Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022

Abstract

Background: This "Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022" is intended to provide clinicians an overview of Food and Drug Administration (FDA) approved anti-obesity medications and investigational anti-obesity agents in development.

Methods: The scientific information for this Clinical Practice Statement (CPS) is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership.

Results: This CPS describes pharmacokinetic principles applicable to those with obesity, and discusses the efficacy and safety of anti-obesity medications [e.g., phentermine, semaglutide, liraglutide, phentermine/topiramate, naltrexone/bupropion, and orlistat, as well as non-systemic superabsorbent oral hydrogel particles (which is technically classified as a medical device)]. Other medications discussed include setmelanotide, metreleptin, and lisdexamfetamine dimesylate. Data regarding the use of combination anti-obesity pharmacotherapy, as well as use of anti-obesity pharmacotherapy after bariatric surgery are limited; however, published data support such approaches. Finally, this CPS discusses investigational anti-obesity medications, with an emphasis on the mechanisms of action and summary of available clinical trial data regarding tirzepatide.

Conclusion: This "Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022" is one of a series of OMA CPSs designed to assist clinicians in the care of patients with pre-obesity/obesity.

Keywords: Anti-obesity medications; Investigational agents; Obesity; Semaglutide; Tirzepatide.

Fig. 1

Drug Metabolism and Transport. Orally administered drugs may initially undergo metabolism in the intestine via gastrointestinal/bacterial enzymes and potentially Phase 1 metabolism in enterocytes, followed by transportation into portal vessels and liver. Afterwards, drugs may undergo Phase 1 and/or Phase 2 enzymatic alterations to form metabolites that may be excreted into the bile. If converted into polar conjugates, metabolites may be released into the circulation, and then excreted by the kidney [19]. Phase 1 drug metabolism: Oxidation, reduction, and/or hydrolysis via cytochrome P450 enzymes. Phase 2 drug metabolism: Conjugation via glucuronidation, acetylation, glutathione conjugation, sulfate conjugation, methylation. Phase 3 drug metabolism: Distribution and elimination of drugs mediated by transporters. Cytochrome P450 (CYP450) proteins generally reside within cellular membranes (i.e., endoplasmic reticulum or mitochondrial membrane) and function to metabolize drugs via Phase 1 drug metabolism. The most common CYP450 isoenzyme for drug metabolism is CYP450 3A4. Organic Anion-Transporting Polypeptides (OATP), Multidrug-Resistant-Associated Protein (MRP), P-glycoproteins (P-gp), and Breast Cancer Resistance Protein (BCRP) facilitate drug movement in and out of intestinal and hepatic cells.

Fig. 2

Illustrative Targets of Anti-Obesity Therapy. Factors that act on the central nervous system responsible for hunger, anabolism, and catabolism often represent targets of anti-obesity drug development [21]. Abbreviations: AgRP: Agouti-related peptide; BDNF: Brain-derived neurotrophic factor; CART: Cocaine and amphetamine regulated transcript; CB1R: Cannabinoid receptor type 1; CCK: Cholecystokinin; CNS: Central Nervous System; CRH: Corticotropin-releasing hormone; GLP-1: Glucagon like peptide – 1; MCH: Melanin concentrating hormone; MCR: Melanocortin receptor; MSH: Melanin Stimulating Hormone; NPY: Neuropeptide Y; POMC: Pro-opiomelanocortin; PYY: Peptide YY; TRH: Thyrotropin-releasing hormone.

Fig. 3a

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonism. GLP-1 is an incretin. Analogues of glucagon-like peptide 1 serve as receptor agonists (GLP-1 RA) that are used to treat obesity, either alone or as a component of combination therapy. Some, but not all, GLP-1 RAs have clinical trial evidence supporting favorable effects on cardiovascular disease (CVD) outcomes [122,[140], [141], [142], [143], [144], [145], [146], [147]]. Abbreviations: DPP IV: Dipeptidyl Peptidase IV. • GLP-1 receptor agnoists may improve nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Fig. 3b

Glucose-dependent insulinotropic polypeptide (GIP; previously known as gastric inhibitory peptide). GIP is an incretin. Its incretin effect is impaired in patients with type 2 diabetes mellitus. Combination glucagon-like peptide-1 receptor agonist (GLP-1 RA) and GIP RA are in development, and are illustrated by tirzepatide (Table 7 and Chart 3). [[148], [149], [150], [151], [152], [153], [154], [155]]. DPP IV: Dipeptidyl Peptidase IV. ∗ Unless combined with GLP-1, it is unclear that GIP receptor agonism alone reduces hunger and reduces body fat. However, GIP may enhance some of the effects of GLP-1 receptor agonism. The anti-nausea effects of GIP agonism may reduce the nausea adverse experiences described with GLP-1 receptor agonists [156,147]. ∗∗ In patients without diabetes, GIP increases insulin secretion and enhances deposition of fat in adipose tissues. In patients with diabetes mellitus, GIP may lose its insulinotropic effect, but retain a stimulatory effect on glucagon secretion – potentially worsening glucose levels [157]. However, as before, GIP receptor agonists may enhance some of the favorable effects of GLP-1 receptor agonists when administered concomitantly.

Fig. 4

Development of anti-obesity medications is following the path of drug development of other metabolic diseases. Like the history of other metabolic diseases, a bias exists among many clinicians that limits pharmacotherapy to treat obesity [[201], [202], [203], [204]].

Fig. 5

Treatment of the Disease of Diabetes Mellitus. Pharmacotherapy for diabetes mellitus began with several drugs that were poorly tolerated or that had adverse side effects. Today, more effective and better tolerated drugs are available [[205], [206], [207]]. NPH: Neutral Protamine Hagedorn. DPP-4: Dipeptidyl-peptidase 4. SGLT2: Sodium-glucose cotransporter-2. GLP-1: Glucagon-like peptide-1.

Fig. 6

Treatment of the Disease of Hypertension. Similar to the path of pharmacotherapy for diabetes mellitus, early hypertension drugs were poorly tolerated or had adverse side effects; today, more effective and well-tolerated drugs are available [208].

Fig. 7

Treatment of the Disease of Hypercholesterolemia. In line with the development of pharmacotherapy for other metabolic diseases, the first hypercholesterolemia drugs were poorly tolerated or had adverse side effects; today, more effective and well-tolerated drugs are available [[209], [210], [211]].

Fig. 8

Treatment of the Disease of Obesity. The development of anti-obesity medication is following the path of drug development of other metabolic diseases. Early anti-obesity drugs had limited weight reduction, were unsafe, poorly tolerated, and did not have proven health or mortality benefits. Current and future anti-obesity medications have the potential to be relatively safe, well tolerated, efficacious, and will (hopefully) prove to have health outcomes and improved mortality benefits [37,108,212].

Fig. 9

Early versus late weight management intervention: Illustrative consequences. Illustrative potential comparative outcomes for early versus delayed intervention in the evaluation and management of pre-obesity or obesity [84,[213], [214], [215], [216], [217], [218], [219], [220], [221]]. One of the objectives of early pharmacologic intervention for pre-obesity/obesity, is to prevent onset and complications of adiposopathic and fat mass consequences such as diabetes mellitus, hypertension, dyslipidemia, sleep apnea, arthritis, and depression (as well as other adverse health consequences of obesity such as cardiovascular disease and cancer). Lack of early intervention may lead to one or more of these complications, resulting in polypharmacy and need to follow multiple disease-oriented guidelines.

Chart 1

Above outlines the estimated degree of mean weight reduction associated with clinically meaningful improvement in illustrative health outcomes [2].