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.
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.
