Annual Review of Medicine
New Frontiers in Obesity
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Treatment: GLP-1 and Nascent
Nutrient-Stimulated
Hormone-Based Therapeutics
Ania M. Jastreboff1 and Robert F. Kushner2
1
Departments of Medicine (Endocrinology & Metabolism) and Pediatrics (Pediatric
Endocrinology), Yale University School of Medicine, New Haven, Connecticut, USA;
email: ania.jastreboff@yale.edu
2
Departments of Medicine (Endocrinology) and Medical Education, Northwestern University
Feinberg School of Medicine, Chicago, Illinois, USA; email: rkushner@northwestern.edu
Keywords
GLP-1 receptor agonists, antiobesity medications, dual receptor agonists,
triple receptor agonists, nutrient-stimulated hormone-based therapies,
NuSH-based therapies
Abstract
Nearly half of Americans are projected to have obesity by 2030, under-
scoring the pressing need for effective treatments. Glucagon-like peptide 1
receptor agonists (GLP-1 RAs) represent the first agents in a rapidly
evolving, highly promising landscape of nascent hormone-based obesity
therapeutics. With the understanding of the neurobiology of obesity rapidly
expanding, these emerging entero-endocrine and endo-pancreatic agents
combined or coformulated with GLP-1 RAs herald a new era of tar-
geted, mechanism-based treatment of obesity. This article reviews GLP-1
RAs in the treatment of obesity and previews the imminent future of
nutrient-stimulated hormone-based anti-obesity therapeutics.
125
 INTRODUCTION
A new generation of highly effective, hormone-based pharmacotherapeutics for obesity is on the
horizon. This is driven, in part, by the understanding of obesity as a disease (1) of energy regula-
tion with complex underlying pathophysiology whereby the energy homeostasis system defends
an elevated fat mass set point (2). In particular, investigation of the role of hormones in regulation
of metabolism and appetitive behavior, and their biological effect on neural energy regulation,
have shifted the obesity therapeutic landscape to target underlying mechanisms with the devel-
opment of hormone-based medications. Among the array of nutrient-stimulated pancreatic and
intestinal hormones that provide appetitive signals is glucagon-like peptide-1 (GLP-1). Originally
developed as therapeutics for the treatment of type 2 diabetes (T2D) based on their incretin ef-
fect, GLP-1 receptor agonists (GLP-1 RAs) are emerging as highly effective obesity therapeutics.
GLP-1 RAs can be deployed as monotherapy, combined with other hormone-based medications,
or engineered as a dual or triple receptor agonist. This article reviews current knowledge regard-
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ing the biology and pharmacological application of GLP-1 RAs for the treatment of obesity and
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provides insight into nascent nutrient-stimulated hormone-based therapeutics on the horizon.

Past Medications
Based on early investigations of rudimentary feeding behavior, a dual-center hypothesis of feed-
ing emerged, with the ventromedial hypothalamus and lateral hypothalamus categorized as
the satiety and hunger centers in the brain, respectively. The monoamine neurotransmitters
norepinephrine, serotonin, and dopamine were identified as circuitry mediators. Accordingly,
the initial medications synthesized for treatment of obesity were sympathomimetic adrenergic
agents, e.g., phentermine, that functioned by stimulating norepinephrine release or by block-
ing its reuptake. A fixed-dose product containing a combination of phentermine and topiramate
(a gamma-aminobutyric acid agonist) was approved by the US Food and Drug Administration
(FDA) in 2012, and another combining naltrexone (a nonselective opioid receptor antagonist)
and bupropion (an inhibitor of dopamine and norepinephrine transporters) was approved by the
FDA in 2014. Orlistat, a gastrointestinal lipase inhibitor approved by the FDA in 1999, is the
only FDA-approved antiobesity medication that does not exert action in the brain. Excess weight
loss for these agents compared to placebo at 1 year ranges from 2.6 kg to 8.8 kg (3). In 2014, the
FDA’s approval of liraglutide 3.0 mg established a new direction for hormone-based treatment for
obesity. Liraglutide is the first GLP-1 RA that was licensed for chronic weight management.

Hormones, the Gut–Brain Axis, and GLP-1

The discovery of entero-endocrine and endo-pancreatic hormones, coupled with a deeper under-
standing of the gut-brain axis, provided a more comprehensive paradigm for the central role of the
endocrine system in energy (4) and defended fat mass set point (2) regulation (Table 1). Among
the gut peptides are GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), incretin
hormones released from specialized entero-endocrine cells in the intestinal mucosa stimulated by
nutrient intake (5). In addition to promoting a glucose-dependent increase in insulin secretion,
GLP-1 inhibits glucagon secretion, reduces gastric emptying, and causes early acute reduction in
appetite and food intake when infused intravenously (6). Other diverse pleomorphic actions of
GLP-1, inclusive of the cardiovascular system, have also been described; these include reduction
of blood pressure, inflammation, and coagulation, as well as promotion of natriuresis and diuresis
(7, 8). Thus, the pharmacological role of GLP-1 in the treatment of T2D and obesity is grounded
in its diverse biological actions.

126 Jastreboff • Kushner

 Table 1 Entero-endo and endo-pancreatic hormone-based-therapeutic targets for obesity treatment
Hormone Receptor and Physiological
(references) Source locations functiona Therapeutic implications
Glucagon-like Major: entero- GLP-1 receptor ↑ Satiety (via CNS FDA-approved GLP-1 RAs for obesity:
peptide-1 endocrine L cells Locations: mechanism)  liraglutide 3 mg SC daily (2014)
(GLP-1) Minor: pancreatic  CNS (hypothalamus, ↓ Gastric emptying  semaglutide 2.4 mg SC weekly (2021)
(79, 80) α cells, CNS NTS, AP, striatum) ↓ Gastric motility  multiple other GLP-1 RAs approved
(NTS)  pancreatic β cells ↑ Postprandial for T2D also used for weight
 heart insulin secretion reduction benefit
 lung  oral GLP-1 RAs in development for
 gastrointestinal tract obesity treatment (Figure 1, oral
 kidney GLP-1 RAs)
Amylin (AMY) Pancreatic β cells AMY receptor ↑ Satiety Under investigation as monotherapy or
(81, 82) (heterodimer of CTR ↓ Gastric emptying in combination with GLP-1 and other
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core protein with ↓ Food intake hormones:

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RAMPs)  cagrilintide (monotherapy) (Figure 1)

Location: CNS  cagri-sema (AMY/GLP-1 dual RA)
(hypothalamus, AP, (Figure 1)
VTA, striatum)  combination with leptin

Cholecystokinin Entero-endocrine CCK-1 receptor ↑ Satiety Preclinical investigation: CCK analogue

(CCK) (80, 83) I cells Location: pancreas ↓ Gastric emptying NN9056
(minor: CNS) ↓ Gastric motility
CCK-2 receptor
Location: CNS
(hypothalamus, NTS)
(minor: GI tract)
Ghrelin (80, 84) Entero-endocrine GHS receptor ↑ Food consumption Preclinical investigation: ghrelin
P/D1 cells Location: CNS Orexigenic antagonists/agonists
(hypothalamus)
(minor: pancreas,
adrenal, pituitary)
GIP (85, 86) Entero-endocrine GIP receptor ↓ Food intake Under investigation as monotherapy or
K cells Locations: ↑ LPL activity in combination with GLP-1 and other
 pancreatic β cells ↑ Postprandial hormones (Figure 1):
 CNS (hypothalamus) insulin secretion  ZP6590 (monotherapy)
 bone  tirzepatide (GIP/GLP-1 dual RA)
 heart FDA approved for T2D
 adipocytes  AMG133 (GIP/GCG dual RA)
 LY3437943 (GIP/GCG/GLP-1
triple RA)
Glucagon (GCG) Pancreatic α cells GCG receptor ↑ Satiety Under investigation as monotherapy or
(87) Locations: ↑ Glycogenolysis in combination with GLP-1 and other
 CNS ↑ Gluconeogenesis hormones for obesity (Figure 1):
 pancreas  HM15136 (monotherapy)
 adipocytes  pemvidutide (GCG/GLP-1 dual RA)
 kidney  BI1456906 (GCG/GLP-1 dual RA)
 liver  LY3437943 (GIP/GCG/GLP-1
triple RA)
(Continued)

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 Table 1 (Continued)
Hormone Receptor and Physiological
(references) Source locations functiona Therapeutic implications
Oxyntomodulin Enteroendocrine Binds GLP-1 and GCG ↑ Satiety Preclinical investigation: OXM analogues
(OXM) (80) L cells receptor ↓ Gastric emptying
Locations: ↓ Food intake
 CNS (hypothalamus)
 pancreas

Pancreatic Pancreatic F cells Y4 receptors ↑ Satiety Preclinical investigation: PP analogues

polypeptide Location: CNS ↓ Gastric emptying
(PP) (88) (hypothalamus, NTS)
Peptide tyrosine Entero-endocrine Y2 receptor ↑ Satiety Under investigation as monotherapy or
tyrosine (PYY) L cells Location: CNS ↓ Gastric emptying in combination with GLP-1 and other
(80) (hypothalamus, NTS) ↓ Gastric motility hormones:
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 NN9775 (PYY-1875 analogue) in

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combination with semaglutide:

NCT04969939
 NN9747(PYY 1562 analogue):
NCT03574584
 PYY analogue in combination with
metreleptinb (leptin analogue) or
AMY

a
Physiologic function as it related to energy regulation and obesity.
b
The focus of Table 1 is entero-endocrine and endo-pancreatic hormones as therapeutic targets for obesity. Leptin and adiponectin are not included as
they are secreted in adipose tissue.
Abbreviations: AMY, amylin; AP, area postrema; CCK, cholecystokinin; CNS, central nervous system; CTR, calcitonin receptor; FDA, US Food and Drug
Administration; GCG, glucagon; GHS, growth hormone secretagogue; GI, gastrointestinal; GIP, glucose-dependent insulinotropic peptide; GLP-1,
glucagon-like peptide-1; LPL, adipocyte lipoprotein lipase; NTS, nucleus tractus solitarius; OXM, oxyntomodulin; RA, receptor antagonist; RAMP,
receptor activity modifying proteins; SC, subcutaneous; T2D, type 2 diabetes; VTA, ventral tegmental area.

The paracrine mechanisms responsible for appetite and weight reduction have been studied
in animals and involve multiple brain regions comprising the homeostatic and hedonic pathways
(9–11). Uptake of semaglutide, one of the two GLP-1 RAs that are currently approved for chronic
weight management, appears to access selected brain regions involved in appetite regulation by di-
rect and circumventricular routes including the arcuate nucleus of the hypothalamus, the nucleus
tractus solitarius of the brain stem, and projections to other appetite-modulating relay nuclei (11,
12). Appetitive brain areas such as the striatum, insula, and orbitofrontal cortex that are commonly
activated by viewing rewarding and energy-dense food pictures (13) are also significantly reduced
by GLP-1 RA (14). Subsequently, weight reduction occurs when these biological actions are trans-
lated into reduced food intake, diminished food cravings and prospective food consumption, and
increased satiety (15–17).
Pharmacological application of native GLP-1 requires modification to its structure to resist
rapid proteolytic degradation by dipeptidyl peptidase 4 (DPP-4), a ubiquitous enzyme that is found
in multiple organ beds. Depending on the specific GLP-1 RA, resistance to DPP-4 action has
been accomplished by amino acid substitutions at selected points in the protein structure and by
prolonging its half-life by attachment to large proteins such as albumin or immunoglobulin (18).
The most common side effects associated with the GLP-1 RA agents, to be discussed below, are
gastrointestinal, including nausea and diarrhea. These are likely caused by direct interactions with
central nervous system GLP-1 receptors, including in the area postrema, and mainly occur at ini-
tiation of treatment during dose escalation. These gastrointestinal side effects wane with time and

128 Jastreboff • Kushner

 do not contribute to the durable weight effects demonstrated by these agents. Depending on the
compound’s pharmacokinetic properties and plasma concentrations, a measured dose-escalation
schedule is recommended to mitigate these side effects (10). The clinical management of patients
receiving these agents is beyond the scope of this review, and readers are referred to additional
articles on this subject (19–21).

PHARMACOLOGICAL APPLICATIONS FOR OBESITY MANAGEMENT

In this section, we review the weight reduction outcomes of approved and emerging GLP-1
RA compounds for obesity that are being developed as monotherapy, combined with other
nutrient-stimulated hormone-based agents, or engineered as dual or triple receptor agonists.
Three therapeutic agents—liraglutide, semaglutide, and tirzepatide—have completed phase III
studies. At this time, liraglutide and semaglutide have regulatory approval for both chronic weight
management and T2D, while tirzepatide is FDA approved for T2D, not yet approved for chronic
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weight mangement.
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Liraglutide: A Daily GLP-1 Receptor Agonist FDA Approved

for Chronic Weight Management
Liraglutide is a GLP-1 RA with 97% homology to human GLP-1. As a result of molecular
modifications of the structure, liraglutide has reduced susceptibility to DPP-4 and is dosed sub-
cutaneously (SC) once daily with a half-life of approximately 11–15 h (22, 23). Liraglutide was
initially approved for the treatment of T2D in the United States in 2010 at doses up to 1.8 mg
once daily. It was subsequently approved for obesity treatment at doses up to 3.0 mg once daily in
2014 for adults, and in 2020 for adolescents (aged ≥12 years).
Specifically targeting obesity, liraglutide has undergone five randomized double-blind placebo-
controlled trials in adults. The series of trials, called SCALE (Satiety and Clinical Adiposity –
Liraglutide Evidence), involved more than 5,000 participants to evaluate liraglutide’s efficacy
and safety for weight management (Table 2). All participants received diet and physical activ-
ity counseling and were randomized to receive liraglutide (3.0 mg SC daily) or placebo with the
primary outcome of change in body weight. The five trials were SCALE (in individuals without
diabetes) (24), SCALE Diabetes (in individuals with T2D) (25), SCALE IBT (intensive behav-
ioral therapy added to treatment) (26), SCALE Maintenance (weight maintenance after initial
weight reduction) (27), and SCALE Obesity and Prediabetes (3-year T2D risk reduction) (28).
Intention-to-treat 1-year placebo-subtracted weight reduction was 5.2%, 4%, 3.4%, and 6.1%
for SCALE, SCALE Diabetes, SCALE IBT, and SCALE Maintenance, respectively. Clinical and
statistical dose-dependent improvements were seen in selected cardiovascular and metabolic out-
come measurements. A subsequent trial, SCALE TEENS, included 251 adolescents with obesity
(average age 14.6 years) who were randomized to receive 56 weeks of liraglutide 3.0 mg daily versus
placebo; both groups received healthy nutrition and physical activity counseling. The liraglutide-
treated group demonstrated a placebo-subtracted weight reduction of 5% (29). In the liraglutide
SCALE trials, the most common adverse effects of nausea, diarrhea, constipation, and vomiting
were reported to be mild and transient.

Semaglutide: A Weekly GLP-1 Receptor Agonist FDA Approved

for Chronic Weight Management
Semaglutide represents the next generation of GLP-1 RAs that are further chemically modified
and designed for once-weekly SC administration with a longer half-life (183 h) (30, 31). Semaglu-
tide was initially approved for the treatment of T2D in the United States at doses up to 1.0 mg

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Table 2 Results of phase III clinical obesity trials with liraglutide, semaglutide, and tirzepatide
Liraglutide 3.0 mg SC daily Semaglutide 2.4 mg SC weekly Tirzepatide
SCALE
SCALE SCALE Obesity and SCALE
SCALE Diabetes SCALE Maintenance Prediabetes TEENS STEP 1 STEP 2 STEP 3 STEP 8
(24) (25) IBT (26) (27) (28) (29) (33) (34) (35) STEP 4 (36) (37) SURMOUNT-1

130
Sema 2.4
weekly Tirzepatide
Obesity + Weight Obesity + 12–17 years Obesity + Weight versus Lira 5 mg, 10 mg,
Obesity T2D IBT maintenance prediabetes old Obesity T2D IBT maintenance 3.0 daily 15 mg

Jastreboff
n 3,731 846 282 422 2,254 251 1,961 1,210 611 902 338 2,539

•
Mean BMI 38.3 (6.4) 37.1 (6.5) 39.3 (6.8) 38.2 (6.2) 38.8 (6.4) 35.3 (5.1) 37.9 (6.7) 35.7 (6.3) 38.0 (6.7) 38.3 (7.0) 37.5 (6.8) 38 (6.8)
(kg/m2 )a

Kushner
Mean age (y)a 45.1 (12.0) 55.0 (10.8) 45.4 (11.6) 45.9 (11.9) 47.5 (11.7) 14.6 (1.6) 46 (12.7) 55.3 (10.6) 46.2 (12.7) 46.4 (11.9) 49 (13.0) 44.9 (12.5)
Comorbid ≥1 T2D Not ≥1 ≥1 0–≥1 ≥1 T2D ≥1 ≥1 ≥1 0–≥1
conditions specified
(cardiovas-
cular and
metabolic)
Duration 56 56 56 56 160 56 68 68 68 68 68 72
(weeks)
Mean weight 8.0 versus 6.0 versus 7.5 versus 6.2 versus 0.2 6.1 versus 1.9 –2.65 versus 14.9 versus 9.6 versus 16.0 versus 17.4 versus 5.0 15.8 versus 20.9 versus 3.1
loss (%) 2.6 2.0 4.0 +2.37 2.4 3.4 5.7 6.4b
with
treatment
versus
placebo
Placebo- 5.4 4.0 3.4 6.1 4.3 5.01 12.4 6.2 10.3 12.4 9.4b 17.8d
subtracted
weight loss
(%)
Categorical 33.1 versus 25.2 versus 30.5 versus 26.1 versus 6.3 24.8 versus 9.9 26.1 versus 69.1 versus 45.6 versus 75.3 versus 79.0 versus 20.4 70.9 versus 83.5 versus 18.8d
change in 10.6 6.7 19.8 8.1c 12 8.2 27.0 25.6b
≥10%
weight loss
with
treatment
versus
placebo

a
Mean age and BMI from active group for total population.
b
Semaglutide versus liraglutide.
c
Participants achieving ≥10% reduction in BMI (rather than % weight loss).
d
Tirzepatide 15 mg weekly dose versus placebo.
Abbreviations: IBT, intensive behavioral therapy; Lira, liraglutide; SC, subcutaneous; SCALE, Satiety and Clinical Adiposity – Liraglutide Evidence; Sema, semaglutide; STEP, Semaglutide
Treatment Effect in People with Obesity; T2D, type 2 diabetes.
 once weekly in 2017 and at 2.0 mg once weekly in 2022. It was subsequently approved at doses up
to 2.4 mg once weekly for chronic weight management in the setting of obesity in 2021.
The STEP (Semaglutide Treatment Effect in People with Obesity) program is designed to
investigate the effect of semaglutide versus placebo on efficacy (weight reduction), safety, and tol-
erability in adults with obesity or overweight (Table 2) (32). In the first four STEP trials, ∼5,000
participants were randomly assigned to receive semaglutide 2.4 mg SC once weekly versus placebo
over 68 weeks. Participants in all treatment groups received lifestyle intervention. In STEP 1, in-
dividuals randomized to semaglutide achieved an average weight reduction of 14.9% compared
to 2.4% for placebo (treatment difference of 12.4%). Furthermore, one-third of the semaglutide
group lost ≥20% body weight versus only 1.7% achieving this target in the placebo group (33). In
the STEP 2 trial (individuals with T2D), participants randomized to semaglutide 2.4 mg, semaglu-
tide 1.0 mg, or placebo lost 9.6%, 7.0%, and 3.4% body weight, respectively (34). The STEP 3 trial
evaluated the effect of adding IBT along with an initial 8-week low-calorie diet. Estimated mean
weight change from baseline was 16% with semaglutide versus 5.7% with placebo (mean differ-
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ence of 10.3%) (35). Compared to the STEP 1 trial, individuals in the STEP 3 placebo group lost
more weight with the addition of IBT; however, mean weight reduction in the semaglutide group
was only 1% greater than that observed in STEP 1. Last, in the STEP 4 trial, all participants
received semaglutide during a 20-week run-in period. Thereafter, individuals who reached the
2.4 mg dose (average weight reduction of 10.6%) were randomized to either continue semaglutide
or switch to placebo. During the subsequent 48 weeks, participants who remained on semaglutide
lost an additional 7.9% body weight whereas the placebo group gained 6.9% body weight (36).
The more recently published STEP 8 trial demonstrates the superiority of weekly semaglutide
2.4 mg versus daily liraglutide 3.0 mg (treatment difference −9.4% body weight) (37).
The first four STEP trials demonstrate the significant biological effect of a sustained-release
GLP-1 RA on subsequent weight reduction over 68 weeks. The STEP 5 trial (37a) evaluates the
effect of semaglutide 2.4 mg versus placebo over 2 years. The weight regain data seen in STEP
4 (36) and the STEP 1 extension study (38), where participants discontinue active medication,
strongly suggest that pharmacological treatment must be sustained to combat the adaptive physi-
ological forces that hinder long-term weight reduction (39). The SELECT (Semaglutide Effects
on Heart Disease and Stroke in Patients with Overweight or Obesity) trial, a randomized double-
blind study investigating whether semaglutide 2.4 mg is superior when added to standard care for
secondary prevention of major adverse cardiovascular outcomes in patients with established CVD
and overweight or obesity, is currently under way (8).

Oral Semaglutide: A Daily Oral GLP-1 Receptor Agonist Under Investigation

for Chronic Weight Management
Most GLP-1 RAs are administered SC rather than orally. Oral administration results in low
bioavailability owing to poor absorption coupled with rapid degradation by proteolytic enzymes
(40). Coformulating semaglutide with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)
facilitates transcellular absorption through the gastric membrane and helps prevent degradation
of semaglutide in the stomach (41). Oral semaglutide is the first, and currently only, daily oral
GLP-1 RA (42) FDA approved for the treatment of T2D (2019) with a dose up to 14 mg daily.
Current and higher doses (25 mg and 50 mg daily) are being investigated for weight effects in
individuals with obesity and without T2D in the OASIS trials (NCT05035095).

Danuglipron: An Oral Small-Molecule GLP-1 Receptor Agonist in Development

Danuglipron is an orally bioavailable, selective, small-molecule GLP-1 RA that is currently
under development for treatment of T2D and obesity. In a phase I randomized double-blind
www.annualreviews.org • GLP-1 and Hormone-Based Obesity Therapeutics 131
 placebo-controlled study to assess the safety, tolerability, and pharmacokinetic and pharmacody-
namic profiles of danuglipron, 98 participants with T2D (taking metformin) were randomized
to receive multiple ascending doses of danuglipron (from 10 mg twice daily to 200 mg daily)
or placebo for 28 days (43). Similar to the side effect profile for other GLP-1 RAs, the most
commonly reported treatment-related adverse effects were nausea, dyspepsia, and vomiting.
The drug was generally safe and well tolerated and demonstrated dose-responsive reductions in
glycemic indices. A change in body weight of −4.4 kg at day 28 was reported with danuglipron
70 mg twice daily (compared with −1.8 kg for placebo), a dose level with a lower incidence of
nausea and vomiting compared to other formulations. The drug is currently undergoing further
clinical development for the treatment of T2D and obesity.

Amylin and Amylin/GLP-1 Dual Receptor Agonists in Development

Amylin is a pancreatic islet cell hormone, cosecreted with insulin from beta cells in response to
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nutrient intake (44, 45). It suppresses postprandial glucagon and delays gastric emptying (46).
The first amylin analogue, pramlintide, was FDA approved in 2005 as an adjunctive therapy to
insulin for individuals with type 1 and type 2 diabetes. Amylin’s impact on appetite and food in-
take, through action in the brain (46–50), has inspired a renewal of focus on amylin analogues
as potential antiobesity medications. Amylin acts on (a) appetitive/energy-regulating neurons in
the hypothalamus impacting food intake, (b) dopaminergic neurons in the ventral tegmental area
impacting reward and motivation, and (c) chemoreceptive neurons in the area postrema/nucleus
tractus solitarius (51).
Cagrilintide, a long-acting, weekly injectable analogue of amylin, has been investigated as
monotherapy in a phase II study (52) as well as in combination with the long-acting GLP-1 RA
semaglutide in a phase Ib study (53). In the phase II trial (52), 706 individuals with obesity [average
body mass index (BMI) 37.8 kg/m2 ] were randomized and titrated to receive either five escalating
doses of weekly cagrilinitide, daily liraglutide 3.0 mg, or placebo for 26 weeks. The participants
who received the highest dose of cagrilintide (4.5 mg weekly) lost 10.6% weight versus 8.4% in
the liraglutide group and 2.8% in the placebo group (52). The phase Ib trial, which included 95
participants with obesity (average BMI 32.1 kg/m2 ), investigated the impact of combining doses
of cagrilintide with semaglutide 2.4 mg. After 20 weeks, which included a 16-week dose titration,
the group that received the combination of semaglutide 2.4 mg plus cagrilintide 2.4 mg weekly
lost 17.1% weight, whereas the group that received monotherapy with semaglutide 2.4 mg weekly
lost 9.8% weight (53). Side effects of cagrilintide include nausea, diarrhea, constipation, fatigue,
and injection-site reactions (52). The combination of cagrilintide with semaglutide (cagri-sema)
is anticipated to enter phase III trials in late 2022. Taken together, these initial trials demon-
strate the promising potential for long-acting amylin analogue monotherapy or amylin/GLP-1
RA combinations to be additional tools in the armamentarium of antiobesity medications.

GIP/GLP-1 Dual Receptor Agonists in Development

GIP is a 42-amino-acid nutrient-stimulated hormone that is secreted from entero-endocrine
cells in response to nutrient intake (54) and works in concert with GLP-1, resulting in glucose-
dependent insulin secretion. Despite being the first incretin hormone to be identified (55), GIP’s
therapeutic potential was initially disregarded. It remained in the shadow of GLP-1, partly because
GIP-stimulated insulin secretion is significantly blunted in individuals with T2D (56); notably, re-
sponsiveness can be restored by mitigating hyperglycemia (57). In addition to GIP’s actions in the
pancreatic beta cell, GIP receptors have been identified in adipose tissue, bone, and the brain (58).
The central nervous system action is of particular interest in terms of GIP’s impact on weight via

132 Jastreboff • Kushner

 central mechanisms (59, 60). GIP is thought to potentially decrease food intake through action in
the hypothalamus (61).
Tirzepatide is a long-acting, weekly (62), injectable, single-molecule GIP/GLP-1 receptor
agonist with a half-life of ∼117 h (63). In the setting of GIP/GLP-1 receptor agonist (dual ago-
nism), GLP-1 quells the potential glucagon-stimulatory effects of GIP (64) and also (re)sensitizes
beta cells to GIP’s incretin effects (57), all while potentially enhancing GIP’s beneficial effects on
weight regulation mechanisms. Tirzepatide was approved for the indication of T2D by the FDA
in May 2022 and by the European Medicines Agency (EMA) in July 2022 based on data from the
SURPASS Diabetes trials (65, 66), which included individuals with T2D (63, 67, 68). Side effects
of tirzepatide in the SURPASS Diabetes trials were mainly gastrointestinal, including nausea, di-
arrhea, and dyspepsia (63, 67). The SURMOUNT-1 trial (69), which investigated the effect of
tirzepatide for weight reduction in individuals with obesity without T2D, recently published re-
sults. The SURMOUNT-1 trial included 2,539 individuals with obesity without T2D, who were
randomized to receive tirzepatide 5 mg, 10 mg, or 15 mg, or placebo for 72 weeks. The partici-
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pants who were randomized to the highest dose of tirzepatide (15 mg) lost 20.9% of their body
weight, whereas the placebo group lost 3.1% (treatment difference of 17.8%) (Table 2). Addition-
ally, more than half of the participants randomized to tirzepatide 10 mg or 15 mg lost ≥20% body
weight versus 3.1% achieving this target in the placebo group. SURMOUNT-2 (individuals with
T2D) (NCT04657003), SURMOUNT-3 (lifestyle weight loss program) (NCT04657016), and
SURMOUNT-4 (weight loss maintenance) (NCT04660643) are all ongoing trials with primary
completion dates in 2023. The SURMOUNT-1 trial demonstrates the impact of dual GIP/GLP-1
receptor agonism as a potential new treatment modality for obesity, demonstrating weight re-
duction that has not been previously demonstrated in phase III obesity treatment trials. Dual
GIP/GLP-1 agonism is being further investigated in the ongoing SURMOUNT Obesity trials.

Glucagon/GLP-1 Dual Receptor Agonists in Development

Glucagon is a 29-amino-acid peptide, secreted from the alpha cells of the pancreatic islets, which
stimulates glycogenolysis (70) and gluconeogenesis (71, 72). Owing to glucagon physiology, which
increases blood glucose, antagonism (rather than agonism) was pursued as a potential target for
T2D treatments (64). Notably, though, since its discovery, glucagon has also been investigated
for its effect on food intake, satiety, and energy expenditure. Preclinical studies demonstrate that
glucagon levels increase following protein ingestion (73), that inhibiting glucagon (action) results
in increased food intake (74), and that glucagon potentially has an effect on thermogenesis via
increasing brown adipose tissue oxygen consumption (75). Glucagon receptor has been localized
to the brain and pancreas, as well as the heart, kidney, liver, and adipose tissue (76), suggesting
pleiotropic effects in the body. Recently, phase I results of a study of the dual GLP-1a/glucagon
agonist BI456906 were presented at the Obesity Society’s annual meeting, ObesityWeek 2021.
In the study, individuals with obesity (average BMI 30.3–30.9 kg/m2 ) received either 6 weeks
of daily or weekly dosing (n = 80) or biweekly dosing (n = 45) to assess tolerability and dosing.
Individuals who received biweekly dosing exhibited a lower withdrawal rate and a weight reduction
of 8.8–13.7% compared to 0.1% weight reduction in the placebo group (77).

GIP/Glucagon/GLP-1 Triple Receptor Agonists in Development

GLP-1, GIP, and glucagon each impact food intake and satiety through disparate mechanisms,
playing complementary roles in maintaining the body’s defended fat mass set point. Thus, a tri-
agonist formulation may have greater efficacy due to additive effects. Known to be reduced in
the setting of T2D, lower GLP-1 levels may be part of an intricate cascade that not only results

www.annualreviews.org • GLP-1 and Hormone-Based Obesity Therapeutics 133

 GLP-1 receptor agonists
approved for obesity treatment
DUAL RA combinations
Semaglutide Weekly SC STEP trials
ENTERO-ENDOCRINE receptor agonists/antagonists
Liraglutide Daily SC SCALE trials
Tirzepatide GIP/GLP-1 Phase III Eli Lilly NCT04184622
dual RA

MONOTHERAPY CT388 GIP/GLP-1 Phase I

Carmot
NCT04838405
dual RA Therapeutics
ENDO-PANCREATIC receptor agonists GIP/GLP-2 Zealand
Dapiglutide Phase I Pharma NCT04838405
dual RA
Novo
Cagrilintide AMY RA Phase II NCT03856047
Nordisk GIP Receptor Antagonist/
AMG133 Phase I Amgen NCT04478708
GLP-1 RA
Zealand
ZP8396 AMY RA Phase I NCT05096598
Pharma
TRIPLE RA combinations
Amylin agonist LA AMY RA Phase I Eli Lilly Not available
DUAL RA combinations PANCREATIC-ENTERO-ENDOCRINE receptor
DACRA QW II AMY/CAL RA Phase I Eli Lilly Not available
PANCREATIC-ENTERO-ENDOCRINE receptor agonists Retatrutide GIP/GCG/GLP-1 Phase II Eli Lilly NCT04881760
triple RA
Cagri-Sema AMY/GLP-1 Phase III Novo NCT03600480
ORAL MONOTHERAPY dual RA Nordisk

ORAL GLP-1 receptor agonists Pemvidutide GCG/GLP-1 Phase II Altimmune NCT05295875

dual RA
Semaglutide GLP-1 RA Phase III Novo Nordisk NCT05035095 GCG/GLP-1 Boehringer
BI456906 dual RA Phase II Ingelheim NCT04667377
Access provided by 189.163.72.104 on 08/14/23. See copyright for approved use.

Danuglipron sm GLP-1 RA Phase II Pfizer NCT04707313

Annu. Rev. Med. 2023.74:125-139. Downloaded from www.annualreviews.org

NN9277 GCG/GLP-1 Phase I Novo NCT03308721

LY3502970 GLP-1R NPA Phase II Eli Lilly NCT05051579 dual RA Nordisk

Figure 1
Novel nutrient-stimulated hormone-based therapies in the pipeline for obesity treatment. In a rapidly expanding landscape of
hormone-based therapies, multiple nascent entero-endocrine and endo-pancreatic agents are in various stages of development for the
treatment of obesity. These include oral formulations of GLP-1 RAs as monotherapeutics as well as dual and triple receptor agonists.
Included in the figure are agents in development specifically for obesity treatment with the corresponding NCT numbers of phase I, II,
and III obesity trials. Abbreviations: AMY, amylin; DACRA, dual amylin and calcitonin receptor agonist; GCG, glucagon; GIP,
glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; LA, long acting; NCT, National Clinical Trial
identifier number; NPA, nonpeptide agonist; RA, receptor agonist; SC, subcutaneous; SCALE, Satiety and Clinical Adiposity –
Liraglutide Evidence; sm, small molecule; STEP, Semaglutide Treatment Effect in People with Obesity.

in dysglycemia but also results in dysregulated (elevated) defended fat mass set point. Aiming to
restore the balance of these hormones may also help reset the defended fat mass set point by al-
tering complementary central (neural) energy-homeostasis pathways. Recently, a GIP/GLP-1/
glucagon triple analogue (LY3437943) completed phase I studies. In the phase I randomized
double-blind placebo-controlled study, 45 adult participants received a single injection of placebo
or ascending dose of LY3437943 (78). The two highest doses of LY3437943, 4.5 mg and 6 mg,
resulted in weight reduction of 2.9 kg and 3.5 kg at day 8 post dose, respectively, with weight re-
duction maintained at day 43. The most common side effects were gastrointestinal and were mild
to moderate in severity. Based on these results, currently, LY34379943 is in phase II undergoing
further clinical development.
Entero-endocrine and endo-pancreatic hormones work in concert impacting food intake,
weight regulation, and glycemic homeostasis. Combining the hormones may be an approach
that targets the many intertwined mechanisms of obesity. A multitude of novel multi-hormone
therapeutics are in the pipeline (Figure 1).

SUMMARY: A NEW ERA OF HORMONE-BASED OBESITY

PHARMACOTHERAPY
An auspicious era of highly effective nutrient-stimulated hormone-based obesity pharmacother-
apeutics has begun. The FDA’s and EMA’s approval of semaglutide 2.4 mg for chronic weight
management ushered in the introduction of antiobesity medications with higher efficacy; semaglu-
tide has demonstrated average placebo-subtracted weight reduction of 12.5%, with one-third of
individuals losing ≥20% body weight. Liraglutide 3.0 mg is also approved in multiple countries
for chronic weight management, and two oral GLP-1 RAs are under investigation for obesity

134 Jastreboff • Kushner

 treatment. Novel hormone-based pharmacotherapies that leverage entero-endocrine and endo-
pancreatic peptides are in various phases of development and present a mechanistic-based and
increasingly effective paradigm for the treatment of obesity. Tirzepatide, a novel single-molecule
GIP/GLP-1 receptor agonist, demonstrated average placebo-subtracted weight reduction of
17.8% with more than half of individuals losing ≥20% body weight. Cagrilintide, an amylin re-
ceptor agonist, when combined with semaglutide, resulted in 17.1% weight reduction versus 9.8%
with semaglutide alone in a phase Ib trial. Thus, by combining or coformulating entero-endocrine
and endo-pancreatic peptides as dual or triple receptor agonists, we can target the multifaceted
pathophysiology of obesity, resulting in reregulation of physiology and resetting of the defended
fat mass set point with ensuing sustained weight reduction and improved metabolic and overall
health. With innovative hormone-based obesity pharmacotherapy presenting great promise for
effective and sustainable weight management, this is truly an exciting and propitious time to be
caring for individuals with the disease of obesity.
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SUMMARY POINTS
1. Hormone-based pharmacotherapy that leverages entero-endocrine and endo-pancreatic
nutrient-stimulated peptides that govern the gut–brain axis presents a novel, mechanism-
based, and increasingly effective paradigm for the treatment of obesity.
2. Two monotherapy GLP-1 RAs, liraglutide and semaglutide, are currently approved for
chronic weight management, producing average placebo-subtracted weight reduction of
5.2% and 12.5%, respectively. Two oral formulations with GLP-1 RA action are under
investigation for weight management.
3. Tirzepatide, a novel single-molecule GIP/GLP-1 receptor agonist, demonstrated av-
erage placebo-subtracted weight reduction of 17.8% with most subjects losing ≥20%
body weight. Combinations or coformulations of nutrient-stimulated hormones such
as GLP-1, GIP, amylin, and/or glucagon as dual or triple receptor agonists target the
multifaceted pathophysiology of obesity.

DISCLOSURE STATEMENT
A.M.J. serves on scientific/medical advisory boards for Boehringer Ingelheim, Novo Nordisk, Eli
Lilly, Pfizer, Rhythm Pharmaceuticals, WW, and IntelliHealth; serves as a consultant for Scholar
Rock; and receives institutional research support from Eli Lilly, Novo Nordisk, and Rhythm Phar-
maceuticals. R.F.K. serves on scientific advisory boards for Novo Nordisk and WW and serves as
a consultant for Altimmune, Pfizer, and Eli Lilly.

ACKNOWLEDGMENTS
A.M.J. acknowledges institutional research support from the National Institutes of Health/
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099039 and R01
DK117651).

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Annual Review of
Medicine

Contents Volume 74, 2023

COVID-19 and Kidney Disease

Maureen Brogan and Michael J. Ross p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
COVID-19 Thrombotic Complications and Therapeutic Strategies
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Alexander C. Fanaroff and Renato D. Lopes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p15

Annu. Rev. Med. 2023.74:125-139. Downloaded from www.annualreviews.org

COVID-19: Challenges of Viral Variants

Jana L. Jacobs, Ghady Haidar, and John W. Mellors p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p31
Post-COVID-19 Condition
Ani Nalbandian, Amar D. Desai, and Elaine Y. Wan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p55
SARS-CoV-2 Vaccination-Induced Thrombotic Thrombocytopenia:
A Rare but Serious Immunologic Complication
Charles S. Abrams and Geoffrey D. Barnes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Endocrine Disorders and COVID-19
Seda Hanife Oguz and Bulent Okan Yildiz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75
Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and
Treatment in Transplant Recipients
Jennifer L. Saullo and Rachel A. Miller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Gender-Affirming Care of Transgender and Gender-Diverse Youth:
Current Concepts
Janet Y. Lee and Stephen M. Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Update in Adult Transgender Medicine
Alyxandra Ramsay and Joshua D. Safer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 117
New Frontiers in Obesity Treatment: GLP-1 and Nascent
Nutrient-Stimulated Hormone-Based Therapeutics
Ania M. Jastreboff and Robert F. Kushner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125
Advances and Applications of Polygenic Scores for Coronary
Artery Disease
Aniruddh P. Patel and Amit V. Khera p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 141
Valvular Heart Disease: New Concepts in Pathophysiology and
Therapeutic Approaches
Mackram F. Eleid, Vuyisile T. Nkomo, Sorin V. Pislaru, and Bernard J. Gersh p p p p p p p p p 155

v
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Myocardial Infarction with Nonobstructive Coronary Arteries

H.R. Reynolds and N.R. Smilowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Lessons Learned from the ISCHEMIA Trial for the Management of
Patients with Stable Ischemic Heart Disease
William E. Boden and Peter H. Stone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Maternal Mortality in the United States: Trends and Opportunities
for Prevention
Siwen Wang, Kathryn M. Rexrode, Andrea A. Florio, Janet W. Rich-Edwards,
and Jorge E. Chavarro p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 199
Primary Aldosteronism and the Role of Mineralocorticoid Receptor
Antagonists for the Heart and Kidneys
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Jordana B. Cohen, Irina Bancos, Jenifer M. Brown, Harini Sarathy,

Annu. Rev. Med. 2023.74:125-139. Downloaded from www.annualreviews.org

Adina F. Turcu, and Debbie L. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 217

Adeno-Associated Virus Gene Therapy for Hemophilia
Benjamin J. Samelson-Jones and Lindsey A. George p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 231
Clonal Hematopoiesis and Its Impact on Human Health
Herra Ahmad, Nikolaus Jahn, and Siddhartha Jaiswal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249
Hepcidin and Iron in Health and Disease
Elizabeta Nemeth and Tomas Ganz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 261
Multispecific CAR T Cells Deprive Lymphomas of Escape
via Antigen Loss
Fateeha Furqan and Nirav N. Shah p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
FGFR2 Inhibition in Cholangiocarcinoma
Arndt Vogel, Oreste Segatto, Albrecht Stenzinger, and Anna Saborowski p p p p p p p p p p p p p p p p 293
Regulation of Erythropoiesis by the Hypoxia-Inducible Factor
Pathway: Effects of Genetic and Pharmacological Perturbations
Gregg L. Semenza p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
Cytokine Storm Syndrome
Randy Q. Cron, Gaurav Goyal, and W. Winn Chatham p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
Systemic Lupus Erythematosus: New Diagnostic and Therapeutic
Approaches
Stephanie Lazar and J. Michelle Kahlenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Genetics of Kidney Disease: The Unexpected Role of Rare Disorders
Mark D. Elliott, Hila Milo Rasouly, and Ali G. Gharavi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
SGLT2 Inhibitors: The Sweet Success for Kidneys
Atit Dharia, Abid Khan, Vikas S. Sridhar, and David Z.I. Cherney p p p p p p p p p p p p p p p p p p p p p 369

vi Contents
ME74_FrontMatter ARjats.cls December 6, 2022 14:53

Use of Race in Kidney Function Estimation: Lessons Learned and the

Path Toward Health Justice
Dinushika Mohottige, Opeyemi Olabisi, and L. Ebony Boulware p p p p p p p p p p p p p p p p p p p p p p p p p 385
Origins of Racial and Ethnic Bias in Pulmonary Technologies
Michael W. Sjoding, Sardar Ansari, and Thomas S. Valley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 401
Cystic Fibrosis Modulator Therapies
Shijing Jia and Jennifer L. Taylor-Cousar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413
Club Cell Secretory Protein in Lung Disease: Emerging Concepts
and Potential Therapeutics
Tereza Martinu, Jamie L. Todd, Andrew E. Gelman, Stefano Guerra,
and Scott M. Palmer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 427
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Annu. Rev. Med. 2023.74:125-139. Downloaded from www.annualreviews.org

Chronic Neuromuscular Respiratory Failure and Home Assisted

Ventilation
Hugo Carmona, Andrew D. Graustein, and Joshua O. Benditt p p p p p p p p p p p p p p p p p p p p p p p p p p p 443
Biological Phenotyping in Sepsis and Acute Respiratory
Distress Syndrome
Pratik Sinha, Nuala J. Meyer, and Carolyn S. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Diverse Approaches to Gene Therapy of Sickle Cell Disease
Shanna L. White, Kevyn Hart, and Donald B. Kohn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 473
Exome/Genome Sequencing in Undiagnosed Syndromes
Jennifer A. Sullivan, Kelly Schoch, Rebecca C. Spillmann, and Vandana Shashi p p p p p p p p 489
All the Tau We Cannot See
Bradley Hyman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 503

Indexes

Cumulative Index of Contributing Authors, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p 515

Cumulative Index of Article Titles, Volumes 70–74 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://www.annualreviews.org/errata/med

Contents vii