Cvac 176

Cardiovascular Research (2022) 00, 1–18 INVITED SPOTLIGHT REVIEW
https://doi.org/10.1093/cvr/cvac176
New therapies for obesity

1 2,3 4
Dimitris Papamargaritis *, Carel W. le Roux , Jens J Holst ,
Downloaded from https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvac176/6854907 by guest on 29 November 2023

and Melanie J Davies 1
1
Diabetes Research Centre, Leicester General Hospital, University of Leicester College of Medicine Biological Sciences and Psychology, Leicester LE5 4PW, UK; 2Diabetes Complications Research
Centre, Conway Institute, University College Dublin, Dublin 4, Ireland; 3Diabetes Research Centre, Ulster University, Coleraine BT52 1SA, UK; and 4Department of Biomedical Sciences and the
NNF Center for Basic Metabolic Research, University of Copenhagen Panum Institute, Copenhagen 2200, Denmark
Received 1 June 2022; revised 16 September 2022; accepted 19 October 2022; online publish-ahead-of-print 30 November 2022
Abstract Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss (WL) through lifestyle
changes results in modest WL long-term possibly due to compensatory biological adaptations (increased appetite and reduced
energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted
in ≥ 15% WL and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development
of new medications over the last decade for the treatment of obesity with main target the reduction of appetite. The efficacy
of semaglutide 2.4 mg/week—the latest glucagon-like peptide-1 (GLP-1) receptor analogue—on WL for people with obesity sug-
gests that we are entering a new era in obesity pharmacotherapy where ≥15% WL is feasible. Moreover, the WL achieved with the
dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently
also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional WL compared with GLP-1 recep-
tor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between
bariatric surgery and the currently available pharmacotherapies.
-Keywords
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Obesity • Pharmacotherapy • Bariatric surgery • Semaglutide • Tirzepatide • Liraglutide
1. Introduction intervention. Recent clinical trials with advanced therapeutic candidates in-
cluding new glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dual
Obesity is a complex, chronic, progressive, and relapsing disease character- agonists demonstrate that the gap of sustained WL between bariatric sur-
ized by abnormal or excessive body fat that impairs health.1 It is one of the gery and pharmacotherapy is gradually closing.14,15
greatest global public health challenges, considering that 13% of the global Here, we review the available interventions for WL and weight mainten-
population lives with obesity and that its prevalence has been tripled since ance with a focus on pharmacological therapies for obesity approved over
1975.2 Obesity drives the pathogenesis of multiple metabolic and mechan- the last decade as well as the emerging development of new obesity phar-
ical complications including type 2 diabetes (T2D), hypertension, dyslipi- macotherapies. We also discuss the future directions of obesity pharmaco-
daemia, sleep apnoea, cardiovascular disease, non-alcoholic fatty liver therapy and the research priorities to support implementation of these
disease, infertility, and osteoarthritis3 which result in a decreased life ex- treatments in clinical practice.
pectancy of 5–20 years and increased healthcare costs.4–7
Lifestyle interventions are the cornerstones for the management of obes-
ity, but even the most intensive programmes still commonly only achieve 2. Obesity treatments
5–10% weight loss (WL) and long-term weight maintenance remains a chal-
lenge.8 Although 5–10% WL reduces cardiometabolic risk factors it may not 2.1 Lifestyle interventions
be enough to make a difference to the lives of people with BMI ≥35 kg/m2 Lifestyle interventions usually include support for health-improving behav-
(Class II obesity and above) and/or to reverse some obesity-related compli- ioural changes including diet, increasing physical activity, and reducing sed-
cations such as sleep apnoea and T2D.9,10 Until recently, pharmacotherapy entary time. Moderate intensity lifestyle interventions such as 500–600 kcal
to achieve and maintain ≥10% WL along with suitable tolerability and safety deficit diet together with advice to increase physical activity to 150 min/week
remained an unmet challenge. Bariatric surgery was the only intervention usually lead to a WL of 2–5% at 12 months and weight maintenance remain
that consistently resulted in ≥15% WL and weight maintenance long- a challenge.
term.11 This amount of WL led to improved quality of life (QoL), significant Intensive lifestyle interventions, which often include partial or total meal
health benefits and reduced mortality.11–13 Despite the considerable bene- replacements, intensive behavioural therapy (IBT), and/or structured exer-
fits of bariatric surgery, it is not feasible or scalable as a population-wide cise, can lead up to ≈10% WL at the end of the first year.16,17
* Corresponding author. Tel: +44 (0)116 258 8973, E-mail: [email protected]

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution,
and reproduction in any medium, provided the original work is properly cited.
2 D. Papamargaritis et al.
In the DROPLET study, a community delivered, low energy (810 kcal/day) the weight-reduced state results in a feeling of constant and exhausting ef-
total diet replacement programme with formula products as the sole food fort to maintain the achieved WL and to prevent the seemingly unavoid-
during the first 8 weeks followed by food reintroduction resulted in mean able weight regain over time.30,32
WL of 10.7 kg at 12 months compared with 3.1 kg at the usual care group RMR is mainly determined by body composition and accounts for
in people with obesity.18 However, at the 3-year follow-up, mean WL was 60–70% of 24 h total energy expenditure in humans.31,33 However, RMR
6.2 kg at the intervention arm compared with 2.7 kg at the usual care19 with in response to WL is often reduced to a greater extent than would be ex-
24% of participants achieving ≥10% WL in the total diet replacement pro- pected based on the measured changes in body composition. This physio-
gramme compared with 13% in usual care, suggesting that for this smaller logical mechanism is called ‘metabolic adaptation’ and is one of the reasons
number of patients this treatment was effective.19 why the body resists further WL and individuals regain weight so easily.33
For example, the participants of the ‘Biggest Loser’ television program lost,

Structured exercise programmes can usually add 1.5–3.5 kg WL to a
dietary intervention, and they have multiple other health benefits such as on average, 40% of their body weight, and their mean RMR decreased by
improvement in body composition, physical function, and cardiorespira- 610 kcal/day—this was on average 275 kcal/day lower compared with
tory fitness.20 There is limited evidence on the effect of structured exercise what was expected based on their body composition.34 This metabolic
on weight maintenance after weight-loss through diet,20 but a recent clin- adaptation persisted 6 years later despite regaining two-thirds of the lost
ical trial showed that the addition of a 52-week structured but flexible aer- weight.33,34
obic exercise programme after a low-calorie diet programme (mean WL In addition, most people who manage to lose ≥10% of their body weight
12%) can lead to 4.1 kg less weight gain compared with people who con- through low-calorie diet experience an increase in their appetite compared
tinue with their usual physical activity.21 However, long-term maintenance with baseline (Figure 1).35 Potential mediators of the increased appetite are
of the recommended amount of moderate to vigorous physical activity can the elevated levels of the hunger hormone ghrelin as well as the reduction
be challenging.22 in leptin and perhaps also satiety gut hormones such as peptide YY (PYY),
The largest trial assessing the effectiveness of intensive lifestyle interven- amylin, and cholecystokinin.35 These changes remain even after 52 weeks
tions was the Look AHEAD study, where 5145 people with obesity and from the completion of the low-calorie diet and despite that participants
T2D were randomized to receive intensive lifestyle support (intervention experience weight regain, for instance, 5.5 kg at the end of the cited
group) vs. a structured education programme (usual care group).23 The in- study.35 Studies assessing the appetite-related responses during and after
tensive lifestyle group lost 8.6% of their initial body weight at 1 year and single bouts of continuous aerobic exercise indicate that subjective feelings
4.7% at 8 years while the usual care arm lost 0.7% at 1 year and 2.1% at of appetite are transiently suppressed during exercise in people with obes-
8 years.8 In the intensive lifestyle group, 37.7% of study participants ity; but energy intake is minimally affected.36,37 Regarding the chronic ef-
achieved ≥10% WL at 1-year post-operatively, and 39.3% of them (324/ fects of aerobic exercise on appetite parameters, the results are
2144, 15.1% of the total population at the intensive lifestyle group) were inconsistent—however, a small increase in hunger at fasting state with a
able to maintain ≥10% WL for 8 years.8 subsequent increase in satiety post-meal and without significant increase
Overall, the Look AHEAD intervention did not demonstrate a reduction on energy intake has been found in a recent systematic review and
in cardiovascular events or a reduction at the risk for new onset heart fail- meta-analysis.36,38
ure or atrial fibrillation.24–26 However, in a post-hoc analysis, those parti- Increased appetite likely plays a quantitatively greater role on weight re-
cipants in the intervention arm who lost ≥10% of their baseline body gain than the decreased energy expenditure because the feedback circuits
weight during the first year (early good responders) had 20% lower risk controlling long-term energy intake have greater overall strength com-
for cardiovascular events over a 10 years follow-up period.27 Similarly, a pared with the feedback circuits controlling energy expenditure.30,32 So,
10% decrease in BMI over the first year in participants at the Look if we consider obesity as a disease of dysregulated appetite where the in-
AHEAD study was associated with a 31% lower risk of incident heart fail- creased hunger and/or the reduced satiety are the main symptoms,39 then
ure, when a 10% decrease in BMI over a 4-year follow-up period was as- lifestyle interventions which usually result in increase of appetite may not
sociated with a 20% lower risk of incident heart failure.25 These results effectively treat the symptoms of the underlying disease and this will lead
suggest that ≥10% WL is associated with cardiovascular benefits for peo- in the majority of the cases to weight regain long-term despite the success-
ple with obesity and T2D. Moreover, the REVERSE-AF study also showed ful initial WL. However, WL maintenance can occur in a smaller number of
that ≥10% weight reduction results in 88% reversal from persistent to par- people who despite WL with lifestyle interventions do not experience in-
oxysmal or no atrial fibrillation.28 creased appetite, suggesting that lifestyle interventions can also be consid-
In general, weight regain is common after lifestyle interventions and ap- ered as effective obesity treatments in a small number of patients and that
proximately 80% of weight lost is expected to be regained over the next 5 there is individual variability in response to different lifestyle interventions
years.29 Only 10–25% of individuals who will undergo different intensity regarding appetite signals and weight regain.31,40
lifestyle interventions will be able to lose and maintain ≥10% WL long- Anti-obesity medications can also effectively treat obesity by counter-
term. The rest of individuals could be considered non-responders to the acting the increased drive to eat and the impaired satiation associated
lifestyle intervention and will need further interventions to achieve and with WL by lifestyle changes and could help with further WL and weight
maintain significant WL. maintenance.41–43 However, as with most management techniques for
chronic diseases, obesity relapses if the treatment is stopped.44
2.1.1 Why is it so challenging to maintain weight loss

with lifestyle changes? 2.2 The example of bariatric surgery
The weight regain after significant WL with lifestyle changes is not simply Bariatric surgery is a collective term for surgical treatment of obesity. It is
attributable to the loss of motivation or compliance from the patients. so far the most successful existing approach for safe and effective obesity
Instead, it is driven by potent biological mechanisms that stimulate food in- treatment and results in sustained WL while at the same time reduces ap-
take and reduce energy expenditure on the background of an ‘obesogenic’ petite.11,45 In the Swedish obese subjects (SOS) study, bariatric surgery was
environment, where ultra-processed, high-calorie foods are easily access- able to induce and maintain ≥15% mean WL over 20 years follow-up
ible, physical activity is reduced and sedentary time increased.30,31 The ma- (compared with 1% WL at the usual care group).11 This amount of sus-
jor drivers of weight regain after treatments that caused significant WL, tained WL was associated with improvement in QoL and obesity-related
include the persistence of a lower resting metabolic rate (RMR) (metabolic complications, reduction by 53% in fatal and 33% in total cardiovascular
adaptation), the lower energy consumption during weight-bearing activ- events, and reduction by 29% in mortality compared with the usual care
ities, and the persistence of increased appetite, probably mediated through group,11,12,46,47 providing a WL threshold associated with multiple clinically
long-lasting increased orexigenic and decreased anorexic signals.30,31 important benefits. Moreover, bariatric surgery in SOS study reduced the
Overall, the increased appetite and the reduced energy expenditure during risk for new onset heart failure by 35% and for new diagnosis of atrial
New therapies for obesity 3

Figure 1 The effect of different weight loss interventions [low-calorie diet, exercise, pharmacotherapy (GLP-1 receptor analogues), and bariatric surgery] on
appetite.
fibrillation by 29% compared with the usual care group.48,49 The benefits of understanding over the last years of the peripheral and central signals
bariatric surgery on reducing cardiovascular events, cardiovascular death, and mechanisms involved in WL and WL maintenance have contributed
all-cause mortality and new onset heart failure compared with the non- to the development of more effective and safe weight-loss medications.
surgical management are consistent across multiple observational, Orlistat, which was approved in 1999 for obesity treatment have demon-
matched-cohort studies, especially in people with obesity and T2D.50,51 strated its safety and efficacy in multiple trials, but it has, at best, modest
The most commonly performed bariatric procedures in the SOS study effect (WL 3–5%) as result of reduced absorption of ingested fat and be-
were gastric band and vertical banded gastroplasty with fewer patients havioural changes (to avoid steatorrhea).60
undergoing Roux-en-Y gastric bypass (RYGB).11 Today, the two most Over the past decade, several agents that act by reducing hunger or pro-
commonly performed bariatric procedures (≈85% of bariatric procedures mote satiation have been approved by regulatory authorities worldwide
worldwide) are sleeve gastrectomy (SG) and RYGB.52 RYGB results in 30% for chronic weight management, including phentermine plus topiramate
WL over the first post-operative year and a sustained 25–27% WL long- (approved only in the USA), bupropion plus naltrexone, and the GLP-1
term.11,53 SG leads to 25% WL at the first post-operative years and around RAs liraglutide 3 mg and semaglutide 2.4 mg.
20% WL long-term.53 WL and WL maintenance after bariatric surgery are
achieved as a consequence of voluntary reduced food intake due to re-
2.3.1 Phentermine-topiramate
duced appetite (Figure 1) rather than through restriction, malabsoprtion
or increased energy expenditure.54 One of the potential mediators for Phentermine-topiramate (PHEN-TPM) is an oral medication approved for
the reduced appetite and food intake after bariatric surgery is the changes obesity treatment in the USA, but not in Europe due to concerns about the
in the peripheral signals of body weight regulation (how the gut communi- medication’s long-term cardiovascular safety. The fixed-dose combination
cates with the brain) through alteration of gut anatomy. More specifically, approved in the USA contains PHEN doses from 3.75 to 15 mg and TPM
both RYGB and SG substantially increase the secretion of multiple satiety doses from 23 to 92 mg for daily administration.
gut hormones after food intake, including GLP-1 and PYY and when the PHEN is a sympathomimetic amine which acts as an appetite suppres-
action of these hormones was blocked after RYGB, the food intake in- sant via the central nervous system.61 It is indicated for short-term use
creased by 20%,55 supporting a role of these gut hormones in early post- in weight management in USA, however, long-term data are not available.
prandial satiety. TPM is an anticonvulsant indicated for use in the treatment of migraine and
However, not every person with severe and complex obesity wants or is epilepsy.61 One of the known effects of TPM is also a decrease in appetite.
fit enough to undergo surgery, and there is no surgical capacity to operate In people without diabetes, 56 weeks of PHEN-TPM 15/92 extended re-
on every person that qualifies for bariatric surgery. So, pharmacotherapies lease (ER) in combination with 500 kcal/day deficit diet resulted in 10.9%
mimicking some of the post-operative physiological changes after bariatric WL compared with 1.6% with placebo and 32.3% of participants achieved
surgery would be a logical approach to try to achieve similar WL. more than ≥15% WL.62 Similar results were reported at the 2-year follow-
up of PHEN-TPM 15/92 ER63 (Table 1).
In people with T2D, 56 weeks of PHEN-TPM ER 15/92 reduces body
weight by 9.6% compared with 2.6% with placebo and improved HbA1c
2.3 Approved pharmacotherapies for by 1.6% (17.5 mmol/mol) compared with 1.2% (13.1 mmol/mol) with pla-
obesity over the last decade cebo78 (Table 2). The most commonly reported adverse events are upper
Numerous obesity medications targeting appetite and reward centres have respiratory tract infection, constipation, insomnia, paraesthesia, sinusitis,
been tried in the past to support WL but the majority has been withdrawn taste change and dry mouth.62–64 PHEN-TPM has also a warning of birth
due to safety concerns.56–58 For example, sibutramine was withdrawn due defects (cleft lip and palate) in the offspring of pregnant women taking
to increased risk of cardiovascular events (myocardial infarction and non- the medication, due to the known teratogenic effect of TPM.
fatal stroke) in people with obesity and pre-existing cardiovascular condi- The improvement in weight with PHEN/TPM was associated with
tions when rimonabant was withdrawn due to increased risk of psychiatric improvements in QoL89 and cardiometabolic risk factors.62–64 A retro-
adverse events including depressed mood disorders, anxiety, and sui- spective analysis of PHEN used concurrently with TPM, either separately
cide.57,58 More recently, lorcaserin was withdrawn from the market be- or in fixed-dose combination showed a trend for a lower rate of major ad-
cause of a signal of increased cancer risk.59 Nevertheless, the better verse cardiovascular events (MACE) and other cardiovascular outcomes
4
Table 1 Large multi-centre clinical trials for approved obesity pharmacotherapies over last decade and tirzepatide in populations without diabetes (or with majority
of participants without diabetes)
Lifestyle Comparator Duration BMI baseline WL (drug/ ≥5% WL (%) ≥ 10% WL ≥ 15% WL Comment
intervention (week) (drug/ comparator) (drug/ (%) (%)
comparator) ETD vs. comparator) (drug/ (drug/
comparator comparator) comparator)
..........................................................................................................................................................................................................................................................
Phentermine/
Topiramate ER
3.75/23, 7.5/46, or
15/92
Gadde, 201164 500 kcal/day deficit vs. placebo 56 36.6/36.7 −7.8% to −9.8%/ 62–70/21 37–48/7 NR 15.6% of participants had T2D
CONQUER diet + advise for PA −1.2%
(7.5/46 and 15/92) ETD: −6.6% to
– 8.6%
Allison, 201262 500 kcal/d deficit diet vs. placebo 56 41.9–42.6/42.0 −5.1% to −10.9%/ 44.9–66.7/17.3 18.8–47.2/7.4 7.3–32.3/3.4
EQUIP + advise for PA −1.56%
(3.75/23 and 15/92) ETD: −3.54%
to −9.34%
Garvey 201263 500 kcal/d deficit diet vs. placebo 108 36.1–36.2/36 −9.3% to −10.5%/ 75.2–79.3/30 50.3–53.9/11.5 24.2–31.9/6.6
SEQUEL + advise for PA −1.8%
(7.5/46 and 15/92) ETD: −7.5% to
–9.7%
Naltrexone/
Buproprion SR
16/360 or 32/360
Greenway 201065 500 kcal/d deficit diet vs. placebo 56 36.1–36.2/36.2 −5.0% to −6.1%/ 39–48/16 20–25/7 9–12/2
COR-I + advise for PA −1.3%
(16/360 and 32/360) ETD: - 3.7% to
−4.8%
Apovian 201366 500 kcal/d deficit diet vs. placebo 56 36.2/36.1 −6.4%/−1.2% 50.5/17.1 28.3/5.7 13.5/2.4 Primary outcome was at 28
COR-II + advise for PA ETD: −5.2% weeks
(32/360)
Wadden 201167 IBT-28 group sessions vs. placebo 56 36.3/37 −9.3%/−5.1% 66.4/42.5 41.5/20.2 29.1/10.9
COR-BMOD plus calorie deficit ETD: −4.2%
(32/360) diet and advise for
PA
Liraglutide 3mg
Pi-Sunyer 201568 500 kcal deficit diet + vs. placebo 56 38.3/38.3 −8.0%/−2.6% 63.2/27.1 33.1/10.6 14.4/3.5
SCALE-Obesity advise for PA ETD: −5.4%
Le Roux 201769 500 kcal deficit diet + vs. placebo 160 38.8/39.0 −6.1%/−1.9% 49.6/23.7 24.8/9.9 11/3.1 79% reduction at the risk of
SCALE-pre-diabetes advise for PA ETD: −4.3% developing diabetes in
people with pre-diabetes
Continued
D. Papamargaritis et al.

Table 1 Continued
Lifestyle Comparator Duration BMI baseline WL (drug/ ≥5% WL (%) ≥ 10% WL ≥ 15% WL Comment
intervention (week) (drug/ comparator) (drug/ (%) (%)
comparator) ETD vs. comparator) (drug/ (drug/
comparator comparator) comparator)
..........................................................................................................................................................................................................................................................
Wadden 202070 IBT-23 brief sessions vs. placebo 56 39.3/38.7 −7.5%/−4.0% 61.5/38.8 30.5/19.8 18.1/8.9
SCALE-IBT plus diet 1200– ETD: −3.4%

1800 kcal/d + advise
for PA
Wadden 2013 41 500kcal deficit diet vs. placebo 56 36/35.2 −6.2%/−0.2% 50.5/21.8 26.1/6.3 NR Weight maintenance study—
SCALE −Maintenance after achieving ≥5% ETD: −6.1% participants randomized
WL with 1200– after they have achieved
1400kcal diet ≥5% weight loss with diet
Blackman 201671 500 kcal deficit diet + vs. placebo 32 38.9/39.4 −5.7%/−1.6% 46.3/18.5 23.4/1.7 NR Apnoea hypopnea Index
SCALE sleep apnea advise for PA ETD: −4.2% (events/hour) reduced by
6.1 events/hour
Kelly 202072 Individualized vs. placebo 56 35.3/35.8 −2.65%/ +2.37% 43.3/18.7 26.1/8.1 NR Participants were adolescents
Liraglutide for counselling on ETD: −5.01% 12 to <18 years old
Adolescents with healthy nutrition +
Obesity advise for PA for
60 min/d
Semaglutide 2.4mga
Wilding, 202115 500 kcal/day deficit vs. placebo 68 37.8/38.0 −14.9%/−2.4% 86.4/31.5 69.1/12 50.5/4.9
STEP-1 diet + advise for PA ETD: −12.4%
Wadden 201373 Low-calorie diet vs. placebo 68 38.1/37.8 −16%/−5.7% 86.6/47.6 75.3/27 55.8/13.2
STEP-3 (1000–1200 kcal) ETD: −10.3%
for 8 weeks and IBT
(30 counselling
sessions)
Rubino, 202174 500 kcal/day deficit vs. placebo 0 →68 38.4 −17.4%/−5.0% 88.7/47.6 79/20.4 63.7/9.2 Medication withdrawal study
STEP-4 diet + advise for PA 20→68 34.5/34.1 −7.9%/ +6.9% —all participants received
ETD: −14.8% Semaglutide 2.4 mg for 20
weeks and then randomized
to placebo vs. Semaglutide
2.4 mg for next 48 weeks
Kadowaki 202275 STEP-6 500 kcal/day deficit vs. placebo 68 86.9/90.2 −13.2%/−2.1% 83/21 61/5 41/3 Study in East Asian population
diet + advise for PA ETD: −11.06% (Japan, South Korea) − 25%
of participants had T2D
Rubino, 202276 500 kcal/day deficit vs. 68 37/37.2 −15.8%/−6.4% 87.2/58.1 70.9/25.6 55.6/12.0
STEP-8 diet + advise for PA liraglutide ETD: −9.4%
3mg
Continued
5

among those receiving PHEN/TPM (including the fixed-dose combination)
..........................................................................................................................................................................................................................................................
than among the unexposed cohort (HR: 0.24; 95% CI, 0.03 to 1.70 for
fixed-dose PHEN-TPM).90 However, the cardiovascular safety of this
treatment requires evaluation in an adequately powered outcome trial.
Comment
2.3.2 Naltrexone-buproprion
Naltrexone is an opioid receptor antagonist that is approved for the treat-
ment of alcohol and opioid dependence.91 Bupropion is a dopamine and
norepinephrine reuptake inhibitor that was first approved for the treat-

ment of depression and later for smoking cessation.91 The exact mechan-
ism whereby the naltrexone/bupropion (NB) combination leads to WL is
comparator)
≥ 15% WL
48.0–70.6/8.8
not fully understood, but it is likely that it promotes satiety, reduces food
(drug/
intake and may enhance energy expenditure through actions at the hypo-
(%)
thalamus and mesolimbic dopamine circuit. Participants in clinical trials

who responded to NB as an obesity treatment reported feeling less hungry
and more full compared with those receiving placebo and they found it eas-
ier to control their food cravings.65
comparator)
68.5–83.5/18.8
≥ 10% WL
In people without diabetes, NB 32/360 together with a 500 kcal deficit

(drug/
(%)
diet resulted in 6.3% WL at 52 weeks compared with 0.9% in the placebo

group.65 In COR-I and COR-II studies, 25–28.3% of those on NB 32/360
achieved ≥10% WL.65,66 Additionally, NB 32/360 in combination with an
WL, weight loss; ER, extended release; SR, slow release; ETD, estimated treatment difference; PA, physical activity; IBT, intensive behavioural therapy; T2D, type 2 diabetes.
IBT program and diet resulted in 9.3% WL vs. 5.1% with placebo.67 In peo-
comparator)
≥5% WL (%)
85.1–90.9/34.5
ple with obesity and T2D, NB 32/360 resulted in 5% mean WL at 56 weeks

compared with 1.8% with placebo.79 26.3% of participants receiving NB
(drug/
32/360 achieved ≥10% WL and HbA1c was reduced by 0.6% compared

with 0.1% in those receiving placebo.79
The most common adverse events with NB 32/360 are nausea, head-
ache, constipation, dry mouth, anxiety, dizziness, hypertension, and vomit-
−20.9%/−3.1%
comparator)
ing.65,79 The NB is contraindicated in people with epilepsy as buproprion is

comparator
ETD: −11.9%
WL (drug/
ETD vs.
to −17.8%
associated with dose-related risk of seizures.

−15.0% to
Physical function and self-esteem improved with NB 32/360 compared

with placebo.92,93 The WL achieved with NB 32/360 was also associated
with improvements in some cardiometabolic risk factors such as HDL
and hepatic insulin resistance markers, however the systolic blood pressure
(SBP) and diastolic blood pressure improved more in the placebo group
comparator)
BMI baseline
37.4–38.2/38.2
compared with the NB 32/360.66

(drug/
A clinical trial on cardiovascular outcomes for NB was terminated early

due to early release of the interim analysis performed after 50% of planned
events (HR 0.88; adjusted 99.7% CI 0.57–1.34 compared with placebo).94
So, the cardiovascular safety of NB remains uncertain and will require fur-
ther revaluation in adequately powered outcome trials.
Duration
(week)
2.3.3 Currently approved pharmacotherapies for

72
obesity based on gut hormones

Comparator
2.3.3.1 GLP-1 receptor agonists

GLP-1 is an incretin hormone secreted predominantly from L cells located
vs. placebo
in the small intestine in response to food intake.95 In addition to the

glucose-lowering actions such as stimulation of glucose-induced insulin se-
cretion, delay in gastric emptying and inhibition of glucagon secretion, ex-
ogenous GLP-1 infusion in humans resulted recurrently in reduced calorie
diet and advise for
intake, reduced appetite and effects on the reward system without direct
500 kcal/day deficit
intervention
changes in energy expenditure.96–98

Lifestyle
GLP-1 RAs have been developed initially for the treatment of T2D, how-
Data presented as treatment-policy estimand.
ever due to their efficacy in inducing WL and reducing appetite, they have
been repurposed in higher doses as treatments for obesity. Exogenous
PA
GLP-1 and GLP-1 RAs may predominantly access the brain via the leaks
in the blood–brain barrier, where the underlying neuronal tissue shows a
Continued
Tirzepatide 5–15mga
dense expression of GLP-1 receptors. In animal experiments, the effect

of GLP-1 RAs on food intake is entirely dependent on central nervous sys-
SURMOUNT-177
tem mechanisms,99 and in humans this is supported by imaging

Jastreboff A, 2022
experiments.100,101
Table 1
2.3.3.2 Liraglutide 3 mg
In 2014, liraglutide 3 mg once daily became the first GLP-1 RA to be ap-
a
proved for the treatment of adults with obesity and in 2021 it was also
Table 2 Large multi-centre clinical trials for approved obesity pharmacotherapies over last decade and tirzepatide in people with type 2 diabetes
Lifestyle Comparator Background Duration BMI baseline Weight loss HbA1c (%) HbA1c (%) ≥ 10% WL ≥ 15% WL HbA1c ≤ 7%
change therapy (week) (drug/ (drug/ baseline change (%) (%) (drug/
comparator) comparator) (drug/ (drug/ (drug/ (drug/ comparator)
ETD vs. comparator) comparator) comparator) comparator)
comparator
..........................................................................................................................................................................................................................................................
Phentermine/
Topiramate
ER 15/92
Garvey 201478 500 kcal/day vs. placebo Diet ± oral glucose 56 35.5/35.2 −9.6%/−2.6% 8.8/8.5 −1.6%/−1.2% 37/9 NR 53/40
OB-202/DM-230 deficit diet lowering meds ETD: −7% ETD: −0.4%
and advise
for PA
Naltrexone/
Buproprion
SR 32/360
Hollander 201379 500 kcal/d vs. placebo Not on or stable dose 56 36.7/36.3 −5.0%/−1.8% 8.0/8.0 −0.6%/−0.1% 26.3/8.0 44.1/26.3
COR-Diabetes deficit diet + glucose-lowering ETD: −3.2% ETD: −0.5%
advise for meds
PA
Liraglutide 3mg
Davies 201580 500 kcal/d vs. placebo diet + exercise or ≤ 3 56 37.1/37.4 −6.0%/−2.0% 7.9/7.9 −1.3/−0.3 25.2/6.7 NR 69.2/27.2
SCALE Diabetes deficit diet + vs. liraglutide oral 37.1/37.4 ETD: −4% 7.9/8.0 ETD: −0.93 25.2/15.9 69.2/66.7
advise for 1.8 mg glucose-lowering −6.0%/−4.7% −1.3/−1.1
PA meds ETD: −1.3% ETD: −0.2
Garvey 202081 IBT-23 sessions vs. placebo Basal insulin + 56 35.9/35.3 −5.8%/−1.5% 7.9/8.0 −1.1/−0.6 22.8/6.6 NR NR
SCALE-Insulin ≤ 2 oral ETD: −4.3% ETD: −0.5
glucose-lowering
meds
Semaglutide
2.4 mga
Davies 202182 500 kcal/d vs. placebo diet + exercise or ≤ 3 68 35.9/35.9 −9.64%/−3.42% 8.1/8.1 −1.6/−0.4 45.6/8.2 25.8/3.2 78.5/26.5
STEP-2 deficit diet + vs. oral 35.9/35.3 ETD: −6.21% 8.1/8.1 ETD: −1.2 45.6/28.7 25.8/13.7 78.5/72.3
advise for semaglutide glucose-lowering − 9.64%/ −1.6/−1.5
PA 1 mg meds −6.99% ETD: −0.2
ETD: −2.65%
Tirzepatide 5–
15 mg
Rosenstock 202114 No new diet or vs. placebo Diet and exercise 40 31.5– 32.2/31.7 −6.3 to −7.8 kg/ 7.80–7.97/8.05 −1.69 to −1.75/ 27 to 38/0 12 to 23/0 78–85/23
SURPASS-1a exercise −1.0 kg −0.09
programme ETD: −5.3 kg ETD: −1.6 to
to −6.8 kg −1.66
Frias 202183 Not described vs. semaglutide Metformin 40 33.8– 34.5/34.2 −7.6 to −11.2 kg/ 8.26–8.32/8.25 −2.01 to −2.3/ 34–57/24 15 to 36/8 82 to 86/79
SURPASS-2a 1mg ≥ 1500 mg/d −5.7 kg −1.86
ETD: −1.9 to ETD: −0.15 to
−5.5 kg −0.45
Continued
7

8
Table 2 Continued
Lifestyle Comparator Background Duration BMI baseline Weight loss HbA1c (%) HbA1c (%) ≥ 10% WL ≥ 15% WL HbA1c ≤ 7%
change therapy (week) (drug/ (drug/ baseline change (%) (%) (drug/
comparator) comparator) (drug/ (drug/ (drug/ (drug/ comparator)
ETD vs. comparator) comparator) comparator) comparator)
comparator
..........................................................................................................................................................................................................................................................
Ludvik 202184 Not described vs. insulin Metfromin ± SGLT-2i 52 33.4–33.7/33.4 −7 to −11.3 kg/ 8.17–8.21/8.12 −1.85 to −2.14/ 35–58/3 12 to 35/0 79–83/58
SURPASS-3a degludec +1.9 kg −1.25
ETD: −8.9 to ETD: −0.60 to
−13.2 kg −0.89
Del Prato 2021 85 Not described vs. insulin ≤ 3 oral glucose – 52 32.5–32.8/32.5 −6.4 to −10.6 kg/ 8.52–8.60/8.51 −2.11 to −2.41/ 32–59/2 13–33/ < 1 75–85/49
SURPASS-4a glargine lowering meds +1.7 kg −1.39
ETD: −8.1 to ETD: −0.72 to
−12.3kg −1.02
Dahl 202186 Not described vs. placebo Insulin glargine ± 40 33.4–33.6/33.2 −5.4 to −8.8 kg/ 8.23–8.36/8.37 −2.11 to −2.40/ 21–42/1 7–24/0 85–90/35
SURPASS-5a metformin +1.6 kg −0.86
ETD: −7.1 to ETD: −1.24 to
−10.5 kg −1.53
Inagaki N87 Not described vs. dulaglutide Diet and exercise 52 28–28.6/27.8 −5.4 to −9.4 kg/ 8.2/8.2 −2.24 to −2.57/ 34–67/3b 16–45/ < 1b 94–99/67b
a a
SURPASS 0.75mg −0.4kg −1.27
J-mono ETD: −4.9 to ETD: −1.1 to
(Japanese −8.9 kg −1.5
population)
Kadowaki T88 Not described No comparator 1 oral glucose-lowering 52 27.6–28.4 −3.8 to −10.3 kgb 8.5–8.6 −2.5 to −3b 20–64b 7–41b 93–98b
SURPASS med
J-combob
(Japanese
population)
WL, weight loss; ER, extended release; SR: slow release; ETD, estimated treatment difference; PA, physical activity; IBT, intensive behavioural therapy; T2D, type 2 diabetes; SGLT-2i: sodium-glucose co-transporters inhibitor.
a
Data presented as treatment-policy estimand.
b
Data presented as efficacy estimand, as there is no available data for treatment-policy estimand.
D. Papamargaritis et al.

approved for adolescents ≥12 years old.72 Liraglutide 3 mg is a long-acting people without diabetes.15 50.5% of those receiving semaglutide 2.4 mg
GLP-1 RA and mechanistic studies have demonstrated that it increases achieved ≥15% WL and 32% achieved ≥20% WL compared with 4.9
post-prandial satiety and fullness, reduces hunger and prospective food and 1.7%, respectively at the placebo group (Table 1).15 In direct compari-
consumption and decreases ad libitum food intake at lunch by ≈16% son with liraglutide 3 mg, semaglutide 2.4 mg results in more than double
(136 kcal).43 Moreover, the mean 24 h energy expenditure was reduced WL (Table 1, STEP-8).76 Additionally, 68 weeks of semaglutide 2.4 mg in
by ≈5% (139 kcal), which was mainly explained by the decrease in food in- combination with IBT and a low-calorie diet during the first 8 weeks re-
take and body weight (Figure 1).43 sulted in 16% WL vs. 5.7% in the placebo group.73
Liraglutide 3 mg in combination with a 500 kcal/day deficit diet resulted In people with T2D, WL with semaglutide 2.4 mg once weekly was 9.6
in 6.1–8% WL in adults without diabetes (Table 1).68,70 For people with vs. 7% with semaglutide 1 mg once weekly (dose approved for T2D treat-
ment) and 3.4% with placebo (Table 2).82 HbA1c was reduced by 1.6% at

T2D, liraglutide 3 mg resulted in 5.8%—6% WL compared with 1.5–2%
WL with placebo (Table 2).80,81 HbA1c reduced by 1.6% with liraglutide 68 weeks with semaglutide 2.4 mg compared with 1.5% with semaglutide
3 mg and 0.4% with placebo.80,81 1 mg and 0.4% with placebo (Table 2).82
Liraglutide 3 mg is also effective for weight maintenance after initial WL Why semaglutide and liraglutide are less effective in people with T2D com-
through diet intervention. In SCALE-Maintenance study, after a 5% WL ob- pared with populations without diabetes is not fully understood, but the different
tained via a diet over 4–12 weeks, liraglutide 3 mg resulted in further 6.1% population demographics in the T2D clinical trials (higher percentage of men), the
WL at 56 weeks compared with placebo (6.2 vs. 0.2%).41 use of background glucose-lowering medications that can contribute to weight
The most common side effects include mild to moderate gastrointestinal gain (such as sulphonylureas) and the reduction of glycosuria due to improve-
problems such as nausea, diarrhoea, constipation and (more rarely) vomiting ment of glycaemic control with GLP-1 RAs may contribute to these results.107
which occurred primarily within the first 4–8 weeks after initiation of liraglutide WL with semaglutide was associated with improvements in QoL and par-
treatment.68,80 Pancreatitis, a rare side effect of GLP-1 RA was reported in ticipants in the semaglutide group were more likely to have clinically mean-
0.7% of participants at liraglutide 3 mg arm [0.3 events per 100 person-years ingful within-person improvements in physical function than with placebo.15
of observation (PYO)] at the 3-year follow-up of SCALE-Prediabetes trial Mild to moderate gastrointestinal problems such as nausea, vomiting and
compared with 0.3% of participants at placebo arm (0.1 events per 100 diarrhoea were the most common side effects of semaglutide.15,108
PYO) and the vast majority of the cases were graded as mild.69 Adverse events leading to discontinuation of semaglutide 2.4 mg ranged be-
The QoL and especially the physical function improved more with use of tween 3 and 7% in STEP programme.15,73–76,82 Acute pancreatitis was re-
liraglutide 3 mg compared with placebo, with people achieving ≥15% WL ported in 0.2% of participants at the STEP-1 trial (0.2 events per 100 PYO).15
having the most benefit.102 In addition, WL with liraglutide 3 mg improves Despite the improvement in multiple cardiovascular risk factors with sema-
also multiple other obesity-related complications, including reduction in glutide 2.4 mg, the cardiovascular safety profile has not yet been confirmed in
T2D incidence by 79% in people with pre-diabetes after 3 years of treat- people with obesity. A large clinical trial (SELECT, NCT03574597) is currently
ment compared with placebo69 and reduction in apnoea-hypopnea index taking place to assess the effect of semaglutide on major cardiovascular out-
in people with sleep apnoea (however, without change in requirement of comes in people with obesity and established cardiovascular disease.
continuous positive airway pressure support).71 However, in SUSTAIN 6 study, semaglutide 1 mg in people with T2D and es-
Liraglutide 1.8 mg (dose approved for T2D treatment) was shown to re- tablished cardiovascular disease resulted in reduction of MACE by 26% com-
duce cardiovascular events in patients with T2D and established cardiovas- pared with placebo (mainly due to reduction in stroke incidence), providing
cular disease (LEADER trial) followed for up to 5 years.103 On the other some reassurance.109 In SUSTAIN-6, there was no effect of semaglutide
hand, in a 24-week clinical trial in people with chronic heart failure (left ven- 1 mg compared with placebo on hospitalization for heart failure,109 but the
tricular ejection fraction ≤45%, n = 241) with and without diabetes, liraglu- impact of semaglutide 2.4 mg in people with heart failure with preserved ejec-
tide 1.8 mg once daily did not improve the left ventricular systolic function tion fraction and obesity will be assessed at the ongoing STEP-HFpEF
compared with placebo and raised some concerns regarding cardiac safety (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials.
of the medication at this population.104 However, a subanalysis of LEADER Finally, oral semaglutide—an approved treatment for T2D at the doses of
trial [including 1667 people with T2D and heart failure at baseline, 7 and 14 mg once daily—is currently undergoing phase 3 trials as treatment
New York Heart Association (NYHA) functional Class I–III] found that for obesity at the dose of 50 mg once daily. In a phase 2, dose-finding trial,
the beneficial effects of liraglutide 1.8 mg vs. placebo on major cardiovas- 40 mg of oral semaglutide in people with T2D resulted in 6.9% WL com-
cular events and mortality were consistent in people with and without pared with 6.4% with injectable semaglutide 1 mg and 1.2% with placebo.110
heart failure and there was no difference between the two groups in hos-
pitalization for heart failure, suggesting that liraglutide 1.8mg use is safe for 2.3.4 Summary of approved pharmacotherapies for
people with T2D and heart failure (NYHA Class I–III).105
obesity management
Liraglutide 3 mg (dose approved for obesity treatment) has been shown
to improve multiple cardiometabolic risk factors, but studies to evaluate Until 2021, the approved pharmacotherapies for chronic weight manage-
cardiovascular outcomes in people with obesity have not been done. An ment (PHEN/TPM, buproprion/naltrexone, liraglutide 3 mg, orlistat) could
analysis of data from SCALE programme demonstrated that liraglutide result in 5–10% mean WL and WL maintenance when combined with
3 mg use was not associated with excess cardiovascular risk compared moderate intensity lifestyle interventions. In 2021, Semaglutide 2.4 mg
with comparators (HR 0.42, 95% CI 0.17–1.08), however the confidence once weekly became the first approved obesity pharmacotherapy which
interval was wide.106 leads to ≈15% WL in people without diabetes when combined with mod-
erate intensity lifestyle interventions, which almost doubles the effective-
ness on WL over previous obesity pharmacotherapies with a good
2.3.3.3 Semaglutide 2.4 mg tolerability and safety profile in clinical trials.
Semaglutide 2.4 mg once weekly is a new long-acting GLP-1 RA which was
approved in 2021 for treatment of obesity in the USA and Europe.
Semaglutide 2.4 mg reduces energy intake in people with obesity during an
3. Emerging treatments for obesity
ad libitum lunch by 35% (−224 kcal vs. placebo) through appetite reduction.42
People received semaglutide reported reduced hunger, increase in fullness
3.1 Gut hormones-dual agonists and triple
and satiety, better control of eating and fewer and weakened food cravings.42 agonists
Moreover, the rate of gastric emptying was reduced as well as the prospective Although GLP-1 RAs and especially semaglutide are effective treatments
food consumption for participants receiving semaglutide 2.4 mg.42 for obesity and T2D, there is still significant efficacy gap regarding WL be-
In clinical trials, 56 weeks of semaglutide 2.4 mg in combination with a tween the currently available pharmacotherapies and bariatric surgery
500 kcal/day deficit diet resulted in 14.9% WL vs. 2.4% with placebo in (Figures 2A and B). Based on the example of bariatric surgery where
multiple gut hormones are increased post-operatively, the combination of hormone. In people without diabetes, GIP stimulates insulin secretion
GLP-1 with other gut hormones such as glucose-dependent insulinotropic but does not change glucagon release during hyperglycaemia, whereas it in-
peptide (GIP), glucagon, amylin, and PYY may complement and enhance creases glucagon release without affecting insulin secretion during hypogly-
further the GLP-1 effect leading to additional WL, increased energy ex- caemia.116,117 In the context of T2D, the ability of GIP to stimulate insulin
penditure and improved metabolic outcomes.111 secretion and to ameliorate glycaemia is impaired.118
Tirzepatide is the first dual co-agonist (acting on GLP-1/GIP receptors) Regarding the effect of GIP on appetite, it has only been assessed in a few
which has been approved for treatment of T2D based on the findings of acute studies in humans.101,119,120 Unlike GLP-1, exogenous GIP infusion
the clinical trials from the SURPASS programme. Moreover, tirzepatide is cur- does not seem to reduce appetite and the combination of GLP-1 with
rently undergoing an extensive programme of phase 3 clinical trials as treat- GIP in people with and without T2D does not lead to any more significant
appetite reduction compared with GLP-1 alone.101

ment for obesity (SURMOUNT). The recently published SURMOUNT-1
trial randomized 2539 participants with obesity (without diabetes) to three On this background, it came as a surprise that the GLP-1/GIP co-agonist,
different doses of tirzepatide (5, 10, and 15 mg, n = 1896) or placebo (n = tirzepatide, had glucose-lowering and weight-loss activities that exceeded
643) with follow-up 72 weeks and showed that tirzepatide 5–15 mg results those of GLP-1 RA comparators in clinical trials.83,121 Tirzepatide is a
in 15–20.9% WL when combined with moderate intensity lifestyle interven- once weekly unimolecular agonist of both GLP-1 and GIP receptors which
tions compared with 3.1% WL with placebo.77 has a deliberate bias towards GIP over GLP-1 activity (it possesses five-fold
Other dual co-agonists acting on GLP-1/amylin receptors and GLP-1/ increased relative potency at human GIP receptor when compared with
glucagon receptors are also being assessed in early phase clinical trials as GLP-1 receptor).122 This has been provided as a potential explanation
potential treatments for obesity and metabolic complications.114,115 for the more prominent effects on weight and glucose compared with
Moreover, triple agonists, for example, GLP-1/GIP/glucagon agonists are the more balanced dual agonists targeting GLP-1 and GIP receptors equally
being explored as potential treatments, although data from clinical trials (although this is difficult to understand given that GIP alone has no effect on
are limited and in early stage. food intake in man). Further research is required to understand the me-
chanisms mediating the effects of tirzepatide on weight and glycaemia.
Compared with GLP-1, however, tirzepatide acts as a biased agonist
3.2 GLP-1/GIP combinations for people with with little beta-arrestin recruitment and receptor internalization, which
obesity and T2D may explain the superior activity on target cells.123
GIP is a 42-amino acid peptide secreted by endocrine K cells in the duode- The phase 3 trials with tirzepatide doses 5–15 mg in people with T2D
num and jejunum in response to nutrient ingestion and is an incretin who are overweight or have obesity (SURPASS programme) have shown
A B
Figure 2 The efficacy gap in weight loss between lifestyle interventions, approved pharmacotherapies for obesity over last decade (plus tirzepatide) and
bariatric surgery in adults without type 2 diabetes (Figure 2A) and in adults with type 2 diabetes (Figure 2B). Data in Figure 2A are based on published clinical
trials used (A) lifestyle interventions (500 kcal deficit diet plus advise for physical activity or intensive behavioural therapy) plus placebo (green background),
15,62,65–68,70
(B) liraglutide 3 mg,68,70 naltrexone/buproprion 32/360,65–67 phentermine/topiramate 15/92,62 semaglutide 2.4 mg,15,74–76 and tirzepatide 5 and
15 mg plus lifestyle interventions (approved obesity pharmacotherapies plus tirzepatide, orange background) or c) sleeve gastrectomy112 and Roux-en-Y
77
gastric bypass112 (bariatric surgery, blue background) in adults without type 2 diabetes. Data in Figure 2B are based on published clinical trials used a) lifestyle
interventions (500 kcal deficit diet plus advise for physical activity or intensive behavioural therapy) plus placebo (green background),78–80,82 (B) liraglutide
3 mg,80,81 naltrexone/buproprion 32/360,79 phentermine/topiramate 15/92,78 semaglutide 2.4 mg82 plus lifestyle interventions, and tirzepatide 5 mg and
15mg84,85,87 (approved obesity pharmacotherapies plus tirzepatide, orange background) or c) sleeve gastrectomy113 and Roux-en-Y gastric bypass113 (bariatric
surgery, blue background) in adults with type 2 diabetes.
marked improvements both on WL and glycaemia, despite that tirzepatide to >10% mean WL in studies with at least 52 weeks follow-up (Table 2),
in SURPASS programme was not combined with lifestyle changes (as pri- despite that at the SURPASS programme there was no additional lifestyle
mary outcome was improvement in glycaemia rather than WL), such as in intervention. Moreover, in people with obesity (without diabetes) tirzepa-
the SCALE and STEP programmes. In SURPASS-3 study, 52 weeks of tir- tide 10 and 15 mg when combined with moderate intensity lifestyle inter-
zepatide 15 mg led to mean WL of 11.3 kg (treatment-policy estimand) ventions can lead to ≈20% mean WL with good tolerability and similar side
compared with 1.9 kg weight gain with insulin degludec and 35% of those effect profile to that of GLP-1 RAs.
on tirzepatide 15 mg were able to achieve ≥15% WL compared with 0% at
the insulin degludec group (Table 2).84 Moreover, HbA1c reduced with tir-
zepatide 15 mg by 2.14% (treatment-policy estimand) in SURPASS-3.84 4. A new era in obesity
Similar findings regarding WL and glycaemic improvement after 52 weeks

of tirzepatide use were also reported at the SURPASS-4 trial (Table 2). 85 pharmacotherapy
In direct comparison with semaglutide 1 mg (dose for treatment of The WL achieved with semaglutide 2.4 mg in people with obesity and the
T2D), tirzepatide 15 mg led to 5.5 kg more WL at 40 weeks and 36% of dual agonist tirzepatide in people with T2D and/or obesity suggests that we
people achieved ≥15% WL compared with 8% with semaglutide 1 mg are entering a new era in obesity pharmacotherapy where ≥15% WL and
(SURPASS-2).83 Tirzepatide 15 mg resulted also in an HbA1c reduction maintenance is feasible (Figure 3A and B).
of 0.45% more compared with semaglutide 1 mg (Table 2).83 These obesity treatments will be presented to patients only if the health-
The safety and efficacy of tirzepatide as treatment for obesity in people with- care providers understand that obesity is a chronic disease which is difficult
out diabetes has been assessed at the recently published SURMOUNT-1 clinical to treat with lifestyle changes alone and the management usually requires a
trial. The study found that tirzepatide 5–15 mg together with a moderate inten- multimodal treatment strategy including pharmacotherapy.107 Both clini-
sity lifestyle intervention for 72 weeks resulted in 30–57% of participants achiev- cians and public or private payers need to understand that sustained WL
ing ≥20% WL and 15–36% ≥ 25% WL compared with 3 and 1.5% with requires lifelong treatment of obesity as otherwise weight regain will occur
placebo, respectively.77 The physical function was improved more with tirzepa- when treatment is discontinued.44 There are however important research
tide compared with placebo at the SURMOUNT-1 study and the mean reduc- priorities over the next years to allow the new obesity pharmacotherapies
tion in total body fat mass was 33.9% with tirzepatide compared with 8.2% with to become more widely acceptable and available.
placebo.77 Between participants with pre-diabetes, 95.3% had reverted to
normoglycaemia in the tirzepatide group at 72 weeks, when compared with
61.9% of participants in the placebo group.77 4.1 The cardiovascular safety of new
Nausea, diarrhea, vomiting, and constipation were the most commonly pharmacotherapies for obesity
reported side effects both in SURPASS programme and in SURMOUNT-1 In the past, multiple WL medications have been withdrawn due to safety
study. Most of them were minor to moderate in severity and temporary. concerns.56–58 Today, good quality evidence is lacking regarding the cardio-
Tirzepatide did not increase the risk of hypoglycaemia in SURPASS pro- vascular benefits of the approved pharmacotherapies for obesity as dis-
gramme unless it was combined with insulin or sulfonylureas.14,85,86 cussed before, although the results of the cardiovascular outcome trials
Decreased appetite was also a commonly reported side effect. Adverse conducted in people with T2D are likely to also apply to people with obes-
events leading to discontinuation of medication ranged from 3–11% with ity. Currently, the SELECT study is taking place and will assess the effect of
tirzepatide 5 mg to 7–11% with tirzepatide 15 mg at SURPASS programme semaglutide 2.4 mg on cardiovascular outcomes in people with obesity and
and between 4.3 and 7.1% at SURMOUNT-1.14,77,83–86 In SURMOUNT-1, established cardiovascular disease but without diabetes. Moreover,
the incidence of pancreatitis was low and similar between tirzepatide and SURPASS-CVOT study will compare dulaglutide vs. tirzepatide on cardio-
placebo group (0.2% in each group), when cholecystitis was reported more vascular outcomes in people with T2D and established cardiovascular dis-
frequently with tirzepatide compared with placebo (the overall incidence ease and will provide evidence on whether the dual GLP-1/GIP co-agonist
was still low, < 0.6%), possibly due to the considerable weight reduction is as safe as GLP-1 RAs. Future studies will be needed to establish the safety
with the medication.77 and benefits of the new medications, including the new combinations of gut
Cardiometabolic risk factors (SBP, total cholesterol, HDL, and LDL) are hormones.
all improved with tirzepatide in people with and without T2D.14,77,85 In
SURPASS-4 study, people with T2D and increased cardiovascular risk
were randomized to tirzepatide 5–15 mg (997 participants) or insulin glar- 4.2 How we can best combine the new
gine (1005 participants) for at least 52 weeks, with treatment continued for pharmacotherapies with lifestyle
a maximum of 104 weeks aiming to provide some initial evidence on car-
diovascular safety of tirzepatide.85 An adjudicated 4-point MACE (cardio-
interventions to achieve weight loss targets
vascular death, myocardial infarction, stroke, hospitalization for unstable and healthy weight maintenance?
angina) occurred in 109 participants and was not increased on tirzepatide The majority of the clinical trials combine pharmacotherapies for obesity
compared with glargine (HR 0.74, 95% CI 0.51–1.08).85 Additionally, a with moderate intensity lifestyle changes. However, intensive lifestyle inter-
pre-specified cardiovascular meta-analysis including all seven randomized ventions including low-calorie diets and structured exercise may be used to
controlled trials from the SURPASS programme compared the time to first support WL in clinical practice. How to best combine an intensive lifestyle
occurrence of a 4-point MACE (cardiovascular death, myocardial infarc- intervention with pharmacotherapies for obesity treatment requires fur-
tion, stroke, and hospitalized unstable angina) between pooled tirzepatide ther investigation.
groups and control groups.124 Overall, 142 participants (109 from the A single-centre clinical trial assessed the efficacy in weight maintenance
SURPASS-4 study) had at least one MACE-4 event. The hazard ratios com- of liraglutide 3 mg and/or a 52-week structured exercise programme vs.
paring tirzepatide vs. controls were 0.80 (95% CI, 0.57–1.11) for MACE-4; placebo and continuing with usual physical activity, in people who
0.90 (95% CI, 0.50–1.61) for cardiovascular death; and 0.80 (95% CI, 0.51– achieved at least 5% WL through an 8-week low-calorie diet (‘respon-
1.25) for all-cause death.124 These results suggest that that there is no ders’ to low-calorie diet).21 The combination of liraglutide 3 mg with a
excess cardiovascular risk with tirzepatide, however the definite impact of structured exercise programme (n = 49) resulted in 15.7% mean total
tirzepatide on cardiovascular disease in people with T2D will be addressed WL at 60 weeks after initiation of the low-calorie diet with 49% of par-
in the ongoing SURPASS-CVOT study (NCT04255433). The impact of ticipants achieving ≥15% WL and 32% achieving ≥20% WL.21 In partici-
tirzepatide in people with heart failure with preserved ejection fraction pants receiving placebo and continuing with usual activity (n = 49) after at
and obesity will also be assessed at the SUMMIT trial (NCT04847557). least 5% WL with the 8-week low-calorie diet, mean WL at 60 weeks was
Overall, the GLP-1/GIP co-agonist tirzepatide, is the first approved 6.2% and only 10% of participants were able to achieve ≥15% WL.21
treatment for T2D which at the higher dose (15 mg) consistently leads Importantly, the addition of the exercise programme also caused a

B
Figure 3 Categorical weight loss (≥10% in Figure 3A, ≥ 15% in Figure 3B) in large clinical trials with the approved obesity pharmacotherapies over the last
decade (plus tirzepatide) in people with and without type 2 diabetes (studies with follow-up 52–72 weeks).
greater loss of fat mass, preservation of lean mass, improved cardio- On the other hand, in the STEP-3 study where semaglutide 2.4 mg was
respiratory fitness and overall improvement in cardiometabolic risk fac- combined with IBT and an 8-week low-calorie diet,15,73 the WL achieved at
tors compared with the WL obtained with liraglutide 3 mg alone.21 The 68 weeks was similar to the WL reported when Semaglutide 2.4 mg was
WL achieved in this trial (at 60 weeks) with the combination of liraglutide combined with a 500 kcal/day deficit diet15 (16 vs. 14.9%) and less when
3 mg plus structured exercise for weight maintenance in people who compared with patients who could tolerate Semaglutide 2.4 mg in the
were ‘responders’ to the initial 8-week low-calorie diet is similar to the STEP 4 study (16 vs. 17.4%).74 These results suggest the possibility that in-
WL reported with semaglutide 2.4 mg once weekly at 68 weeks when tensive lifestyle treatments may not be able to provide additional WL to
combined with a 500 kcal deficit diet15 (STEP-1 study, Table 1) and signifi- effective obesity medications such as semaglutide and tirzepatide.
cantly more than the 8% WL in SCALE-Obesity where liraglutide 3 mg However, lean muscle mass loss remains a challenge, because with effective
was combined with 500 kcal deficit diet and advise for physical activity obesity treatments patients consume small amount of calories and may not
(Table 1).68 be enough space in their diet to ensure adequate protein intake, thus
rendering them catabolic and burning muscle mass. The addition of exer- wider use and acceptability by healthcare professionals, individuals living
cise to these effective pharmacological interventions may further improve with obesity and healthcare systems.
body composition, physical function, and cardiorespiratory fitness.21
Further studies are necessary to help us understand how to best combine
the new pharmacotherapies with different lifestyle interventions not only 5. Other gut hormones in the pipeline
to maximize WL, but also to optimize body composition and health
benefits. as potential future therapeutic
Moreover, the sustainability of WL achieved through different combina- candidates
tions of intensive lifestyle and pharmacotherapy needs to be assessed with

long-term studies, together with the changes in body composition, appe- 5.1 Amylin analogues
tite, and energy expenditure over time. Amylin is a pancreatic β-cell hormone that is co-secreted with insulin in re-
sponse to food intake.129 It functions as a satiety signal, acting upon brain
regions involved in both homeostatic and hedonic appetite regulation; it
also slows the gastric emptying, and thereby suppresses post-prandial glu-
4.3 The long-term clinical effectiveness cagon responses to meals.129
and cost-effectiveness of new Cagrilintide is a weekly subcutaneous amylin analogue that is under de-
velopment as treatment for obesity. In a phase 2 study, people with obesity
pharmacotherapies were randomly assigned to cagrilintide 0.3–4.5 mg, liraglutide 3.0 mg, or
Similar to treatments for other chronic diseases such as hypertension or placebo for 26 weeks.114 Cagrilintide led to dose-dependent weight reduc-
diabetes, at the moment that the treatment for obesity stops the disease tions and greater WL at all doses compared with placebo at 26 weeks.114
will relapse and body weight will increase again, as was seen in the STEP WL with cagrilintide 4.5 mg (10.8%) was greater than with liraglutide
1 extension study.44 In this exploratory analysis, a representative subset 3.0 mg (9.0%) or placebo (3.0%).114 Cagrilintide 4.5 mg resulted in ≥10%
of participants (n = 327) who completed 68 weeks of treatment with se- WL in 53.5% of participants and ≥15% WL in 18.7% of participants.114
maglutide 2.4 mg in STEP-1 trial and achieved mean WL of 17.3% of their Gastrointestinal disorders were the most common adverse events, primar-
baseline weight, underwent an off-treatment extension (including lifestyle ily nausea.114
intervention) for an additional year.44 One year after withdrawal of sema- Different doses of cagrilintide were also evaluated in a phase 1b study in
glutide 2.4 mg and lifestyle intervention, participants regained two-thirds of combination with semaglutide 2.4 mg. At 20 weeks, cagrilintide 2.4 mg and
their prior WL resulting in final total WL of 5.6% from baseline weight.44 semaglutide 2.4 mg led to 17.1% WL compared with 9.8% loss with sema-
Cardiometabolic improvements seen with semaglutide treatment were glutide 2.4 mg plus placebo.130 This increased WL was not accompanied by
also reverted towards baseline at the end of the off-treatment extension worsening tolerability, suggesting that the two apparently complementary
period for most parameters.44 mechanisms of action may be combined for potential additive WL. Further
Additionally, in the STEP-4 trial, adults who were overweight or had clinical trials assessing the safety and efficacy of the combination of sema-
obesity completed a 20-week run-in of weekly treatment with subcutane- glutide plus cagrilintide as treatment of obesity are expected to take place
ous semaglutide, 2.4 mg, with a mean WL of 10.6%, and then were rando- over next years.
mized to continued treatment with subcutaneous semaglutide vs. placebo
for an additional 48 weeks.74 At the end of the trial, people receiving sema-
glutide 2.4 mg lost a further 7.9% of their body weight whereas those on 5.2 Glucagon agonists
placebo regained 6.9% of their body weight (almost 70% of the weight Glucagon is a 29-amino acid peptide that is secreted from pancreatic
lost).74 α-cells in response to low levels of blood glucose or increasing levels of
These results suggest that ongoing treatment is required to maintain im- amino acids. It increases blood glucose through stimulation of glycogenoly-
provements in weight, although this topic so far has been poorly explored. sis in the liver, but it also reduces food intake, increases satiety and possibly
Perhaps, an initial WL could be maintained long-term with lower doses of energy expenditure.131
anti-obesity medications. For example, 1.2 mg liraglutide was sufficient to The concept of GLP-1/glucagon co-agonists includes the concurrent ac-
maintain WL for a year after an initial 12% WL obtained with a low-calorie tivation of the GLP-1 receptors leading to decreased energy intake and the
diet.125 glucagon receptors causing increased energy expenditure and reduced en-
Currently, there is a lack of long-term data on the effectiveness and ergy intake. Animal studies with potent GLP-1/glucagon co-agonists were
safety of obesity pharmacotherapies and on the improvement in promising, however the results of the clinical studies in humans for the dual
obesity-related comorbidities (so far the longest follow-up study is GLP-1/glucagon receptor agonist cotadutide, currently under develop-
for liraglutide 3 mg up to 3 years after initiation of treatment).69 ment, were less impressive.115,132 In a phase 2b, randomized, double-blind
The release of the STEP-5 study results (presented but not published study, adults who were overweight or had obesity with T2D were rando-
yet) demonstrate that 104 weeks of semaglutide 2.4 mg once weekly mized to receive cotadutide 100 , 200 or 300 μg; placebo; or open-label
results in 15.2% WL compared with 2.6% with placebo, with 36.1% liraglutide 1.8 mg for 54 weeks.115 The body weight reduction with cotatu-
of participants in semaglutide group achieving ≥20% WL at the end tide 300 μg was 5.02% at week 54 (compared with −0.68% in placebo
of the study.126 group and −3.33% with liraglutide 1.8 mg) and 15.5% of people on cotadu-
Studies in real-world settings with long-term follow-up on the new tide 300 μg achieved ≥10% WL. Cotadutide also significantly lowered
obesity pharmacotherapies may also provide detailed information about HbA1c by 1.03–1.19% at week 54 while reduction with placebo was 0.45
the cost-effectiveness of these interventions and may facilitate their ap- and 1.17% with liraglutide 1.8 mg.115 Gastrointestinal disorders, including
proval by public and private payers for long-term use. Long-term data diarrhoea, nausea, and vomiting, were the most commonly reported ad-
will provide additional information on the potential long-term side effects verse events with cotadutide at any tested dose and more patients stopped
of obesity pharmacotherapy including adverse events due to significant cotatutide due to side effects compared with placebo or liraglutide
long-term WL. WL through bariatric surgery has been associated with in- 1.8 mg.115 However, glucagon is also thought to increase hepatic lipid oxi-
creased risk for fractures127 and increased risk of self-harm behaviors128— dation and inhibit lipogenesis and ad hoc analysis of this trial with cotatutide
whether these complications will be observed with the new pharma- demonstrated improvements in hepatic parameters and supports further
cotherapies need further investigation. evaluation of cotadutide in non-alcoholic steatohepatitis.115
In summary, further evidence on the long-term safety (especially cardio- Another GLP-1/glucagon receptor dual agonist (SAR425899) was re-
vascular safety), clinical effectiveness and cost-effectiveness of the new cently evaluated in single-ascending dose and multiple-ascending dose
pharmacotherapies for obesity in real-world settings will support their phase 1 trials where it was given once a day over 28 days.133 At the highest
maintenance doses tested, there was a reduction of HbA1c by 0.54–0.59% management. Similarly, in obesity, despite that research has mainly fo-
when given to patients who were overweight or had obesity with T2D, and cused in combinations of gut hormones, new treatments targeting dif-
mean WL of 2.4–5.5 kg over the 28 days.133 SAR425899 was generally well ferent pathways such as Setmelanotide and Bimagrumab have also
tolerated, with treatment-emergent adverse effects of reduced appetite been developed.
and nausea.133 Setmelanotide is an melanocortin-4 receptor agonist that reduces body-
Regarding triple agonists, evidence from experimental studies in ani- weight and hunger in individuals with ultra-rare obesity genetic disorders
mals suggests that the addition of GIP activity into dual GLP-1 and gluca- caused by leptin receptor (LEPR) or pro-opiomelanoctin (POMC) defi-
gon receptor agonism provides improved WL and glycaemic control ciency (80% of participants in POMC trial and 45% of participants in
while protecting against the diabetogenic risk of chronic glucagon agon- LEPR trial achieved at least 10% WL after 1 year of medication use).140
ism.133,134 Importantly, the addition of the GIP component may allow

Individuals with these genetic variants have severe hunger (hyperphagia)
an increased potency of the agonist at the glucagon receptor. and early-onset severe obesity resulting from disruption at the melanocor-
However, very limited data is available from clinical trials—a phase 1 clin- tin pathway, which plays pivotal part in body weight regulation.140
ical study in healthy individuals (lean to overweight) with a new unimol- Setmelanotide has now been approved in the USA and Europe for chronic
ecular GLP-1, GIP, and glucagon receptor triagonist (SAR441255) weight management in patients 6 years and older with obesity resulting
showed that the triagonist improved glycaemic control during a mixed- from POMC, PCSK1, or LEPR deficiency confirmed by genetic testing.
meal tolerance test and was well tolerated.134 Additionally, a recent ab- Bimagrumab is a fully human monoclonal antibody that binds the activin
stract presented the results of a 12-week, phase 1 study, where the safety type 2 receptors and prevents the actions of natural ligands, including
and tolerability of multiple doses of another GLP-1/GIP/glucagon myostatin and activin A, that otherwise negatively regulate skeletal muscle
co-agonist (LY3437943) compared with placebo were assessed in 72 growth.141,142 In phase 2 clinical trials, 48 weeks of treatment with
people with T2D. The triple co-agonist showed similar safety and toler- Bimagrumab in individuals living with obesity and T2D resulted in WL of
ability profile to other incretins and led to placebo-adjusted reduction in 6.5% compared with 0.5% (−0.18 kg) in the placebo group, with a reduc-
HbA1C of up to 1.56% and to placebo-adjusted weight reduction of up to tion in total body fat mass by 20.5% (−7.49 kg) and an increase in the lean
8.96 kg.135 Further trials in larger populations of people with T2D and mass by 3.6%, suggesting that Bimagrumab could be a potential treatment
obesity are required to confirm the therapeutic potential of GLP-1/ for sarcopenic obesity. HbA1c fell by 0.76% compared with a rise by 0.04%
GIP/glucagon receptor triagonists. with placebo.141 Dietary intake based on 24 h recall did not differ from
baseline at the end of the study, suggesting that increase in energy expend-
iture could be a mechanism of action for the WL with this medication.141
5.3 PYY analogues Overall, Setmelanotide is considered the first approved personalized
PYY is a peptide hormone that is co-secreted with GLP-1, particularly from treatment for obesity (for individuals with confirmed ultra-rare obesity
distal epithelial L cells in the gut in response to food intake. PYY3–36 is the genetic disorders) when the early phase trials with Bimagrumab provide
active form of the peptide and acts as a satiety hormone, suppressing food evidence that we may succeed in improving the quality of WL and preserve
intake via activation of Y2 receptors in the hypothalamus. Infusion of lean mass in the treatment of obesity.
PYY3–36 in people with obesity causes a 30% reduction in food intake.136
A recent phase 1 study investigating a long-acting PYY3–36 analogue de-
monstrates a reduction of 38–55% in food intake vs. placebo at 30 days
after initiation of treatment and WL of 2.87–3.58 kg compared with 7. Conclusion
placebo.137
The co-administration of GLP-1 and PYY3-36 in humans also reduced WL ≥10% and maintenance is challenging with lifestyle changes alone due
energy intake compared with placebo and more than the sum of the indi- to compensatory increases in appetite and reduction in energy expend-
vidual infusions, demonstrating a synergistic effect.138,139 A long-acting PYY iture. Bariatric surgery is currently the most effective intervention for sus-
analogue in combination with semaglutide is now being assessed in a phase tained WL ≥20% and leads to multiple health benefits, but surgical
2 study as treatment for obesity (NCT04969939). procedures are difficult to scale to treat the entire population. Over the
last decade, a number of medications have been approved for chronic
weight management in people with obesity but Semaglutide 2.4 mg once
5.4 Summary of potential future obesity weekly (a new GLP-1 RA) is the first one which leads to ≈15% WL (in peo-
treatments based on gut hormones ple without diabetes). Moreover, the WL achieved in people with T2D
Except of the approved GLP-1 RAs for weight management and the and/or obesity at phase 3 clinical trials with the recently approved for
GLP-1/GIP co-agonist tirzeparide which has completed phase 3 trials as T2D management dual agonist tirzepatide suggests that combination of
treatment for T2D and/or obesity, multiple other gut hormones such as gut hormones may lead to additional WL compared with GLP-1 RAs alone.
amylin, glucagon and PYY are being tested in early phase clinical trials as po- Judging from the results of clinical trials in individuals with T2D, these treat-
tential treatments for obesity and obesity-related complications, either as ments may also have beneficial cardiovascular effects. Additional research
monotherapies (amylin, PYY) or in combination with GLP-1 as dual assessing long-term safety, effectiveness, and cost-effectiveness of these
(GLP-1/amylin, GLP-1/PYY, and GLP-1/glucagon) and triple co-agonists new pharmacotherapies (semaglutide 2.4 mg and tirzepatide) in trials
(GLP-1/GIP/glucagon). A phase 3 trial assessing the efficacy and safety of and real-world settings will help us to understand better their position in
the combination of semaglutide 2.4 mg with cagrilintide 2.4 mg once week- the weight management algorithms for people with obesity and/or T2D.
ly for people with obesity and T2D is expected to start at the last trimester Furthermore, novel pharmacological interventions combining GLP-1 with
of 2022 (REDEFINE 2, NCT05394519). In the near future, there is a real other gut hormones are currently under development and may offer in
prospect of the above described gut hormone combinations to deliver im- the future the potential to bridge further the efficacy gap between bariatric
proved weight-related outcomes over the currently available treatments surgery and the currently available pharmacotherapies.
for obesity and T2D. Conflict of interest: D.P. has acted as speaker for Novo Nordisk and
has received grants from Novo Nordisk, Novo Nordisk UK Research
Foundation, Academy of Medical Sciences/Diabetes UK, and Health
6. Obesity treatments not based on Education East Midlands. C.W.l.R. reports grants from the Irish Research
gut hormones Council, Science Foundation Ireland, Anabio, and the Health Research
Board. He serves on the advisory boards of Novo Nordisk, Herbalife, GI
It is common practice in chronic diseases such as hypertension or dia- Dynamics, Eli Lilly, Johnson & Johnson, Sanofi Aventis, AstraZeneca,
betes to target multiple mechanisms to achieve optimal disease Janssen, Bristol-Myers Squibb, Glia, and Boehringer Ingelheim. C.W.l.R. is
a member of the Irish Society for Nutrition and Metabolism outside the 14. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, Mao H, Cui X,
area of work commented on here. He is the chief medical officer and dir- Karanikas CA, Thieu VT. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist
tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised,
ector of the Medical Device Division of Keyron since January 2011. Both of
phase 3 trial. Lancet 2021;398:143–155.
these are unremunerated positions. C.W.l.R. was a previous investor in 15. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM,
Keyron, which develops endoscopically implantable medical devices in- Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF.
tended to mimic the surgical procedures of sleeve gastrectomy and gastric Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989.
bypass. The product has only been tested in rodents and none of Keyron’s 16. Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, Peters C,
products are currently licensed. They do not have any contracts with other Zhyzhneuskaya S, Al-Mrabeh A, Hollingsworth KG, Rodrigues AM, Rehackova L,
Adamson AJ, Sniehotta FF, Mathers JC, Ross HM, McIlvenna Y, Welsh P, Kean S, Ford I,
companies to put their products into clinical practice. No patients have
McConnachie A, Messow CM, Sattar N, Taylor R. Durability of a primary care-led weight-

been included in any of Keyron’s studies and they are not listed on the management intervention for remission of type 2 diabetes: 2-year results of the DiRECT
stock market. C.W.l.R. was gifted stock holdings in September 2021 and open-label, cluster-randomised trial. Lancet Diabetes Endocrinol 2019;7:344–355.
divested all stock holdings in Keyron in September 2021. He continues 17. Wadden TA, West DS, Delahanty L, Jakicic J, Rejeski J, Williamson D, Berkowitz RI, Kelley
to provide scientific advice to Keyron for no remuneration. J.J.H. is a mem- DE, Tomchee C, Hill JO, Kumanyika S. The Look AHEAD study: a description of the life-
ber of advisory boards for Novo Nordisk and has acted as a speaker for style intervention and the evidence supporting it. Obesity (Silver Spring) 2006; 14:737–752.
18. Astbury NM, Aveyard P, Nickless A, Hood K, Corfield K, Lowe R, Jebb SA. Doctor referral
Novo Nordisk and Lilly. M.J.D. has acted as consultant, advisory board
of overweight people to low energy total diet replacement treatment (DROPLET): prag-
member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and matic randomised controlled trial. BMJ 2018;362:k3760.
Sanofi, an advisory board member and speaker for AstraZeneca, an advis- 19. Astbury NM, Edwards RM, Ghebretinsea F, Shanyinde M, Mollison J, Aveyard P, Jebb SA.
ory board member for Janssen, Lexicon, Pfizer, and ShouTi Pharma Inc., a Extended follow-up of a short total diet replacement programme: results of the doctor
speaker for Napp Pharmaceuticals, Novartis, and Takeda Pharmaceuticals referral of overweight people to low energy total diet replacement treatment
International Inc. and has received grants in support of investigator and in- (DROPLET) randomised controlled trial at 3 years. Int J Obes (Lond) 2021;45:2432–2438.
20. Bellicha A, van Baak MA, Battista F, Beaulieu K, Blundell JE, Busetto L, Carraça EV, Dicker D,
vestigator initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly,
Encantado J, Ermolao A, Farpour-Lambert N, Pramono A, Woodward E, Oppert JM. Effect
Boehringer Ingelheim, Astrazeneca, and Janssen. of exercise training on weight loss, body composition changes, and weight maintenance in
adults with overweight or obesity: an overview of 12 systematic reviews and 149 studies.
Funding Obes Rev 2021;22(Suppl 4):e13256.
21. Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, Svane MS, Bandholm
This work was supported by the NIHR Leicester Biomedical Research T, Bojsen-Møller KN, Blond MB, Jensen JB, Stallknecht BM, Holst JJ, Madsbad S, Torekov SS.
Centre. D.P. is funded through an National Institute for Health and Care Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med
Research (NIHR) Clinical Lectureship. 2021;384:1719–1730.
22. Unick JL, Gaussoin SA, Hill JO, Jakicic JM, Bond DS, Hellgren M, Johnson KC, Peters AL,
Coday M, Kitzman DW, Bossart S, Wing RR. Four-year physical activity levels among inter-
Data availability vention participants with type 2 diabetes. Med Sci Sports Exerc 2016;48:2437–2445.
Data derived from sources in the public domain. Reference details are pro- 23. Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS, Johnson KC, Kahn SE,
vided in full. Knowler WC, Yanovski SZ. Look AHEAD (action for health in diabetes): design and meth-
ods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2
diabetes. Control Clin Trials 2003;24:610–628.
References 24. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM,
1. Bray GA, Kim KK, Wilding JPH. Obesity: a chronic relapsing progressive disease process. A Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO,
position statement of the World Obesity Federation. Obes Rev 2017;18:715–723. Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler
2. WHO. Obesity and Overweight. WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A,
3. Haslam DW, James WP. Obesity. Lancet 2005;366:1197–1209. Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M,
4. Biener A, Cawley J, Meyerhoefer C. The high and rising costs of obesity to the US health Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular ef-
care system. J Gen Intern Med 2017;32:6–8. fects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154.
5. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obes- 25. Pandey A, Patel KV, Bahnson JL, Gaussoin SA, Martin CK, Balasubramanyam A, Johnson
ity. Jama 2003;289:187–193. KC, McGuire DK, Bertoni AG, Kitzman D, Berry JD. Association of intensive lifestyle inter-
6. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J, Qizilbash N, Collins vention. Fitness, and body mass Index with risk of heart failure in overweight or obese
R, Peto R. Body-mass index and cause-specific mortality in 900 000 adults: collaborative adults with type 2, diabetes Mellitus: an analysis from the Look AHEAD trial. Circulation
analyses of 57 prospective studies. Lancet 2009;373:1083–1096. 2020;141:1295–1306.
7. Cawley J, Biener A, Meyerhoefer C, Ding Y, Zvenyach T, Smolarz BG, Ramasamy A. Direct 26. Alonso A, Bahnson JL, Gaussoin SA, Bertoni AG, Johnson KC, Lewis CE, Vetter M,
medical costs of obesity in the United States and the most populous states. J Manag Care Mantzoros CS, Jeffery RW, Soliman EZ. Effect of an intensive lifestyle intervention on atrial
Spec Pharm 2021;27:354–366. fibrillation risk in individuals with type 2 diabetes: the Look AHEAD randomized trial. Am
8. Wadden TA, Bantle JP, Blackburn GL, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Heart J 2015;170:770–777.e775.
Dutton GR, Egan C, Evans M, Foreyt JP, Sengardi SG, Gregg EW, Hazuda HP, Hill JO, 27. Gregg EW, Jakicic JM, Blackburn G, Bloomquist P, Bray GA, Clark JM, Coday M, Curtis JM,
Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Egan C, Evans M, Foreyt J, Foster G, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jeffery
Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Montgomery B, Nathan DM, RW, Johnson KC, Kitabchi AE, Knowler WC, Kriska A, Lang W, Lewis CE, Montez MG,
Nelson J, Patricio J, Peters A, Pi-Sunyer FX, Pownall H, Rickman AD, Vitolins M, Walkup Nathan DM, Neiberg RH, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Redmon B,
MP, West DS, Williamson D, Wing RR, Wyatt H, Yanovski SZ. Eight-year weight losses Regensteiner J, Rejeski J, Ribisl PM, Safford M, Stewart K, Trence D, Wadden TA, Wing
with an intensive lifestyle intervention: the look AHEAD study. Obesity (Silver Spring) RR, Yanovski SZ. Association of the magnitude of weight loss and changes in physical fitness
2014;22:5–13. with long-term cardiovascular disease outcomes in overweight or obese people with type
9. Tahrani AA, Morton J. Benefits of weight loss of 10% or more in patients with overweight 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet
or obesity: a review. Obesity (Silver Spring) 2022;30:802–840. Diabetes Endocrinol 2016;4:913–921.
10. Cefalu WT, Bray GA, Home PD, Garvey WT, Klein S, Pi-Sunyer FX, Hu FB, Raz I, Van Gaal 28. Middeldorp ME, Pathak RK, Meredith M, Mehta AB, Elliott AD, Mahajan R, Twomey D,
L, Wolfe BM, Ryan DH. Advances in the science, treatment, and prevention of the disease Gallagher C, Hendriks JML, Linz D, McEvoy RD, Abhayaratna WP, Kalman JM, Lau DH,
of obesity: reflections from a diabetes care editors’ expert forum. Diabetes Care 2015;38: Sanders P. PREVEntion and regReSsive effect of weight-loss and risk factor modification
1567–1582. on atrial fibrillation: the REVERSE-AF study. Europace 2018;20:1929–1935.
11. Sjöström L. Review of the key results from the Swedish obese subjects (SOS) trial - a pro- 29. Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med
spective controlled intervention study of bariatric surgery. J Intern Med 2013;273:219–234. Clin North Am 2018;102:183–197.
12. Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, 30. Aronne LJ, Hall KD, J MJ, Leibel RL, Lowe MR, Rosenbaum M, Klein S. Describing the
Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, weight-reduced state: physiology, behavior, and interventions. Obesity (Silver Spring)
Lindroos AK, Lönroth H, Näslund I, Olbers T, Stenlöf K, Torgerson J, Agren G, Carlsson 2021;29(Suppl 1):S9–s24.
LM. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 31. Busetto L, Bettini S, Makaronidis J, Roberts CA, Halford JCG, Batterham RL. Mechanisms of
2007;357:741–752. weight regain. Eur J Intern Med 2021;93:3–7.
13. Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, 32. Polidori D, Sanghvi A, Seeley RJ, Hall KD. How strongly does appetite counter weight loss?
Larsson B, Narbro K, Sjöström CD, Sullivan M, Wedel H. Lifestyle, diabetes, and cardiovas- Quantification of the feedback control of human energy intake. Obesity (Silver Spring) 2016;
cular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693. 24:2289–2295.
33. Ravussin E, Smith SR, Ferrante AW Jr. Physiology of energy expenditure in the 57. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen
weight-reduced state. Obesity (Silver Spring) 2021; 29(Suppl 1):S31–s38. C, Sharma AM, Shepherd GM, Rode RA, Renz CL. Effect of sibutramine on cardiovascular
34. Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, Chen KY, Skarulis MC, outcomes in overweight and obese subjects. N Engl J Med 2010;363:905–917.
Walter M, Walter PJ, Hall KD. Persistent metabolic adaptation 6 years after “the biggest 58. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the
loser” competition. Obesity (Silver Spring) 2016; 24:1612–1619. weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007;370:
35. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J. 1706–1713.
Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011;365: 59. Sharretts J, Galescu O, Gomatam S, Andraca-Carrera E, Hampp C, Yanoff L. Cancer risk
1597–1604. associated with Lorcaserin: the FDA’s review of the CAMELLIA-TIMI 61 trial. N Engl J
36. Dorling J, Broom DR, Burns SF, Clayton DJ, Deighton K, James LJ, King JA, Miyashita M, Med 2020;383:1000–1002.
Thackray AE, Batterham RL, Stensel DJ. Acute and chronic effects of exercise on appetite, 60. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M,
energy intake, and appetite-related hormones: the modulating effect of adiposity, sex, and Singh S. Association of pharmacological treatments for obesity with weight loss and ad-

habitual physical activity. Nutrients 2018;10:1140. verse events: a systematic review and meta-analysis. JAMA 2016;315:2424–2434.
37. Douglas JA, King JA, Clayton DJ, Jackson AP, Sargeant JA, Thackray AE, Davies MJ, Stensel 61. Smith SM, Meyer M, Trinkley KE. Phentermine/topiramate for the treatment of obesity.
DJ. Acute effects of exercise on appetite, ad libitum energy intake and appetite-regulatory Ann Pharmacother 2013;47:340–349.
62. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY,
hormones in lean and overweight/obese men and women. Int J Obes (Lond) 2017;41:
Troupin B, Day WW. Controlled-release phentermine/topiramate in severely obese
1737–1744.
adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012; 20:330–342.
38. Beaulieu K, Blundell JE, van Baak MA, Battista F, Busetto L, Carraça EV, Dicker D, Encantado
63. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day
J, Ermolao A, Farpour-Lambert N, Pramono A, Woodward E, Bellicha A, Oppert JM. Effect
WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with
of exercise training interventions on energy intake and appetite control in adults with over-
controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a
weight or obesity: a systematic review and meta-analysis. Obes Rev 2021;22(Suppl 4):
randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95:297–308.
e13251.
64. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects
39. Grannell A, Fallon F, Al-Najim W, le Roux C. Obesity and responsibility: is it time to rethink
of low-dose, controlled-release, phentermine plus topiramate combination on weight and
agency? Obes Rev 2021;22:e13270. associated comorbidities in overweight and obese adults (CONQUER): a randomised,
40. Iepsen EW, Lundgren J, Holst JJ, Madsbad S, Torekov SS. Successful weight loss mainten- placebo-controlled, phase 3 trial. Lancet 2011;377:1341–1352.
ance includes long-term increased meal responses of GLP-1 and PYY3-36. Eur J 65. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD,
Endocrinol 2016;174:775–784. Dunayevich E. Effect of naltrexone plus bupropion on weight loss in overweight and obese
41. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L. Weight main- adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
tenance and additional weight loss with liraglutide after low-calorie-diet-induced weight Lancet 2010;376:595–605.
loss: the SCALE maintenance randomized study. Int J Obes (Lond) 2013; 37:1443–1451. 66. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E. A ran-
42. Friedrichsen M, Breitschaft A, Tadayon S, Wizert A, Skovgaard D. The effect of semaglutide domized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk
2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in factors (COR-II). Obesity (Silver Spring) 2013;21:935–943.
adults with obesity. Diabetes Obes Metab 2021;23:754–762. 67. Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O’Neil PM, Perri MG, Pi-Sunyer FX,
43. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 Rock CL, Erickson JS, Maier HN, Kim DD, Dunayevich E. Weight loss with naltrexone
analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabol- SR/bupropion SR combination therapy as an adjunct to behavior modification: the
ism in obese, non-diabetic adults. Int J Obes (Lond) 2014; 38:784–793. COR-BMOD trial. Obesity (Silver Spring) 2011;19:110–120.
44. Wilding JP, Batterham RL, Davies M, Gaal LFV, Kandler K, Konakli K, Lingvay I, McGowan 68. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW,
BM, Kalayci Oral T, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF. Weight Violante Ortiz R, Jensen CB, Wilding JP. A randomized, controlled trial of 3.0 mg of liraglu-
regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial exten- tide in weight management. N Engl J Med 2015;373:11–22.
sion. Diabetes Obes Metab 2022;24:1553–1564. 69. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, Ortiz RV, Wilding
45. le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lönroth H, JPH, Skjøth TV, Manning LS, Pi-Sunyer X. 3 Years of liraglutide versus placebo for type 2
Fändriks L, Ghatei MA, Bloom SR, Olbers T. Gut hormones as mediators of appetite and diabetes risk reduction and weight management in individuals with prediabetes: a rando-
weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246:780–785. mised, double-blind trial. Lancet 2017;389:1399–1409.
46. Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, Ahlin S, Anveden 70. Wadden TA, Tronieri JS, Sugimoto D, Lund MT, Auerbach P, Jensen C, Rubino D.
Å, Bengtsson C, Bergmark G, Bouchard C, Carlsson B, Dahlgren S, Karlsson J, Lindroos AK, Liraglutide 3.0 mg and intensive behavioral therapy (IBT) for obesity in primary care: the
Lönroth H, Narbro K, Näslund I, Olbers T, Svensson PA, Carlsson LM. Bariatric surgery and SCALE IBT randomized controlled trial. Obesity (Silver Spring) 2020; 28:529–536.
long-term cardiovascular events. JAMA 2012;307:56–65. 71. Blackman A, Foster GD, Zammit G, Rosenberg R, Aronne L, Wadden T, Claudius B, Jensen
47. Carlsson LMS, Sjöholm K, Jacobson P, Andersson-Assarsson JC, Svensson PA, Taube M, CB, Mignot E. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe
Carlsson B, Peltonen M. Life expectancy after bariatric surgery in the Swedish obese sub- obstructive sleep apnea: the SCALE sleep apnea randomized clinical trial. Int J Obes (Lond)
jects study. N Engl J Med 2020;383:1535–1543. 2016;40:1310–1319.
48. Jamaly S, Carlsson L, Peltonen M, Jacobson P, Sjöström L, Karason K. Bariatric surgery and 72. Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD,
the risk of new-onset atrial fibrillation in Swedish obese subjects. J Am Coll Cardiol 2016;68: Prabhu N, Randomized ASA. Controlled trial of liraglutide for adolescents with obesity.
N Engl J Med 2020;382:2117–2128.
2497–2504.
73. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, Lingvay I, O’Neil PM,
49. Jamaly S, Carlsson L, Peltonen M, Jacobson P, Karason K. Surgical obesity treatment and the
Rubino DM, Skovgaard D, Wallenstein SOR, Garvey WT. Effect of subcutaneous semaglu-
risk of heart failure. Eur Heart J 2019;40:2131–2138.
tide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with
50. Aminian A, Zajichek A, Arterburn DE, Wolski KE, Brethauer SA, Schauer PR, Kattan MW,
overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021;325:1403–1413.
Nissen SE. Association of metabolic surgery with major adverse cardiovascular outcomes
74. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, Lingvay I,
in patients with type 2 diabetes and obesity. Jama 2019;322:1271–1282.
Mosenzon O, Rosenstock J, Rubio MA, Rudofsky G, Tadayon S, Wadden TA, Dicker D.
51. Eliasson B, Liakopoulos V, Franzén S, Näslund I, Svensson AM, Ottosson J, Gudbjörnsdottir
Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss mainten-
S. Cardiovascular disease and mortality in patients with type 2 diabetes after bariatric sur-
ance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;
gery in Sweden: a nationwide, matched, observational cohort study. Lancet Diabetes
325:1414–1425.
Endocrinol 2015;3:847–854. 75. Kadowaki T, Isendahl J, Khalid U, Lee SY, Nishida T, Ogawa W, Tobe K, Yamauchi T, Lim S.
52. Angrisani L, Santonicola A, Iovino P, Ramos A, Shikora S, Kow L. Bariatric Surgery Survey Semaglutide once a week in adults with overweight or obesity, with or without type 2 dia-
2018: similarities and disparities among the 5 IFSO chapters. Obes Surg 2021;31: betes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy,
1937–1948. placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol 2022;10:193–206.
53. Arterburn D, Wellman R, Emiliano A, Smith SR, Odegaard AO, Murali S, Williams N, 76. Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock J, Sørrig R, Wadden TA,
Coleman KJ, Courcoulas A, Coley RY, Anau J, Pardee R, Toh S, Janning C, Cook A, Wizert A, Garvey WT. Effect of weekly subcutaneous semaglutide vs daily liraglutide on
Sturtevant J, Horgan C, McTigue KM. Comparative effectiveness and safety of bariatric pro- body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized
cedures for weight loss: a PCORnet cohort study. Ann Intern Med 2018;169:741–750. clinical trial. JAMA 2022;327:138–150.
54. Miras AD, le Roux CW. Mechanisms underlying weight loss after bariatric surgery. Nat Rev 77. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S,
Gastroenterol Hepatol 2013;10:575–584. Liu B, Bunck MC, Stefanski A. Tirzepatide once weekly for the treatment of obesity. N Engl J
55. Svane MS, Jørgensen NB, Bojsen-Møller KN, Dirksen C, Nielsen S, Kristiansen VB, Toräng Med 2022;387:205–216.
S, Wewer Albrechtsen NJ, Rehfeld JF, Hartmann B, Madsbad S, Holst JJ. Peptide YY and 78. Garvey WT, Ryan DH, Bohannon NJ, Kushner RF, Rueger M, Dvorak RV, Troupin B.
glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended
surgery. Int J Obes (Lond) 2016;40:1699–1706. release. Diabetes Care 2014;37:3309–3316.
56. Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and 79. Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, Klassen P, Fujioka K.
challenges. Nat Rev Drug Discov 2022;21:201–223. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy
on body weight and glycemic parameters in overweight and obese patients with type 2 dia- Buse JB. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;
betes. Diabetes Care 2013;36:4022–4029. 375:311–322.
80. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, Andreasen AH, Jensen 104. Jorsal A, Kistorp C, Holmager P, Tougaard RS, Nielsen R, Hänselmann A, Nilsson B, Møller
CB, DeFronzo RA. Efficacy of liraglutide for weight loss among patients with type 2 dia- JE, Hjort J, Rasmussen J, Boesgaard TW, Schou M, Videbaek L, Gustafsson I, Flyvbjerg A,
betes: the SCALE diabetes randomized clinical trial. JAMA 2015;314:687–699. Wiggers H, Tarnow L. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ven-
81. Garvey WT, Birkenfeld AL, Dicker D, Mingrone G, Pedersen SD, Satylganova A, Skovgaard tricular function in stable chronic heart failure patients with and without diabetes (LIVE)-a
D, Sugimoto D, Jensen C, Mosenzon O. Efficacy and safety of liraglutide 3.0 mg in indivi- multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail 2017;19:
duals with overweight or obesity and type 2 diabetes treated with basal insulin: the 69–77.
SCALE insulin randomized controlled trial. Diabetes Care 2020;43:1085–1093. 105. Marso SP, Baeres FMM, Bain SC, Goldman B, Husain M, Nauck MA, Poulter NR, Pratley RE,
82. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Thomsen AB, Buse JB. Effects of liraglutide on cardiovascular outcomes in patients with dia-
Shimomura I, Viljoen A, Wadden TA, Lingvay I. Semaglutide 2·4 mg once a week in adults betes with or without heart failure. J Am Coll Cardiol 2020;75:1128–1141.

with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, 106. Davies MJ, Aronne LJ, Caterson ID, Thomsen AB, Jacobsen PB, Marso SP. Liraglutide and
double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971–984. cardiovascular outcomes in adults with overweight or obesity: a post hoc analysis from
83. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, SCALE randomized controlled trials. Diabetes Obes Metab 2018;20:734–739.
Cui X, Brown K. Tirzepatide versus semaglutide once weekly in patients with type 2 dia- 107. Lingvay I, Sumithran P, Cohen RV, le Roux CW. Obesity management as a primary treat-
betes. N Engl J Med 2021;385:503–515. ment goal for type 2, diabetes: time to reframe the conversation. Lancet 2022;399:
84. Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, Bray R, Rodríguez Á. 394–405.
Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or 108. Wharton S, Calanna S, Davies M, Dicker D, Goldman B, Lingvay I, Mosenzon O, Rubino
without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, DM, Thomsen M, Wadden TA, Pedersen SD. Gastrointestinal tolerability of once-weekly
open-label, parallel-group, phase 3 trial. Lancet 2021;398:583–598. semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between
85. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, Aizenberg D, Wynne AG, gastrointestinal adverse events and weight loss. Diabetes Obes Metab 2022;24:94–105.
Riesmeyer JS, Heine RJ, Wiese RJ. Tirzepatide versus insulin glargine in type 2 diabetes and 109. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J,
increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multi- Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T. Semaglutide
centre, phase 3 trial. Lancet 2021;398:1811–1824. and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:
86. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á. Effect of subcutaneous 1834–1844.
tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with 110. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of
type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 2022;327:534–545. oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic con-
87. Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide mono- trol in patients with type 2 diabetes: a randomized clinical trial. Jama 2017;318:1460–1470.
therapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS 111. Alexiadou K, Anyiam O, Tan T. Cracking the combination: gut hormones for the treatment
J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes of obesity and diabetes. J Neuroendocrinol 2019;31:e12664.
Endocrinol 2022;10:623–633. 112. Capristo E, Panunzi S, De Gaetano A, Spuntarelli V, Bellantone R, Giustacchini P, Birkenfeld
88. Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y. Safety and efficacy of tirzepatide as an AL, Amiel S, Bornstein SR, Raffaelli M, Mingrone G. Incidence of hypoglycemia after gastric
add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in bypass vs sleeve gastrectomy: a randomized trial. J Clin Endocrinol Metab 2018;103:
Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 2136–2146.
3 trial. Lancet Diabetes Endocrinol 2022;10:634–644. 113. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood
89. Kolotkin RL, Gadde KM, Peterson CA, Crosby RD. Health-related quality of life in two ran- B, Nissen SE, Bhatt DL. Bariatric surgery versus intensive medical therapy in obese patients
domized controlled trials of phentermine/topiramate for obesity: what mediates improve- with diabetes. N Engl J Med 2012;366:1567–1576.
ment? Qual Life Res 2016;25:1237–1244. 114. Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, Pedersen
90. Ritchey ME, Harding A, Hunter S, Peterson C, Sager PT, Kowey PR, Nguyen L, Thomas S, SD, Pietiläinen KH, Rubino D, Batterham RL. Once-weekly cagrilintide for weight manage-
Cainzos-Achirica M, Rothman KJ, Andrews EB, Anthony MS. Cardiovascular safety during ment in people with overweight and obesity: a multicentre, randomised, double-blind,
and after use of phentermine and topiramate. J Clin Endocrinol Metab 2019;104:513–522. placebo-controlled and active-controlled, dose-finding phase 2, trial. Lancet 2021;398:
91. Apovian CM. Naltrexone/bupropion for the treatment of obesity and obesity with type 2 2160–2172.
diabetes. Future Cardiol 2016;12:129–138. 115. Nahra R, Wang T, Gadde KM, Oscarsson J, Stumvoll M, Jermutus L, Hirshberg B, Ambery P.
92. Kolotkin RL, Chen S, Klassen P, Gilder K, Greenway FL. Patient-reported quality of life in a Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or
randomized placebo-controlled trial of naltrexone/bupropion for obesity. Clin Obes 2015; obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 2021;
5:237–244. 44:1433–1442.
93. Halseth A, Shan K, Gilder K, Malone M, Acevedo L, Fujioka K. Quality of life, binge eating 116. Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE, Nauck MA. Gastric
and sexual function in participants treated for obesity with sustained release naltrexone/ inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy hu-
bupropion. Obes Sci Pract 2018;4:141–152. man subjects at euglycaemia. Diabetologia 2003;46:798–801.
94. Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, Perez A, Smith SR. Effect of 117. Khoo B, Tan TM. Combination gut hormones: prospects and questions for the future of
naltrexone-bupropion on Major adverse cardiovascular events in overweight and obese obesity and diabetes therapy. J Endocrinol 2020;246:R65–r74.
patients with cardiovascular risk factors: a randomized clinical trial. JAMA 2016;315: 118. Christensen MB, Gasbjerg LS, Heimbürger SM, Stensen S, Vilsbøll T, Knop FK. GIP’s in-
990–1004. volvement in the pathophysiology of type 2 diabetes. Peptides 2020;125:170178.
95. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409–1439. 119. Bergmann N, Lund A, Gasbjerg L, Meessen E, Andersen M, Bergmann S, Hartmann B, Holst
96. Näslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rössner S, Hellström PM. J, Jessen L, Christensen M. Effects of combined GIP and GLP-1 infusion on energy intake,
Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese appetite and energy expenditure in overweight/obese individuals: a randomised, crossover
men. Int J Obes Relat Metab Disord 1999;23:304–311. study. Diabetologia 2019;62:665–675.
97. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and sup- 120. Bergmann NC, Gasbjerg LS, Heimbürger SM, Krogh LSL, Dela F, Hartmann B, Holst JJ,
presses energy intake in humans. J Clin Invest 1998;101:515–520. Jessen L, Christensen MB, Vilsbøll T, Lund A, Knop FK. No acute effects of exogenous
98. Williams DL. The diverse effects of brain glucagon-like peptide 1 receptors on ingestive glucose-dependent insulinotropic polypeptide on energy intake. Appetite, or energy ex-
behaviour. Br J Pharmacol 2022;179:571–583. penditure when added to treatment with a long-acting glucagon-like peptide 1, receptor
99. Sisley S, Gutierrez-Aguilar R, Scott M, D’Alessio DA, Sandoval DA, Seeley RJ. Neuronal agonist in men with type 2 diabetes. Diabetes Care 2020;43:588–596.
GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest 2014; 121. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z,
124:2456–2463. Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor
100. Farr OM, Upadhyay J, Rutagengwa C, DiPrisco B, Ranta Z, Adra A, Bapatla N, Douglas VP, agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active
Douglas KAA, Nolen-Doerr E, Mathew H, Mantzoros CS. Longer-term liraglutide admin- comparator-controlled phase 2 trial. Lancet 2018;392:2180–2193.
istration at the highest dose approved for obesity increases reward-related orbitofrontal 122. Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist K, Cui X, Briere D,
cortex activation in response to food cues: implications for plateauing weight loss in re- Cabrera O, Roell W. LY3298176, A novel dual GIP and GLP-1 receptor agonist for the
sponse to anti-obesity therapies. Diabetes Obes Metab 2019;21:2459–2464. treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol
101. Holst JJ. Treatment of type 2 diabetes and obesity on the basis of the incretin system: the Metab 2018;18:3–14.
2021 banting medal for scientific achievement award lecture. Diabetes 2021;70: 123. Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME,
2468–2475. van der Velden WJ, Stutsman C, Cardona GR, Urva S, Emmerson PJ, Holst JJ, D’Alessio
102. Kolotkin RL, Fujioka K, Wolden ML, Brett JH, Bjorner JB. Improvements in health-related DA, Coghlan MP, Rosenkilde MM, Campbell JE, Sloop KW. Tirzepatide is an imbalanced
quality of life with liraglutide 3.0 mg compared with placebo in weight management. Clin and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020;5:e140532.
Obes 2016;6:233–242. 124. Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S.
103. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med
Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, 2022;28:591–598.
125. Iepsen EW, Lundgren J, Dirksen C, Jensen JE, Pedersen O, Hansen T, Madsbad S, Holst JJ, Nowotny I, Einig C, Jan C, Rharbaoui F, Gassenhuber J, Prochnow HP, Agueusop I,
Torekov SS. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plas- Porksen N, Smith WB, Nitsche A, Konkar A. Effects on weight loss and glycemic control
ma leptin during maintenance of weight loss. Int J Obes (Lond) 2015; 39:834–841. with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.
126. https://sciencehub.novonordisk.com/content/dam/hcpexperience/kol/en/congresses/ow/ Cell Metab 2022;34:59–74.e10.
2021/ow21-step-5-primary-lb/pdfs/PPT_Garvey_Two_year_effect_semaglutide_2.4mg_ 135. https://diabetesjournals.org/diabetes/article/71/Supplement_1/340-OR/146500/340-OR-
STEP_5_no%20animations.pdf. LY3437943-LY-a-Novel-Triple-GIP-GLP-1.
127. Ahlin S, Peltonen M, Sjöholm K, Anveden Å, Jacobson P, Andersson-Assarsson JC, Taube 136. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom
M, Larsson I, Lohmander LS, Näslund I, Svensson PA, Carlsson LMS. Fracture risk after SR. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003;349:
three bariatric surgery procedures in Swedish obese subjects: up to 26 years follow-up 941–948.
of a controlled intervention study. J Intern Med 2020;287:546–557. 137. Tan TM, Minnion J, Khoo B, Ball LJ, Malviya R, Day E, Fiorentino F, Brindley C, Bush J, Bloom
128. Neovius M, Bruze G, Jacobson P, Sjöholm K, Johansson K, Granath F, Sundström J, Näslund SR. Safety and efficacy of an extended-release peptide YY analogue for obesity: a rando-

I, Marcus C, Ottosson J, Peltonen M, Carlsson LMS. Risk of suicide and non-fatal self-harm mized, placebo-controlled, phase 1 trial. Diabetes Obes Metab 2021;23:1471–1483.
after bariatric surgery: results from two matched cohort studies. Lancet Diabetes Endocrinol 138. Neary N, Small C, Druce M, Park A, Ellis S, Semjonous N, Dakin C, Filipsson K, Wang F,
2018;6:197–207. Kent A. Peptide YY3-36 and glucagon-like peptide-17–36 inhibit food intake additively.
129. Dehestani B, Stratford NR, le Roux CW. Amylin as a future obesity treatment. J Obes Endocrinology 2005;146:5120–5127.
Metab Syndr 2021;30:320–325. 139. De Silva A, Salem V, Long C, Makwana A, Newbould R, Rabiner E, Ghatei M, Bloom S,
130. Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, Lau DCW. Matthews P, Beaver J. The gut hormones PYY 3–36 And GLP-1 7–36 Amide reduce
Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administra- food intake and modulate brain activity in appetite centers in humans. Cell Metab 2011;
tion of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a 14:700–706.
randomised, controlled, phase 1b trial. Lancet 2021;397:1736–1748. 140. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K,
131. Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH. The metabolic Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J,
actions of glucagon revisited. Nat Rev Endocrinol 2010;6:689–697. Stewart M, Yuan G, Wabitsch M, Kühnen P. Efficacy and safety of setmelanotide, an
132. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-
Robertson D, Jain M, Petrone M, Rondinone C, Hirshberg B, Jermutus LMEDI. , a GLP-1 arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol 2020;8:960–970.
and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: 141. Heymsfield SB, Coleman LA, Miller R, Rooks DS, Laurent D, Petricoul O, Praestgaard J,
a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 2018; Swan T, Wade T, Perry RG, Goodpaster BH, Roubenoff R. Effect of bimagrumab vs pla-
391:2607–2618. cebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 rando-
133. Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, mized clinical trial. JAMA Netw Open 2021;4:e2033457.
Bossart M, Larsen PJ. A novel dual glucagon-like peptide and glucagon receptor agonist 142. Fournier B, Murray B, Gutzwiller S, Marcaletti S, Marcellin D, Bergling S, Brachat S, Persohn
SAR425899: results of randomized, placebo-controlled first-in-human and first-in-patient E, Pierrel E, Bombard F, Hatakeyama S, Trendelenburg AU, Morvan F, Richardson B, Glass
trials. Diabetes Obes Metab 2019;21:120–128. DJ, Lach-Trifilieff E, Feige JN. Blockade of the activin receptor IIb activates functional brown
134. Bossart M, Wagner M, Elvert R, Evers A, Hübschle T, Kloeckener T, Lorenz K, Moessinger adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol Cell
C, Eriksson O, Velikyan I, Pierrou S, Johansson L, Dietert G, Dietz-Baum Y, Kissner T, Biol 2012;32:2871–2879.

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Cardiovascular Research (2022) 00, 1–18 INVITED SPOTLIGHT REVIEW

New therapies for obesity

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* Corresponding author. Tel: +44 (0)116 258 8973, E-mail: [email protected]

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2.1.1 Why is it so challenging to maintain weight loss

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SCALE-IBT plus diet 1200– ETD: −3.4%

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among those receiving PHEN/TPM (including the ﬁxed-dose combination)

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thalamus and mesolimbic dopamine circuit. Participants in clinical trials

In people without diabetes, NB 32/360 together with a 500 kcal deﬁcit

diet resulted in 6.3% WL at 52 weeks compared with 0.9% in the placebo

ple with obesity and T2D, NB 32/360 resulted in 5% mean WL at 56 weeks

32/360 achieved ≥10% WL and HbA1c was reduced by 0.6% compared

ing.65,79 The NB is contraindicated in people with epilepsy as buproprion is

associated with dose-related risk of seizures.

Physical function and self-esteem improved with NB 32/360 compared

compared with the NB 32/360.66

A clinical trial on cardiovascular outcomes for NB was terminated early

2.3.3 Currently approved pharmacotherapies for

obesity based on gut hormones

2.3.3.1 GLP-1 receptor agonists

in the small intestine in response to food intake.95 In addition to the

changes in energy expenditure.96–98

dense expression of GLP-1 receptors. In animal experiments, the effect

tem mechanisms,99 and in humans this is supported by imaging

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