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©2025 American Medical Writers Association. All rights reserved.  
ISSN 2163-5315

AMWAJournal.org     35

ABSTRACT 
Over 800 million people worldwide meet the criteria for obe-
sity, highlighting the need for safe and effective treatments. 
Recent advances reshaped the paradigm of adipose as an 
organ that regulates hunger, satiety, insulin sensitivity, and 
inflammation. Clinical obesity is a chronic condition linked 
to excess visceral adipose in which the health risk has already 
manifested. This definition reflects our understanding of 
obesity, rather than relating it to body size, weight-based 
conditions, or elevated body mass index. Clinical guide-
lines recommend pharmacotherapy for children and adults 
meeting the criteria for obesity. Because few independent 
diverse trials compare obesity drugs, doctors must resort to 
trial-and-error to predict usefulness. And the lack of diversity 
may impact drug safety for at-risk populations. For example, 
Black and Hispanic adults are at the highest risk for obesity, 
but few participated in drug trials. The discovery of incretins 
led to incretin-based hormone drugs that bind glucagon-like 
peptide-1 or glucose-dependent insulinotropic polypeptide 
receptors. The media attention around these repurposed type 
2 diabetes drugs brings hope for obesity treatment in clinical 
practice. Manufacturers market incretin drugs as a panacea 
for neurological, metabolic, and cardiovascular conditions. 
Filling a unique therapeutic gap between lifestyle modifi-
cation and bariatric surgery, incretin drugs may help some 
people. Yet, with any medication, balancing benefits and risks 
optimizes health. Thus, 
long-term safety stud-
ies comparing incretin 
drugs in a diverse pop-
ulation are needed for 
the development of safe 
and effective treatments. 
Understanding the 
health benefits after bar-
iatric surgery, drug ther-
apy, and combination 
therapy may help guide 
future clinical practice.

A magical remedy to control human metabolism has evaded 
scientists for over 130 years. Since the nineteenth century, 
manufacturers have sold various weight-lowering tonics, 
banned from sale because of safety issues. As the philos-
opher Santayana said, “Those who cannot remember the 
past are condemned to repeat it.” And predictably, without 
understanding the underlying cause for adipose dysfunc-
tion or correcting past clinical trial design flaws, manufac-
turers continue to develop risky treatments for obesity—a 
controversial word defined by the Centers for Disease 
Control and Prevention (CDC) as a body mass index (BMI) 
of 30 or more. Since the US Food and Drug Administration 
(FDA) began regulating drugs in 1938, manufacturers have 
failed to produce safe and effective medicines to regulate 
metabolism.1 Amphetamines and sympathomimetic drugs 
led to abuse, cardiac damage, suicidality, cancer, and even 
death (Figure 1).2 With over 800 million people worldwide 
meeting criteria for obesity, the need for safe treatments led 
to the discovery of incretins.
 Incretin drugs include glucagon-like peptide-1 (GLP-1)  
receptor agonists (RAs) and dual-acting therapies that 
bind GLP-1 and glucose-dependent insulinotropic poly-
peptide (GIP) receptors. Recent media campaigns focus 
attention on these repurposed therapies, bringing hope for 
clinical obesity treatment. These incretin drugs improve 
glycemic control and lower total body weight up to 20%, 

Incretin Drug Revolution: The Challenges of Hope

Alicia Racelis, PhD  / Contract Health Editor at WebMD, Fayetteville, GA

SCIENCE SERIES

Figure 1. Timeline for FDA regulation of drugs treating clinical obesity.2 Bold italicized dates signify the year of 
removal. FDA, US Food and Drug Administration.

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AMWAJournal.org     36Incretin Drug Revolution: The Challenges of Hope

but questions remain.3 As medical writers, sorting fact from 
misinformation preserves data integrity and conveys related 
health risks. Although one must acknowledge the role that 
incretin therapies play in balancing human metabolism, 
conclusions must be drawn with caution. Contrary to news 
reports, this article points out some critical issues regard-
ing obesity clinical trials and raises concerns about the side 
effects and long-term safety of incretin drugs.

DEFINING DISEASE: CLINICAL TRIALS FOR OBESITY
The World Health Organization defines obesity as uncon-
trolled adipose accumulation that impairs health. About 
42% of US adults meet criteria for obesity, and the child 
and adolescent rate has almost quadrupled since 1990.4,5 
Despite a century of continued investigation, our under-
standing of obesity as a chronic disease is not shared across 
scientific, public health, or political fields. Without common 
symptoms or diagnostic biomarkers, identifying the under-
lying cause for adipose dysfunction remains difficult. The 
controversy about obesity influences social stigma, clinical 
practice, public health policy, and more. Evidence demon-
strating that individuals with elevated BMI can be metaboli-
cally healthy contributes to the confusion.6

 Defining clinical obesity as a higher visceral mass asso-
ciated with an existing metabolic dysfunction reflects our 
current understanding of the adipose organ.7,8 This defini-
tion links visceral adipose mass to metabolic health rather 
than body size, weight-based conditions, or elevated BMI. 
Intra-abdominal distribution of visceral adipose causes 
chronic low-grade inflammation, hypertrophy, and fibrosis 
with increased health risks (Figure 2).4

In 2023, the American Medical Association (AMA) recog-
nized that using BMI as the only defining characteristic for 
obesity can racially exclude and harm certain individuals.9 
Although imaging modalities more precisely calculate adi-
pose distribution, the low cost and ease of application keeps 
BMI in use. Variations in body shape, bone mass, genetics, 
and waist circumference can alter the risk estimate.8 For 
example, BMI fails to identify sarcopenic obesity, a loss of 
muscle mass in the presence of clinical obesity. To resolve 
this, the AMA recommends combining BMI with other indi-
ces.9 However, obesity clinical trials and population studies 
continue to use BMI.
 In the past 40 years, the obesity pandemic patterns have 
changed. Interestingly, recent urbanization has shifted the 
obesity prevalence to least-developed countries. The influx 
of unprocessed, high-calorie foods and other common driv-
ers may contribute to the rising rates.10 In children, devel-
opmental factors affecting weight can disrupt the balance of 
energy intake and expenditure. These broad environmental, 
preconception, and prenatal exposures are risk factors for 
obesity with consequences into adulthood.5 In adults, com-
plex interconnected risk factors influence weight:10

• Biological
• Social
• Food industry influences
• Physical safety
• Lived experiences

 Evidence shows a higher risk of developing obesity for 
youth living in lower social strata or exposed to inequalities.5 
Similarly, racial and ethnic disparities exist in the prevalence 

Figure 2. Health risks related to clinical obesity.4,5 Adult is defined as age ≥20 years, and youth is defined as age 2-19 years. 
GERD, gastroesophageal reflux disease; GI, gastrointestinal; PCOS, polycystic ovarian syndrome.

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AMWAJournal.org     37Incretin Drug Revolution: The Challenges of Hope

for obesity in the United States (Figure 3). The increased prev-
alence of obesity in Black and Hispanic adults underscores 
the need for diversity in obesity clinical trials.

Lack of Diversity in Clinical Trials for Obesity
Clinical trials for obesity should accurately reflect the 
characteristics of the disease population.13 But a recent 
meta-analysis revealed that obesity clinical trial participants 
comprised of 74% White adults, mainly women (Table 1).13 
In the United States, the CDC reports the highest risk for 
obesity in Black (50%) and Hispanic (45%) adults, but only 
18% Black and 19% Hispanic adults participated in the drug 
trials.13 This lack of diversity during obesity drug testing cre-
ates a gap in understanding the risks and benefits of obe-
sity therapies for diverse populations. Future studies aim to 
increase diversity by decentralizing clinical trial centers. But 
some of the difficulty surrounding diversity in testing is the 
need for clear guidance in clinical obesity care.

GUIDING CLINICAL CARE FOR OBESITY
Evidence suggests that lifestyle modification and physical 
activity remain cornerstones for optimizing health but only 
provide minimal reductions in weight. Using these data, all 
guidelines suggest pharmacotherapy for adults who are not 
pregnant and have a BMI ≥27 in the presence of a weight- 
related condition or a BMI of ≥30.14 Similarly, the American 
Academy of Pediatrics recommends pharmacotherapy for 
children 8 years and older who meet criteria for obesity.11

 The latest clinical guidelines for individuals with obesity 
tether lifestyle modification to all pharmacotherapy treat-
ment, tailoring therapy to each individual.14 Thus, for treat-
ment optimization, clinicians need a wide range of effective 
and safe medications for obesity.15 Because a large body 
of evidence suggests that weight reductions between 10% 

and 15% improves cardiometabolic health, guidelines aim 
for reductions of ≥10%.4 Yet before 2021, most clinical trial 
participants reported obesity drug inefficacy rates ranging 
from 59% to 80% (Figure 5). As an alternative, bariatric sur-
gery became a standard obesity option as part of a flexible 
care approach. For some patients, bariatric surgery remains 
a viable long-term solution, improving glucose and lipid 
levels.4 However, postsurgical complications combined with 
facility and specialist requirements limit widespread use.
 The success of individualized obesity care plans 
depends on identifying individuals for treatment and 
applying the correct therapy at the right time. Health care 
providers remember the past and remain vigilant when pre-
scribing new obesity drugs. However, media attention drives 
the demand for incretin drugs, highlighting drug claims of 
lowered glycemic index, cardiovascular risk, and weight 
loss of 20% or more.16 Although incretin therapies may fill 
the therapeutic gap between lifestyle modification and sur-
gery, balancing health benefits with risks remains important 
when choosing drug treatment.

Approved Long-Term Pharmacotherapies for  
Clinical Obesity
In the United States, 6 long-term drugs treat clinical obesity, 
mainly targeting weight loss (Table 1). Like any treatment, 
balancing health benefits with risk helps optimize care.  
Yet without robust, independent clinical trials comparing 
treatments, doctors typically use trial-and-error when  
prescribing obesity drugs. Another common practice is 
off-label use of low-cost therapies. For example, phenter-
mine and topiramate are 2 of the most used drugs in pedi-
atrics. Although phentermine is approved for short-term 
weight loss in children, topiramate is not. But phentermine 
with topiramate (Phen/Top) is approved for long-term 
weight loss in patients 12 years and older. Topiramate, an 
antiepileptic drug, can affect cognition, sleep, and memory; 
because of carbonic anhydrase inhibition, the compound 
also increases risk of taste alteration, metabolic acidosis, 
and nephrolithiasis. Topiramate has teratogenic effects and 
can cause fetal harm. As an alternative, the FDA approved 
naloxone with bupropion (Nal/Bu) for use in adults.  
Nal/Bu may elevate blood pressure and increase risk of  
hepatotoxicity or suicidal ideation.

Comparing Long-Term Therapies for Weight Loss
One review of 28 random controlled trials included orli-
stat, Phen/Top, Nal/Bu, and liraglutide. Interestingly, the 
study showed that clinical trial participants reported the 
most success using Phen/Top (75% efficacy) compared with 
orlistat (44%), Nal/Bu (55%), or liraglutide (63%).18 More 
recently, a systematic review and meta-analysis was  

Figure 3. US racial and ethnic differences in the prevalence of adults 
with BMI ≥30 and youth greater than the ninety-fifth percentile.11,12 
Adults are defined as age ≥20 years, and youth are defined as age 
2-19 years. BMI, body mass index.

 

9%

25%
26%

17%17%

50%

45%
42%

0%

10%

20%

30%

40%

50%

60%

ASIAN BLACK HISPANIC WHITE

Youth Adults

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AMWAJournal.org     38Incretin Drug Revolution: The Challenges of Hope

performed using 53 clinical trials for obesity drugs. The  
findings showed that tirzepatide effectively reduced waist 
circumference by 6.77 cm compared with semaglutide  
(3.74 cm) and liraglutide (2.30 cm).19 In a subanalysis,  
semaglutide was the only incretin drug to effectively reduce 
low-density lipoprotein and total cholesterol yet showed the 
highest discontinuation rate because of gastrointestinal (GI) 
events. In fact, safety concerns for the incretin drugs are 
warranted at higher doses. Except for orlistat, a local-acting 
lipase inhibitor, all obesity therapies act by increasing nor-
epinephrine to decrease appetite. Understanding neuroen-
docrine signals that regulate hunger helps elucidate related 
health risks for these drugs.

Pharmacotherapies: Balancing Appetite
Two opposing types of neurons in the hypothalamus balance 
energy intake to control appetite. The agouti-related peptide/
neuropeptide Y (AgRP/NPY) neurons constantly co-release 
γ-aminobutyric acid (GABA) and NPY peptides to lower sym-
pathetic activity, turning on appetite (Figure 4). Once food 
enters the stomach, the gut releases incretins and adipose 
releases leptin, slowing intestinal motility to prolong  
satiety.20 The opposing pro-opiomelanocortin/cocaine- 

amphetamine-related transcript (POMC/CART) neurons 
receive these gut signals to enhance sympathetic release of 
norepinephrine, turning off appetite. Many pharmacother-
apies for weight loss increase sympathetic activity and nor-
epinephrine to turn off appetite.
 GABA-modulating drugs like topiramate increase the 
brain’s sympathetic activity to lower appetite. But sympath-
omimetic drugs like phentermine stimulate sympathetic 
release of norepinephrine to lower appetite.16 Bupropion 
and naltrexone also stimulate sympathetic activity but 
directly activate POMC/CART neurons to diminish hunger. 
Interestingly, naltrexone acts as a long-acting opioid antag-
onist to change the brain’s response to food by altering 
the dopamine-reward system.16 Incretin drugs mimic the 
actions of GLP-1 and GIP that stimulate glucose-dependent 
increases in insulin, slow gastric emptying, and extend sati-
ety to lower appetite. Although GLP-1 RAs suppress pancre-
atic-glucose-dependent release of glucagon, GIP receptor 
agonists stimulate it.15 But the low permeability of incretin 
drugs likely prevent access through the blood-brain barrier. 
Supporting this, studies indicate that incretin drugs signal 
the hypothalamus via the dorsal vagal complex, which may 
explain the negative side effects like nausea and vomiting.15

Table 1. FDA-Approved Drugs for Clinical Obesity Treatment11,16,17

Drug Name Brand Name Usage, y Dosage Clinical Trial Demographics

Orlistat Alli (OTC); Xenical ≥12 Capsule: Alli, 60 mg; Xenical, 120 mg XENDOS 
55% women; mean age, 43 y; average BMI, 37;  
71% White adults

Phentermine with  
topiramate

Qsymia ≥12 Phentermine/topiramate:  
3.75 mg/23 mg; 7.5 mg/46 mg; 
11.25 mg/69 mg; 15 mg/92 mg

EQUIP 
83% women; mean age, 43 y; average BMI,42;  
80% White adults

CONQUER 
70% women; mean age, 51 y; average BMI, 36;  
85% White adults

Naltrexone with  
bupropion

Contrave (US);  
Mysimba (EU)

≥18 Naltrexone/bupropion: 8mg/90mg COR-I 
85% women; mean age, 44 y; average BMI 36;  
82% White adults

COR-II 
85% women; mean age, 44 y; average BMI, 36;  
83% White adults

Liraglutide Saxenda ≥12 18 mg dial-a-dose pen delivering 
customizable doses: 30 at 0.6 mg; 15 
at 1.2 mg; 10 at 1.8 mg; 7 at 2.4 mg; 
6 at 3 mg

SCALE 
78% women; mean age, 45 y; average BMI, 38;  
85% White adults

Semaglutide Wegovy ≥12 Single-use, color-coded pens: teal, 
0.25 mg; pink, 0.5 mg; brown, 1mg; 
blue, 1.7mg; black, 2.4 mg

STEP 1 
73% women; mean age, 46 y; average BMI, 38;  
75% White adults

Tirzepatide Zepbound ≥18 Single-use 0.5 mL pen or vial, comes 
in doses: 2.5 mg; 5 mg; 7.5 mg; 10 
mg; 12.5 mg; 15 mg

SURMOUNT-1 
67.5% women; mean age, 45 y; average BMI, 38;  
70% White adults

BMI, body mass index; COR-I, Contrave Obesity Research I; COR-II, Contrave Obesity Research II; EU, European Union; FDA, US Food and Drug Administration; OTC, over  
the counter; SCALE, Satiety and Clinical Adiposity Liraglutide Evidence; STEP 1, Semaglutide Treatment Effect in People with Obesity; XENDOS, Xenical in the Prevention of 
Diabetes in Obese Subjects.

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AMWAJournal.org     39Incretin Drug Revolution: The Challenges of Hope

The Incretin Drug Revolution
Incretin drugs are not new. Liraglutide debuted a 
decade ago, but the drug was not as effective com-
pared with the more recent incretin drugs. The dose 
required to treat obesity is almost twice that for glu-
cose management in type 2 diabetes. During the 
Satiety and Clinical Adiposity Liraglutide Evidence 
trials, liraglutide reduced total body weight by 6.1%.21 
Liraglutide did not receive much publicity with high 
discontinuation rates, GI side effects, and cancer risk. 
To improve safety and effectiveness, the manufacturer 
of liraglutide set out to find a compound with a longer 
half-life.
 Researchers discovered semaglutide, extending 
the half-life to 168 hours. During the Semaglutide 
Treatment Effect in People with Obesity trials, this 
compound improved cardiometabolic health and 
reduced weight by 12.6% (Figure 5).21 But similar to 

Figure 4. Pharmaceutical action to extend satiety for energy homeostasis.20 α-MSH, α-melanocortin stimulating hormone; AgRP/NPY, agouti-related 
peptide/neuropeptide Y; ARC, arcuate nucleus; BAT, brown adipose tissue; CCK, cholecystokinin; EE, energy expenditure; FFAs, free fatty acids; GABA, 
γ-aminobutyric acid; GLP-1 RA, glucagon-like peptide-1 receptor agonist drugs including tirzepatide; MC4R, melanocortin 4 receptor; POMC/CART,  
pro-opiomelanocortin/cocaine-amphetamine-related transcript; PYY, peptide YY; SNS, sympathetic nervous system; WAT, white adipose tissue;  
Y1R, NPY 1 receptor.

20%

41%
32%

23%

57%
65%

80%

59%
68%

77%

43%
35%

≥≥10% ≥≥10% ≥≥10% ≥≥10% ≥≥10% ≥≥10%

ORLISTAT PHEN/TOP NAL/BU LIRAGLUTIDE SEMAGLUTIDE TIRZEPATIDE

% Effective % Ineffective

Figure 5. Percent of individuals experiencing ≥10% weight reduction from drug 
treatment during clinical trial testing.17,21 Nal/Bu, naltrexone with bupropion.

other incretin therapies, almost 40% of trial participants reported 
nausea, 70% experienced GI disorders, and almost 10% discontin-
ued the drug.15

 The newest incretin drug, tirzepatide, binds GLP-1 and GIP 
receptors in the gut.16 This dual-acting drug has been the most  

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AMWAJournal.org     40Incretin Drug Revolution: The Challenges of Hope

successful incretin therapy thus far, with 62% of participants 
having ≥15% weight reduction, and more than half having 
≥20% weight reduction (Figure 6). However, about a quarter 
of participants discontinue treatment because of GI symp-
toms.22 It has been shown that incretin therapies remain 
ineffective for about 20% of individuals.23 Some patients 
require dose adjustments, therapy changes, or surgery to 
reach weight goals. Although there are several known bene-
fits for incretin therapies, several challenges remain.

Challenges of Incretin Therapy: Shifting Satiety
The incretin drug revolution brings hope for treating  
obesity and many weight-related conditions. However,  
sympathetic-extension of satiety may increase long-term 
risks for chronic disease, including risk for renal disorders 
and thyroid cancer.16 The brain’s default hunger state may 
support long-term health, fueling cellular activity through 
fatty acid metabolism. In contrast, incretin drugs shift the 
metabolic state to satiety, forcing the brain and other tissues 
to rely on glucose.24 Although the consequences of this shift 
are unclear, sympathomimetic and incretin drugs increase 
risk for hypertension, glaucoma, and heart rate (Table 2).25,26

 Incretin drugs may also come with increased risk for 
anxiety. One study linked chronic activation of AgRP/NPY 
neurons with increased anxiety and colitis.27 Supporting 
this, some individuals taking incretin drugs report 
increased anhedonia and suicidality.15 Other challenges 
of incretin drugs are 
linked to gastric emp-
tying and include 
ileus, gastroparesis, 
and decreased drug 
absorption.28,29

 Another compli-
cating issue includes 
the plateau effect. 
Over time, increased 
incretin drug dosing 

may no longer decrease net body mass. This effect has 
been reported by individuals taking semaglutide and high-
lights lifestyle modifications as an important part of over-
all treatment.15 Using incretin therapies requires a life-long 
commitment because health gains disappear with discon-
tinuation. Some studies report up to two-thirds of the origi-
nal weight returns after discontinuation.29

LOOKING AHEAD
In summary, incretin therapies bring a dynamic phase in 
drug development for treating obesity. These drugs lower 
glycemic index, reduce cardiovascular risk, and may ben-
efit liver and neurodegenerative conditions. However, the 
health risks of prolonged satiety states to cardiac, renal, 
and other tissues remain unclear. Incretin drugs have been 
linked to increased risk for thyroid cancer, suicidality, and 
elevated heart rate. These medication side effects must be 
balanced with health benefits and cost, which factor heav-
ily into optimizing individualized clinical obesity treatment 
plans. Given the limited number of high-quality random-
ized trials comparing obesity drugs, doctors must resort to 
trial-and-error to predict usefulness. In addition, long-term 
safety studies in diverse populations are needed to better 
understand incretin drug effects on growth and develop-
ment. By 2030, more than 8.5 billion people are estimated  
to meet criteria for obesity worldwide.10 Now more than 
ever, learning from past mistakes can help improve the 
quality of clinical obesity care. It is crucial to determine the 
risks and long-term health benefits of bariatric surgery, 
drug therapy, and combination treatments to help guide 
future clinical practice.

Acknowledgments
I thank Naomi B. Bishop, MD, for her review of the man-
uscript. All figures and tables are compiled, graphed, and 
designed by the author. The references used in the tables 
and graphs are cited.

Author declaration and disclosures: The author notes no  
commercial associations that may pose a conflict of interest in 
relation to this article.

Author contact: racelis@msn.com

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16% 11%
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62% 57%

84% 89%
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38% 43%

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https://www.cdc.gov/obesity/adult-obesity-facts/index.html
https://www.cdc.gov/obesity/adult-obesity-facts/index.html
https://www.cdc.gov/obesity/childhood-obesity-facts/childhood-obesity-facts.html
https://www.cdc.gov/obesity/childhood-obesity-facts/childhood-obesity-facts.html



