric lipase inhibitor	120 mg orally 3 times daily	Malabsorption syndrome or cholestasis	Malabsorption of fat-soluble vitamins A, D, E, and K	Flatulence, bloating, and diarrhea
Phentermine/topiramate ER^‖ (3.75/23 mg, 7.5/46 mg, 11.25/69 mg and 15/92 mg)	Combination of sympathomimetic amine, anorectic and ER antiepileptic drug	Start with 3.75/23 mg orally once daily for 14 days; increase to 7/46 mg once daily and monthly titration upward to achieve weight loss; discontinue if <3% weight loss on 11.25/69 mg or <5% weight loss on maximum dose of 15/92 mg after 12 weeks	Glaucoma, hyperthyroidism, or MAOI use within 14 days	Teratogenicity (risk of cleft palate and/or cleft lip), suicidal ideation, changes in memory or concentration, metabolic acidosis, hypokalemia (especially in patients on potassium-wasting diuretics), rise in creatinine levels, increase in HR, acute myopia, or acute angle-closure glaucoma	Peripheral neuropathy (usually transient), dyspepsia, insomnia, constipation, and dry mouth
Naltrexone SR (8 mg)/bupropion SR^‖ (90 mg)	Combination opioid antagonist and aminoketone antidepressant	Upward titration over 4 weeks to maximum of 2 tablets twice daily	Uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia, chronic opioid use, MAOI use within 14 days, abrupt discontinuation of alcohol or seizure medications	Suicidal ideation, decrease in seizure threshold, acute angle glaucoma, hepatotoxicity to naltrexone component and increase in HR and/or BP	Nausea, constipation, headache, vomiting, dizziness, dry mouth, and diarrhea
Liraglutide^‖ (3.0 mg)	GLP-1 receptor agonist	Start with 0.6 mg subcutaneously once daily for 7 days; titrate upward weekly to 1.2 mg, 1.8 mg, 2.4 mg, and then maximum dosage of 3.0 mg once daily	Family or personal history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2) syndrome	Thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, increase in HR, renal impairment and hypoglycemia (with concomitant use of insulin secretagogue or insulin)	Nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, abdominal pain, fatigue, dizziness, increase in lipase levels, and suicidal behavior or ideation
Semaglutide (2.4 mg)	GLP-1 receptor agonist	Start with 0.25 mg subcutaneously once weekly for 4 weeks; titrate upward in 4-week intervals until the maximum dose of 2.4 mg is reached	Personal or family history of medullary thyroid carcinoma or in patients with MEN2 syndrome	Thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, hypoglycemia (with concomitant use of insulin secretagogue or insulin), acute kidney injury, hypersensitivity, diabetic retinopathy complications	Nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with T2D, flatulence, gastroenteritis, and gastroesophageal reflux disease
Setmelanotide (2 mg) For patients with obesity due to POMC, PCSK1, or LEPR deficiency	Melanocortin 4 receptor agonist	Patients ≥12 years of age: start with 2 mg (0.2 mL) subcutaneously once daily for 2 weeks; monitor patients for GI AEs and titrate dose accordingly	None	Disturbance in sexual arousal, depression and suicidal ideation, skin pigmentation and darkening of preexisting nevi, not approved for use in neonates or infants (due to benzyl alcohol preservative)	Injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection

*Approved for BMI ≥30 kg/m² or ≥27 kg/m² with at least one comorbid condition such as diabetes mellitus, hypertension, hyperlipidemia or sleep apnea. ‡All contraindicated in pregnancy; medications should not be prescribed with known allergy or hypersensitivity to any drug components. §With co-use of antidiuretic medications, weight loss can cause hypoglycemia; serum glucose levels should be monitored before and during treatment. ^‖Effect on cardiovascular morbidity and mortality has not been established.

Pharmacotherapies for obesity management that are available in Europe, Asia, and/or Australia are sub-sets of those agents currently available in the United States.

5-HT_2c: 5-hydroxytryptamine receptor 2C, AE: adverse event, BMI: body mass index, BP: blood pressure, ER: extended release, GI: gastrointestinal, GLP-1, glucagon-like peptide-1: HR: heart rate, LEPR: leptin receptor, MAOI: monoamine oxidase inhibitor, MEN2: multiple endocrine neoplasia type 2, OTC: over the counter, PCSK1: proprotein convertase subtilisin/kexin type 1, POMC: pro-opiomelanocortin, SR: sustained release.

Figure 2. Anti-obesity medications and T2D risk management [62]. Data from XENDOS trial (orlistat) = 4-year duration; CONQUER trial (phentermine-topiramate), COR-1 trial (naltrexone/bupropion), and SCALE trial (liraglutide) = 56-week duration. ER: extended release, FPG: fasting plasma glucose, PP2: postprandial 2-hour plasma glucose, SBP: systolic blood pressure, SR: sustained release, T2D: type 2 diabetes, TC: total cholesterol, TG: triglyceride.

From Oh TJ. The role of anti-obesity medication in prevention of diabetes and Its complications. J Obes Metab Syndr. 2019;28:158–166, licensed under CC BY-NC 4.0.

Table 4. Surgical options [63–67] (Arterburn AIM 2018; Topart 2017; Marinari 2006; Cottam 2020)

Bariatric procedure	Advantages	Disadvantages	Total body weight loss at year 1 [64]	Total body weight loss at year 5 [64]
Vertical sleeve gastrectomy (VSG)	Improves metabolic disease Maintains small intestinal anatomy Micronutrient deficiencies infrequent Most common bariatric surgical procedure Can be part of a staged approach	Gastroesophageal reflux disease Limited long-term data	25%	19%
Roux-en-Y gastric bypass (RYGB)	Greater improvement in metabolic disease Large dataset available	Increased risk of malabsorptive complications over VSG Technically more challenging than LAGB or VSG	31%	26%
Laparoscopic adjustable gastric banding (LAGB)	Least invasive Removable	5-year removal rate (international) 25% to 40% Any metabolic benefits are dependent on weight loss	14%	12%
Biliopancreatic diversion with duodenal switch (BPD-DS)	Greatest amount of weight loss, and resolution of metabolic disease	Greater risk of macro- and micronutrient deficiencies versus RYGB Technically challenging	41% [65]	37% [66]
Loop duodenal switch	May be simpler and safer than BPD-DS, with fewer micronutrient deficiencies	Long-term data not available Two-step procedure	37% [67]	(Limited data available)

Figure 3. Diet versus RYGB surgery [68]. GLP-1: glucagon-like peptide-1, PYY: peptide YY, RYGB: Roux-en-Y gastric bypass.

From Pucci A, Batterham RL. Mechanisms underlying the weight loss effects of RYGB and SG: similar, yet different. J Endocrinol Invest. 2019;42:117–128, licensed under Creative Commons CC BY.

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