Anti-Obesity Medications and Investigational Agents

[madman]

Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022
Harold E. Bays, Angela Fitch, Sandra Christensen, Karli Burridge, Justin Tondt


ABSTRACT

Background: This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is intended to provide clinicians with 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 the 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 a 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.

1. Introduction

Beginning in 2013, the Obesity Medicine Association (OMA) created and maintained an online Adult “Obesity Algorithm” (i.e., educational slides and eBook) that underwent yearly updates by OMA authors and was reviewed and approved annually by the OMA Board of Trustees [1]. This was followed by a similar Pediatric “Obesity Algorithm” with updates approximately every two years by OMA authors. This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is one of a series of OMA Clinical Practice Statements (CPS) derived from the Obesity Algorithm designed to assist clinicians in the care of patients with the disease of obesity, with anticipation that forthcoming newer anti-obesity agents will provide additional safe and effective treatments for obesity. Finally, anti-obesity drug development is mirroring the path of past treatment of other metabolic diseases (e.g., diabetes mellitus, hypertension, and dyslipidemia), wherein proven cardiovascular disease outcome benefits will likely be the binary switch that will transform the current limited use of anti-obesity medications into standards of care for patients with obesity.




2. Overview and objectives of anti-obesity medication treatment

In addition to appropriate nutrition, physical activity, and healthful behavior, anti-obesity medication treatment is one of the four nonsurgical OMA pillars of obesity management. Weight reduction of as little as 5–10% (or in some cases, as little as 3%) can improve both adiposopathy (“sick fat disease”) and fat mass disease [2–5]. The purpose of anti-obesity medication treatment is to (a) serve as an adjunct to appropriate nutrition, physical activity, and healthful behavior to facilitate a more healthy body weight, (b) treat sick fat disease (adiposopathy) and its adverse cardiometabolic consequences, (c) treat fat mass diseases, (d) slow the progression of weight regain, (e) serve as an adjunct to bariatric surgery in enhancing weight reduction, and (f) generally improve the health and quality of life of patients with pre-obesity or obesity [5,6]. Table 1 describes ten takeaway messages regarding anti-obesity medications.




3. Pharmacokinetics and obesity

3.1. Drug absorption

3.2. Drug metabolism (Fig. 1)

3.3. Drug distribution

3.4. Drug excretion


4. Food and Drug Administration principles


5. Anti-obesity medications

5.1. Anti-obesity medication summary See Table 2.

5.2. Sympathomimetic amines

5.3. Phentermine
5.3.1. Indications and use [16]
5.3.2. Potential Drug Interactions [16]
5.3.3. Pharmacokinetics [16]
5.3.4. Most common adverse reactions [16]
5.3.5. Contraindications [16]
5.3.6. Warnings and precautions [16]

5.4. Semaglutide
5.4.1. Indications and use [42]
5.4.2. Potential Drug Interactions [42]
5.4.3. Pharmacokinetics [42]
5.4.4. Most common adverse reactions [42]
5.4.5. Contraindications [42]
5.4.6. Warnings and precautions [42]
5.4.7. Additional information

5.4.8. Semaglutide STEP clinical trials (Semaglutide Treatment Effects in People with obesity)
5.4.8.1. Semaglutide Cardiovascular Outcomes Trial in Patients with type 2 diabetes (SOUL trial).
5.4.8.2. Semaglutide Effects on Heart Disease and Stroke in Patients with overweight or obesity (SELECT) [83]

5.5. Liraglutide
5.5.1. Indications, use, and dosing [14,15,44,84–86]
5.5.2. Potential Drug Interactions [14,15,44,84,85]
5.5.3. Pharmacokinetics [14,15,44,84,85]
5.5.4. Most common adverse reactions [14,15,44,84,85]
5.5.5. Contraindications [14,15,44,84,85]
5.5.6. Warnings [44,85]
5.5.7. Other potential benefits

5.6. Phentermine HCl/topiramate extended release
5.6.1. Indications and use [12,13,44,45,84,85]
5.6.2. Potential Drug Interactions [12,13,44,45,84,85]
5.6.3. Pharmacokinetics [45,84]
5.6.4. Most common adverse reactions [12,13,44,45,84]
5.6.5. Laboratory abnormalities may include [12,13,45,85]
5.6.6. Contraindications [45]
5.6.7. Warnings and precautions [12,13,44,45,84,85]
5.6.8. Glaucoma

5.7. Naltrexone HCl/bupropion HCl extended release
5.7.1. Indications and use [17,44,84,85]
5.7.2. Potential Drug Interactions
5.7.3. Pharmacokinetics [17,44,84,85]
5.7.4. Most common adverse reactions [17,44,84,85]
5.7.5. Contraindications [17]
5.7.6. Warnings [17,44,84,85]

5.8. Orlistat
5.8.1. Indications and use [18,98]
5.8.2. Potential Drug Interactions [18,44,60,85,98]
5.8.3. Pharmacokinetics [18,98]
5.8.4. Most common adverse reactions [18,98]
5.8.5. Contraindications [18]
5.8.6. Warnings and precautions [18,44,48,60,85]

5.9. Non-systemic superabsorbent oral hydrogel
5.9.1. Description and mechanism of action [99]
5.9.2. Indications and use [99]
5.9.3. Potential Drug Interactions [99]
5.9.4. Pharmacokinetics [99]
5.9.5. Most Common Adverse Reactions [99]
5.9.6. Contra-indications [99]
5.9.7. Warnings [99]
5.9.8. Precautions [99]

5.10. Setmelanotide
5.10.1. Indications and use [100]
5.10.2. Dosing [100]
5.10.3. Warnings and precautions [100]
5.10.4. Adverse reactions [100]
5.10.5. Drug interactions [100]
5.10.6. Pharmacokinetics [100]

5.11. Metreleptin subcutaneous injection
5.11.1. Indications and use [101]
5.11.2. Potential Drug Interactions [101]
5.11.3. Pharmacokinetics [101]
5.11.4. Most common adverse reactions [101]
5.11.5. Contra-indications [101]
5.11.6. Warnings and precautions [101]

5.12. Lisdexamfetamine dimesylate
5.12.1. Potential Drug Interactions [102]
5.12.2. Pharmacokinetics [102]
5.12.3. Most common adverse reactions [102]
5.12.4. Contraindications [102]
5.12.5. Warnings [102]

5.13. Comparative efficacy of anti-obesity medications (see Charts 1 and 2)


6. Combination anti-obesity medications

6.1. Obesity and glucose transporters


7. Anti-obesity medication treatment and bariatric surgery


8. Investigational anti-obesity medications
Table 3 shows takeaway messages regarding anti-obesity drug development.

8.1. Priorities of anti-obesity drug development: fundamentals

8.2. Priorities of anti-obesity drug development: objectives

8.3. Anti-obesity drug development: treatment targets

8.4. Hypothalamic obesity
8.4.1. First-order arcuate nucleus neurons
8.4.2. Second-order arcuate nucleus neurons
8.4.3. Causes of hypothalamic obesity
8.4.4. Hypothalamic obesity pharmacotherapy


9. Anti-obesity drugs in development

Tables 6–8 show anti-obesity drugs in development, including therapies, mechanisms, and notes about each investigational agent. Fig. 3a shows the mechanistic effects of glucagon-like peptide-1 (GLP-1) receptor agonism. Fig. 3b shows the mechanistic effects of glucose-dependent insulinotropic polypeptide (GIP) agonism. Figs. 4–8 shows the paths of development of pharmacotherapy for several metabolic diseases, including diabetes mellitus, hypertension, hypercholesterolemia, and obesity. Fig. 9 shows illustrative consequences of early versus late weight management interventions (see Chart 1).

9.1. Tirzepatide

Table 5 lists many of the more clinically relevant gastrointestinal hormones. Fig. 3a shows the mechanistic effects of glucagon-like peptide-1 (GLP-1) receptor agonism. Fig. 3b shows the mechanistic effects of glucose-dependent insulinotropic polypeptide (GIP) agonism. Tirzepatide is a once-weekly injectable GLP-1 and GIP receptor agonist. Both GIP and GLP-1 are incretins, which are gut peptides that enhance increased insulin secretion after oral nutrient intake [191]. Tirzepatide is approved for the treatment of type 2 diabetes mellitus. It is currently undergoing development as a potential anti-obesity medication for chronic weight loss maintenance (see Chart 3).




10. Conclusions

This OMA Clinical Practice Statement on anti-obesity medications and investigational agents provides an overview of non-surgical pharmacotherapy interventions in the treatment of obesity. This “AntiObesity Medications and Investigational Agents: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022” is one of a series of OMA CPSs designed to assist clinicians in the care of patients with the disease of pre-obesity/obesity.

 

[madman]

Table 1 Anti-Obesity Medications. Shown are 10 takeaway messages regarding antiobesity medications, including their mechanisms of action, approvals, illustrative side effects, and sentinel contraindications [7]. All anti-obesity medications are contraindicated in patients with hypersensitivity to the drug (e.g., anaphylaxis, angioedema), and should not be used in patients with overweight/pre-obesity or obesity who are pregnant or planning to become pregnant.

 

[madman]

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 the liver. Afterward, 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.

 

[madman]

Table 2 Summary of Anti-Obesity Medications. All anti-obesity medications are contraindicated in patients with hypersensitivity to the drug (e.g., anaphylaxis, angioedema), should not be used in patients planning to become pregnant or who are pregnant, and all may require downward dose adjustment of concomitant anti-diabetes-medication-to-avoid hypoglycemia, especially in patients treated with insulin and sulfonylureas.

 

[madman]

Chart 1. Above outlines the estimated degree of mean weight reduction associated with clinically meaningful improvement in illustrative health outcomes [2].

 

[madman]

Table 3 Ten Takeaway Messages Regarding Anti-Obesity Drug Development. Shown are takeaway messages regarding current and future anti-obesity drug development.

 

[Nelson Vergel]

Great find, @madman !

 

[madman]

Table 4 Historic Adverse Consequences of Past Drug Treatments for Obesity. Since the 1800s, multiple therapies used to treat obesity have encountered unacceptable adverse side effects. The table lists historic discontinued anti-obesity therapeutics and their adverse health consequences [7,123–125]. None of these are currently indicated to treat obesity.

 

[madman]

Table 5 Illustrative Gastrointestinal Hormones. Anti-obesity drug development often involves analog adaptations of hormones and other factors applicable to gastrointestinal responses to food intake [128–138].

 

[madman]

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.

 

[madman]

Table 6 Anti-Obesity Drugs in Development. GLP-1 receptor agonists form the foundation of several anti-obesity drugs in development.

 

[madman]

Table 7 Glucagon Like Peptide – 1 Receptor Agonism Combinations. Many anti-obesity drugs in development combine a GLP-1 RA with other investigational drug/s, resulting in dual or triple mechanisms of action [170].

 

[madman]

Table 8 Other Anti-Obesity Drug Monotherapies in Development. This table lists illustrative anti-obesity drugs in development, mechanisms of action, and applicable notes.

 

[madman]

Fig. 3a. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonism. GLP-1 is an incretin. Analogs of glucagonlike 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 [122,140–147]. Abbreviations: DPP IV: Dipeptidyl Peptidase IV.

*GLP-1 receptor agonists may improve nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

 

[madman]

Fig. 3b. Glucose-dependent insulinotropic polypeptide (GIP; previously known as a 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). [148–155]. 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 nausea and adverse experiences described with GLP-1 receptor agonists [156, 147]. ** In patients without diabetes, GIP increases insulin secretion and enhances the 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.

 

[madman]

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 [201–204].

 

[madman]

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 [205–207]. NPH: Neutral Protamine Hagedorn. DPP-4: Dipeptidyl-peptidase 4. SGLT2: Sodium-glucose cotransporter-2. GLP-1: Glucagon-like peptide-1.

 

[madman]

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].

 

[madman]

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 [209–211].

 

[madman]

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].