What You Need to Know About Anti-Obesity Medications

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Unfortunately, obesity continues to be the leading and pervasive health challenge worldwide. In the United States, the prevalence of obesity, defined as having a body mass index (BMI) of ≥30kg/m², is trending upward, reaching nearly 42% in 2020.¹ Globally, the statistics are just as dismal. The prevalence of obesity is estimated to rise from 14% to 24% of the population, affecting nearly 2 billion adults, children, and adolescents by 2035.² In 2013, the American Medical Association (AMA) declared obesity a chronic and degenerative disease and echoed what was already acknowledged back in 1998 and 2008, respectively, by the National Institutes of Health and the American Obesity Society.

One hope of declaring obesity as a disease was to eliminate the unfair stigma and bias experienced by the patients and to affect policy, research, and access to obesity treatment, including anti-obesity medications (AOMs). The purpose of AOMs is not to replace following a healthy lifestyle; rather they can be taken in conjunction with following a healthy and calorie-controlled diet and engaging in physical activity to help patients achieve their weight loss goals. AOMs can also serve as an adjunct to metabolic and bariatric surgery (MBS).³ AOMs are shown to treat adipose-related diseases and slow the progression of weight regain.³

A Closer Look at the History of AOMs

AOMs are not a new concept in the United States but unfortunately, some have a grim safety record. As early as the 1950s and ‘60s, amphetamine derivatives such as desoxyephedrine, phentermine, and diethylpropion were gaining popularity as weight loss medications.⁴ However, due to links to cardiovascular issues, these were replaced by serotonin (5-HT) releasing agents in the 1970s and ‘80s and the weight loss medication called fenfluramine and dexfenfluramine gained momentum.⁴ In the 1990s, fenfluramine was often combined with phentermine to increase the efficacy as a weight loss medication. Although fenfluramine was known to increase the risk of pulmonary hypertension, the combination of the two increased the risk for cardiac valvulopathy and finally lead to the market discontinuance of fenfluramine and dexfenfluramine. In Europe, sibutramine, orlistat, and rimonabant were approved for the long-term clinical management of obesity. However, both sibutramine and rimonabant were discontinued in Europe secondary to serious cardiovascular and psychiatric side effects, respectively. Rimonabant was never approved for used in the United States.⁴ In a 1959, the Food and Drug Administration (FDA) approved phentermine for short term use.⁴

Currently, there are six FDA-approved AOMs in the United States:⁵

• Orlistat, approved in 1999
• Phentermine-topiramate combination, approved in 2012
• Bupropion-naltrexone combination, approved in 2014
• Liraglutide, 3.0 mg, approved in 2014
• Setmelanotide, approved in 2020 for rare genetic diseases of obesity
• Semaglutide, 2.4 mg approved in 2021

Tirzepatide was FDA approved in 2022 for the treatment of type 2 diabetes mellitus, but is also used off-label for obesity treatment.6 Sibutramine and lorcaserin were recalled by the FDA in 2010 and 2020, respectively.⁵ Sibutramine showed elevated risk of nonfatal myocardial infarction and lorcaserin showed increased cancer risk.⁵

The Mechanism of Action of AOMs

How do AOMs help patients lose weight? The mechanism of action (MOA) of AOMs are specific and target areas of the body such as the central nervous system, specific organs of the gastrointestinal system, and adipose tissue responsible for hunger, appetite, satiety, caloric and nutrient absorption, and fat dysfunction. For example, orlistat works by inhibiting the action of pancreatic lipase and therefore impairs the digestion of dietary fat leading to calorie reduction.⁵ The MOA of phentermine-topiramate combination is not fully understood. This medication is a sympathomimetic and carbonic anhydrase inhibitor and decreases appetite and food intake and also increases the sense of satiety and fullness.⁵ Alterations of the sense of taste has also been reported and leads to decreased intake.⁵ The MOA of bupropion-naltrexone is an opioid receptor antagonist/dopamine agonist and reuptake inhibitor.⁵ It causes increased satiety, suppressed appetite, and increases energy expenditure.⁵ Liraglutide and semaglutide are glucagon-like peptide-1 (GLP-1) agonist and works by slowing gastric emptying to increase satiety, decrease food intake and the sense of food reward.⁵ Setmelanotide is prescribed for those with mutations in the MC4R gene which is a component of the leptin-melanocortin pathway.⁵ A mutation in this gene results in severe childhood-onset obesity and hyperphagia. Setmelanotide works as an agonist of melanocortin 4 receptor (MC4R) and regulates energy balance and body weight.⁵

More recently, wide attention has focused on the GLP-1 agonists for weight loss and diabetes control. The medications, semaglutide (Wegovy, Ozempic) and liraglutide (Saxenda) fall into this category. How do they work? Glucagon-like peptide-1 (GLP-1) agonists are also known as GLP-1 receptor agonists, incretin mimetics, or GLP-1 analogs.7 GLP-1 is an incretin hormone that stimulates insulin secretion after food intake. For the treatment of type 2 diabetes, GLP-1 agonist not only stimulates insulin, but also delays gastric emptying and inhibits the production of glucagon from the pancreas in response to high blood sugar. GLP-1 agonists are shown to improve cardiovascular health by improving the ejection fraction of the left ventricle, contractility of the heart muscle, and improve coronary blood flow, cardiac output, and endothelial function.⁷ 

The relevance of GLP-1 for weight loss is its role in how it regulates appetite and hunger. GLP-1 stimulates the sense of fullness and satiety by decreasing gastric emptying, which ultimately leads to lowered food and caloric intake. GLP-1 also modulates appetite by influencing the brain-gut relationship. For example, although GLP-1 is primarily secreted by the enteroendocrine cells, GLP-1 receptors are also present in the central nervous system, and therefore, promotes satiety, affects mechanistic properties of the GI tract and results in negative energy balance.⁸ In addition, it has been reported that GLP-1 agonists decrease cravings by altering the sense of taste and hedonic desire for certain foods.⁸ Tirzepatide (Mounjaro), combines the role of both GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. Mounjaro is a diabetic medicine, and not approved for weight loss, however, the mechanism of action is similar to both Wegovy and Ozempic. GIP is an incretin hormone that works synergistically with GLP-1. The benefit of GIP is the anti-emetic property, and since nausea and vomiting are common side effects of the GLP-1 medications, the addition of GIP helps to mitigate these symptoms.⁹

Adverse Effects and Contraindications of AOMs

As with all medication, AOMs have potential side effects and contraindications. All anti-obesity medications are contraindicated in patients with allergies to the drug.³ They should not be used in women who are pregnant or planning pregnancy and should be used with caution in patients with diabetes and on anti-diabetes medications such as insulin and sulfonylureas to avoid hypoglycemia.³

Table 1 shows the potential side effects, interactions, and more detail about AOMs.

In Conclusion

It is well accepted that weight loss of approximately 5–10% can improve weight-related conditions such as type 2 diabetes mellitus, high blood pressure, high cholesterol, obstructive sleep apnea, and certain cancers. Anti-obesity medications (AOMs) are not a substitution for a healthy diet and active lifestyle. They serve as an adjunct treatment and may also be taken with metabolic and bariatric surgery to thwart significant weight regain after surgery. The overarching goal of using AOMs is to assist patients who suffer from the disease of obesity to gain a quality of life and improve their health. All AOMs have potential side effects and patients considering them should have a conversation with an obesity medicine specialist or a primary care physician who specializes in the treatment of obesity and related conditions. In terms of wound care, the AOMs should be a consideration especially if the patient has concomitant type 2 diabetes and obesity, as both these diseases can exacerbate wounds and hinder healing.

Unfortunately, AOMs, unless used to treat type 2 diabetes, are not typically covered by Medicare or private insurance for weight loss. AOMs can be very costly, some upwards of more than $1000 per month. Some Medicaid plans may offer broad coverage for certain AOMs for weight loss, but this is state-specific. Patients can try working with the manufacturers who offer discounts, although financially, these medications may still be out of reach for many. Providers and employees should align themselves with patient-advocacy and work with insurance companies and manufacturers to encourage coverage. Patients can be their own best advocate and talk to their health care and insurance providers for solutions and persist in the pursuit of their healthful goals.
 
Lillian Craggs Dino, DHA, RDN, LDN, is Associate Faculty in the College of Allopathic Medicine at Nova Southeastern University at Nova Southeastern University. She is an Adjunct Assistant Professor at Nova Southeastern University College of Osteopathic Medicine Nutrition Program and the College of Allopathic Medicine as well as an associate faculty member of the University of Phoenix College of Health Professions. She is on the Scientific Advisory Board of Bariatric Fusion and also serves on the Executive Council of the American Society for Metabolic and Bariatric Surgery Integrated Health (ASMBS-IH) as Member-at-Large.

References
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2.    World Obesity Federation. World Obesity Atlas 2023. Accessed July 17, 2023.
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5.    Min Oo W, Mobasheri A, Hunter DJ. A narrative review of anti-obesity medications for obese patients with osteoarthritis. Expert Opin Pharmacother. 2022;23:12. 1381-1395. doi: 10.1080/14656566.2022.2104636.
6.    Farzam K, Patel P. Tirzepatide. [Updated 2023 May 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. https://www.ncbi.nlm.nih.gov/books/NBK585056/. Accessed July 23, 2023.
7.    Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. [Updated 2023 Jan 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
8.    Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15(3):181–187. https://doi.org/10.1007/s11154-014-9289-5.
9.    Hayes MR, Borner T, De Jonghe BC. The role of GIP in the regulation of GLP-1 satiety and nausea. Diabetes. 2021; 70(9):1956–1961. https://doi.org/10.2337/dbi21-0004.