REVIEW
A Revolution in the Treatment of Obesity
Reynold Spector, MD
Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ.
ABSTRACT
Forty percent of Americans are obese and 20% are overweight. Until recently, notwithstanding great
efforts to combat this chronic, worsening epidemic, the only therapy that “worked” was surgery. However,
recently, a new class of safe drugs (incretins) have been developed that cause obese patients to lose »20 to
25% of their body weight. Herein we recount this revolution and its implications.
Ó 2024 Published by Elsevier Inc. The American Journal of Medicine (2024) 137:925−928
KEYWORDS: Agonists; GIP; GLP-1; Glucagon; Incretins; Insulin; Semaglutide; Tirzepatide
Recently, a new revolutionary class of drugs (incretins) sleep apnea, and premature death.4-7 There is no perfect
became available that cause obese patients to lose safely as explanation for the recent increase in obesity, but one pro-
much as 25% of their body weight, with huge secondary posal is implicit in Darwin’s theory of evolution. When
benefits.1-4 On November 7, 2023, the US Food and Drug they were hunter-gatherers and food was plentiful, those
Administration (FDA) approved tirzepatide (Mounjaro; Eli who put on more weight would be likely to survive famines.
Lilly and Company, Indianapolis, Ind) for the treatment of Thus, there may be an inborn tendency in some to overeat
overweight and obesity.1 Prior to proceeding, it is important when food is inexpensive and plentiful.
to define what we mean by obesity. Although there are Past efforts to control obesity, often unsuccessful, fell
many ways of categorizing obesity, we, as almost all inves- into 5 categories: behavioral interventions, nutritional inter-
tigators do, will define obesity according to the level of ventions, physical activity, pharmacotherapy, and meta-
body mass index (BMI). BMI is the weight in kilograms bolic and bariatric surgery.4 Only surgical interventions
divided by the square of the height in meters; a normal BMI could consistently decrease weight by 20% or more. In the
is between 19 and 25, 25 to 30 is termed overweight, and recent past, several endogenous hormones were found to
>30 is considered obese. Obesity is caused by generic, play key roles in growth and obesity in animals—specifi-
environmental, and social factors and the availability of cally, ghrelin and leptin. After much hope and work on
cheap food. In some individuals there is a so-called set ghrelin, nothing useful emerged for humans. However,
point that keeps the weight stable over long periods of time. metreleptin, an analog of leptin, turned out to be useful in
However, the obese, often poor patients on the fringes of lipodystrophy and the very rare obese patient with leptin
society, will tend to eat more and the set point is too weak deficiency. In humans, there are multiple factors, including
to control weight. It is now clear that obesity is a major hormones, peptides, secretions by fat cells, and neuroendo-
chronic problem, because 40% of adult Americans are crine cells in the stomach and intestines, which ultimately
obese, 20% are overweight, and obesity is becoming a help determine weight by acting on the pancreas alpha (glu-
major problem in children.4 Moreover, obesity is either cagon) or beta cells (insulin) and sometimes, the brain.
causally or indirectly related to cardiovascular disease, dia- Two pharmaceutical targets are the glucagon-like peptide 1
betes, certain types of cancer, arthritis of the hips and knees, (GLP-1) receptor and the glucose-dependent insulinotropic
polypeptide (GIP) receptor. GLP-1 and GIP are secreted by
the neuroendocrine cells in the intestine after meals and
Funding: This review had no funding. cause a feeling of satiety. Semaglutide, a GLP-1 receptor
Conflicts of Interest: None.
Authorship: The sole author is responsible for all content: Writing −
agonist, the first truly effective incretin approved by the
original draft, review & editing, Formal analysis, Conceptualization. FDA for the treatment of diabetes, causes about a 10%
Requests for reprints should be addressed to Reynold Spector, MD, decrease in body weight and is associated with fewer car-
551 North Road, #1212, Westfield, MA 01085 diovascular events and lower blood pressure and favorable
E-mail address: [email protected]
0002-9343/© 2024 Published by Elsevier Inc.
https://doi.org/10.1016/j.amjmed.2024.05.023
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926 The American Journal of Medicine, Vol 137, No 10, October 2024
modification of other risk factors after 3 years of use.3 Tir- view, there is no doubt that this is the most important clini-
zepatide is both a GLP-1 and GIP receptor agonist. Chemi- cal advance of the 21st century. Examples of the utility of
cally, it is a 39 linear polypeptide with one C20 fatty diacid these drugs, beyond diabetes and weight loss, lie in orthope-
moiety attached to the lysine at the C20 position.7 It has a dic surgery, cardiology, and sleep apnea. In orthopedic sur-
half-life of 5 days (Figure8,9). This dual agonism probably gery, surgeons will often not replace knees or hips in very
accounts for its potency, twice that of semaglutide. These obese patients. However, now some surgeons are using
drugs act on the receptors in the pancreas to reduce gluca- these incretin drugs for months to lower the patient’s weight
gon secretion and augment insulin to make them suitable for surgery.
secretion and reduce gastric empty- CLINICAL SIGNIFICANCE Similarly, cardiologists are using
ing times. These actions reduce these drugs in obese patents because
appetite and thus provoke weight Incretins, a new drug class, have come they have been shown to reduce
loss. However, it appears that these on the market; these enable obese cardiovascular events and have
drugs will have to be taken indefi- patients (40% of American adults) to shown impressive symptom relief in
nitely to maintain the loss of lose up to 20% of their body weight obese diabetic patients with heart
3,5
weight, but it is also possible that, over 1 year. failure. On April 17, 2024, tirze-
after 4-5 years, the set point for Only gastrointestinal surgery is as patide was submitted to the FDA
one’s weight might be reset and the for approval for sleep apnea because
effective.
obese no longer require incretin it cut down the number of apneic
Clinicians play a critical role in
treatment. However, most patients episodes by »65%.
who lose weight tend to gain it back counseling patients. The second group of issues sur-
when they go off the treatment.2 These safe and effective drugs, sema- round the individual patient and his
With tirzepatide, a once-weekly glutide and especially, tirzepatide, or her physician. Ideally, for obese
self-administered subcutaneous have become so popular that the drug people without an obvious treatable
auto-injection of up to 15 mg, there companies that make them cannot cause, such as Cushing’s disease, a
was on average sustained 20% keep up with the demand. reasonable physician—after trying
weight loss over 18 months. In the This review details the physiology and diet, exercise, and counseling, and
phase 3 trials, only 3% of the pharmacology of these drugs. finding the patient unable to lose
patients discontinued the drug weight, a common occurrence—
because of adverse drug effects.1 would want to try tirzepatide.4 If the
Tirzepatide was started at 2.5 mg patient takes it, he or she would lose
weekly for a month, to minimize side effects, and slowly substantial weight and benefit greatly, as noted above.
increased to 15 mg if tolerated. The most common side However, there is a danger associated with the use of these
effect is nausea, which generally decreases over time. Thus, drugs. The patient may feel that because he’s taking the
a 250-pound man or woman would weigh, on the average, drug, he can eat more; such behavior may neutralize some
200 pounds after 18 months of treatment. of the effects of the drug. In clinical trials, patients are
The economic and medical consequences of obesity are closely watched, and counseled about diet, and the results
massive. The diseases associated with obesity (cardiovascu- may not reflect what will happen in the real-life use of the
lar disease, increased blood pressure, arthritis of the knee drugs. Thus, the importance of having a caring, knowledge-
and hip, depression, sleep apnea, and premature death) take able physician to monitor these obese patients is, in my
a heavy toll on society, for example, lost time from work, view, crucial to realize the potential results with such
and estimates of the cost of obesity are very large, perhaps drugs.
250 to 300 billion dollars a year. However, the manufac- In summary, American society has multiple issues to
turer of tirzepatide is reported to be asking for approxi- deal with in terms of treatment of the chronic disease called
mately $1000 a month.7 To control weight loss, these drugs obesity; first is the cost. How much are Americans, society,
require continuous treatment for many years, if not indefi- government, and insurers willing to pay for this very expen-
nitely.2 The cost for treating, let’s say, just the worst 20 mil- sive treatment for a chronic condition affecting over
lion obese Americans would be astronomically expensive at 100 million Americans. Because not every obese person
$200 billion per year. Because many of the obese patients can be treated, how will the treatment allocation be han-
are older people, perhaps the government—with a new law dled? Will obese patients with arthritis, diabetes, sleep
that would allow Medicare to both pay for and negotiate apnea, or cardiovascular disease be favored (secondary pre-
with the drug makers—could decrease the cost, maybe by vention) over those who are just obese? Another question
half. At present, in some states, Medicaid or private insur- is: how soon will competitors develop similar drugs, which
ance covers these drugs.10 Moreover, there will be intense will allow for substantial lowering of the cost of such
basic research to find a similar drug that’s patentable that drugs? Tirzepatide is a potent complex drug that is heavily
could be in competition (see below). It is clear that, unless patented. Lilly has another drug (retatrutide) that is a GLP-
there are major changes in our society, only the wealthy 1, GIP, and glucagon agonist that, in phase 2 trials, caused
will be able to afford this marvelous therapy. But in my a 25% weight loss in obese subjects, vs 20% for tirzepatide
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Spector A Revolution in the Treatment of Obesity 927
Figure (A) Tirzepatide is a synthetic linear peptide molecule containing 39 amino acids. Residues derive from GIP,
but 2 residues are unique. The structure includes a fatty acid moiety connected to lysine at residue 20 of the peptide
sequence. It also contains 2 non-coded residues (alpha aminoisobutyric acid) at positions 2 and 13. These 2 and the
fatty acid moiety are responsible for its long half-life and a high affinity for plasma albumin. The molecular formula
of tirzepatide is C 225, H 348, N 48, and O 68. The molecular weight is 4813. Tirzepatide is the first and only (at
present) FDA agent that functions as a dual agonist for the human GLP-1 and GIP receptors with profound conse-
quences as indicated in the text. Of course, in vivo tirzepatide takes a different shape, with alpha-helical portions that
are flexible and have high affinity for the GIP and GLP-1 receptors.8,9 (B) GIP only interacts with the GIP receptor;
GLP-1 interacts only with the GLP-1 receptor; GCG interacts only with the GCG receptor. Semaglutide interacts
only with the GLP-1 receptor; tirzepatide interacts with both the GLP-1 receptor and the GIP receptor: retatrutide,
which is not yet on the market, interacts with all 3 receptors. The concentration of incretin or effective drug to half
saturate the receptors in picomoles/liter are very similar »1 to 15 pM. The difference is that incretins are metabolized
by a specific enzyme, have short half-lives, and are gone within minutes or hours. As noted in the text, tirzepatide has
a half-life of »5 days. The average free plasma concentration of tirzepatide is »30 picomolar when 15 mg is given
each week subcutaneously. Thus, throughout the week, at 15 mg one is not very hungry because GIP and GLP-1
receptors are saturated with incretin or drug, or both.8,9
FDA = US Food and Drug Administration; GCG = glucagon; GIP = glucose-dependent insulinotropic polypeptide;
GLP-1 = glucagon-like peptide 1.
(Figure). Moreover, Lilly recently purchased Versanis can be done, but doing it on the scale required will be diffi-
(Boston, Mass), which has a weight loss drug: bimagrumab. cult, expensive, and will require superb presidential, con-
It may be difficult to compete with Lilly for years, further gressional, pharmaceutical, and physician leadership.
complicating equitable distribution for the individual
patient. Investors have noted that the potential value of
Lilly’s weight loss drugs is so great that Lilly is now the ACKNOWLEDGMENTS
world’s largest drug company. Thus, we now know what The author thanks Edward Goetzl for his wise advice.
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928 The American Journal of Medicine, Vol 137, No 10, October 2024
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