# Obesity and its treatment: Toward new approaches

Bérénice Segrestin, Blandine Gatta Cherifi

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Bérénice Segrestin, Blandine Gatta Cherifi. Obesity and its treatment: Toward new approaches. Annales d'Endocrinologie = Annals of Endocrinology, 2025, 86 (2), pp.101712. 10.1016/j.ando.2025.101712. inserm-05344979

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Les Essentiels de la SFE

# Obesity and its treatment: Toward new approaches

Bérénice Segrestin<sup>a,b,*</sup>, Blandine Gatta Cherifi<sup>c,d,e</sup>

<figure><img src="image_3.png" /></figure>

## INFO ARTICLE

Keywords :

Obesity

Phenotyping

Individualized treatment

Lean mass

## ABSTRACT

Obesity has until now been defined in terms of body mass index, a parameter which lacks sensitivity. The definition rather needs to take account of the pathophysiology and impact of the mechanical, metabo- lic and psychological complications associated with excess adiposity, as proposed by the French Health Authority in 2022. Initial phenotyping of pathophysiological determinants and complications make it pos- sible to precisely define treatment objectives and the means used to achieve them. For example, excess adiposity is associated with hypervolemia, which increases the risk of heart failure independently of clas- sic cardiovascular risk factors, due in particular to myocardial remodeling and diastolic dysfunction. In this indication, SGLT2 (sodium/glucose cotransporter 2) inhibitors may be relevant. A global approach, invol- ing assessment of eating behavior and sensations, energy expenditure and emotional eating, enables us to identify drug treatments suited to each profile. Obesity is a recurrent pathology requiring the de velopment of new combined or sequential drug treatments. Currently under development, inhibitors of the myostatin/activin A pathway conserve lean body mass during weight loss, a crucial factor in limiting weight regain and maintaining functional capacity. Beyond medical or surgical approaches to obesity, lifelong lifestyle interventions are central to improving quality of life and limiting the risks associated with excess adiposity.

© 2025 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## 1. Introduction

As the global burden of obesity increases [1], with 890 mil- lion adults [2] affected worldwide and 10 million in France (OFEO 2024, unpublished), there is an urgent need to continue developing appropriate care to improve quality of life and reduce the many complications associated with excess adiposity. Body mass index (BMI) is not enough to define this complex multifactorial disease: a new definition of obesity is needed, that takes account of the pathophysiology and the psychological impact of stigmatization. We will see how this redefinition and classification will also help to adapt and individualize treatment approaches. The search for new diagnostic methods to detect complications such as heart fa ilure, and new pharmacological targets, notably to preserve lean body mass during weight-loss phases, will provide solutions to as yet unresolved questions.

## 2. Obesity: beyond BMI

Obesity was recognized as a disease by the World Health Orga- nization (WHO) as early as 1948 [2] and later by scientific societies, including the American Medical Association [3] in 2012. It is defined as excess adiposity that can be detrimental to health [4]. Studies on the links between BMI and mortality were at the origin of the defi- nition of thresholds for overweight (25 kg/m² ≤ BMI < 30 kg/m²) and obesity (BMI ≥ 30 kg/m², or in Asian populations ≥ 27.5 kg/m²), with mortality being lowest with BMI between 22.5 and 25 kg/m² [5]. An increase of 5 kg/m² in BMI increases mortality by 30%, linked to cardiovascular pathologies, diabetes and cancer. There is also a demonstrated link between body fat and mortality, with mortality rising by 10% for a 10% increase in body fat [6].

The interest and scientific relevance of defining obesity as a disease are debated, particularly with the idea that this could contribute to medicalizing the condition [7] and reinforce stigma [7], thus encouraging the maintenance of unhealthy eating habits.

All things considered, the use of BMI as a diagnostic criterion for obesity is flawed. BMI may in fact lead to under- or over-diagnosis of obesity as currently defined. The BMI criterion is highly specific

<footnote><sup>a</sup> F-CRIN - FORCE (French Obesity Research Centre of Excellence), CRNH, CARMEN lab INSERM U1060/University of Lyon/INRA U1235, Lyon1 University, Lyon, France</footnote>

<footnote><sup>b</sup> Endocrinology-Diabetes-Nutrition Department, hospices civils de Lyon, Lyon, France</footnote>

<footnote><sup>c</sup> Service d'endocrinologie, diabétologie et maladies métaboliques, CRMPradort, CHU de Bordeaux, Bordeaux, France</footnote>

<footnote><sup>d</sup> Inserm U1215, "Physiopathologie de la balance enérgétique et obésité", Neurocentre Magendie, université de Bordeaux, Bordeaux, France</footnote>

<footnote><sup>e</sup> UFR des sciences médicales, université de Bordeaux, Bordeaux, France</footnote>

<footnote>* Corresponding author. Endocrinology-Diabetes-Nutrition Department, hospices civils de Lyon, Lyon, France.</footnote>

<footnote>Adresse e-mail : berénice.segrestin@chu-lyon.fr (B. Segrestin).</footnote>
<table><caption>**Table 1**
Addressing stigma and prejudice in the diagnosis and management of patients with obesity/chronic adiposity-related diseases and assessing prejudice and stigma as determinants of disease severity [12].</caption><thead><tr><th>Stadium</th><th>Definition of adiposity-related chronic disease (ABCD) stage</th></tr></thead><tbody><tr><td>1</td><td>No known cardiovascular, mechanical or other physical complications of ABCD. Increased risk of complications (e.g. cancer) that can be reduced by weight loss AND/OR<br>Weight-related prejudice and stigma, psychological conditions and the social determinants of health do not adversely affect quality of life, but may require management as part of an individualized care plan</td></tr><tr><td>2</td><td>One or more mild-to-moderate ABCD complications and an increased risk of other complications AND/OR<br>Presence of internalized weight-related prejudice and stigma, psychological disorders, or social determinants of health that adversely affect quality of life or could potentially adversely affect quality of life, or ABCD treatment. These issues need to be taken into account when developing an effective, individualized treatment plan</td></tr><tr><td>3</td><td>At least one serious complication of ABCD and an increased risk of other complications AND/OR<br>Presence of internalized weight-related prejudice and stigma, psychological disorders or social determinants of health that have pronounced adverse effects on quality of life or render treatment ineffective. Intervention to address and remedy these problems must be implemented in the interests of the patient's well-being and to ensure treatment efficacy</td></tr></tbody></table>

Adapted from the American Association of Clinical Endocrinology Consensus 2023.

for adiposity, but not very sensitive [8], since 50% of subjects with BMI < 30 kg/m² have excess adiposity. BMI does not take account of the distribution of adipose tissue [9] or provide information on the pathophysiology of the disease or the individual's clinical phenotype [10].

It is therefore proposed to redefine the framework of obesity as a disease by introducing the concept of clinical obesity [7], a pathology in which excess adiposity is already the cause of metabolic or organ abnormalities.

Improved phenotyping of the condition associated with obesity is a necessary response to these questions. The Edmonton Obesity Staging System (EOSS, Canada) classifies 5 stages of obesity from 0 to 4, with assessment of comorbidities, psychological symptoms and functional limitations [11], assessing the impact of complications, but is clinician-dependent and does not include pathophysiological data. The Society of American Endocrinologists proposed a definition and classification of Adiposity-Based Chronic Disease (ABCD), with the aim of moving away from a model centered on weight or BMI. This classification takes into account not only of complications associated with ABCD, but also the impact on health and quality of life due to weight-related stigma or internalized stigma (i.e., internalization and adherence to social norms and stereotypes about weight) [12] (Fig. 1 and Table 1). Recently, the French National Health Authority drew up new good practice guidelines, with a classification in 3 levels of severity, also with the aim of organizing access to care [13]. Level 1 should be managed by general practitioners and primary care paramedics: e.g., level 1a: $30 \le IMC \le 35 \text{ kg/m}^2$, common adult-onset obesity with no metabolic abnormalities and little functional impact. Level 3 should be assessed in a specialized obesity center with access to a medical care and rehabilitation service specialized in nutrition (e.g., level 3b, secondary obesity, with end-stage chronic pathologies, and major functional impact (walking perimeter < 100 meters) after failed bariatric surgery).

Worldwide harmonization of staging is now necessary to personalize care and better guide therapy (lifestyle intervention/available drug treatments/bariatric surgery). This harmonization will also enable relevant clinical research studies to be carried out on homogeneous populations. The recently published EASO (European Association for the Study of Obesity) reading grid is interesting on several points [14]. It advocates assessing waist-to-height ratio to analyze the distribution of adipose tissue, a parameter that is easy to use in everyday practice and is a marker of cardiometabolic risk [15]. In this consensus, the diagnosis of obesity also includes patients with BMI between 25 and 30 kg/m² and waist-to-height ratio ≥ 0.5, thus including in the definition people with excess adiposity distributed at the abdominal level, and therefore at high risk of cardiometabolic pathologies [16]. The EASO also proposes screening for sarcopenic obesity, with an assessment of strength, muscle performance and body composition. Finally, this framework stresses the importance of explaining that the pathology is chronic and at risk of relapse [14].

### 3. Phenotyping obesity for better treatment

Evaluating and classifying obesity, in particular according to etiology, medical complications, functional and psychological impact, is an essential step in adapting and personalizing treatment. Characterization of pathologies associated with excess adiposity (e.g., heart failure) can be hampered by unsuitable diagnostic tools in this population. Treatment first targets weight loss, followed by weight maintenance to improve quality of life and reduce the complications associated with excess adiposity. There is considerable inter-individual variability in weight response, irrespective of the care plans implemented, which combine lifestyle interventions, drug treatments and/or bariatric surgery [17,18]. Analysis of factors predictive of response to treatment [19] enables a tailored, individualized care plan to be proposed. One step may be to establish a weight target according to the patient's profile and associated complications. Analysis of pathophysiological determinants (dietary behavior, energy expenditure, genetics in the case of rare obesity, or even metagenomics) will enable us to fine-tune the therapeutic tools for the patient in order to achieve the target.

#### 3.1. Screening for complications: considering the diagnosis of heart failure

Excessive adiposity contributes to an increase in blood volume, leading to hemodynamic stress. This can lead to cardiomegaly, with remodeling of myocardial tissue, reduced myocardial contractility and diastolic dysfunction, leading to heart failure [20]. Adiposity level correlates positively with risk of heart failure. The obesity-heart failure association is not explained by cardiovascular risk factors such as dyslipidemia, diabetes or hypertension [21]. One third of men with severe obesity (BMI ≥ 40 kg/m²) experience heart failure [22]. Severe obesity increases the risk of heart failure by a factor of 4 [21]: most frequently heart failure with preserved left ventricular ejection fraction (LVEF) [23,24]. In this study, the clinical symptoms of heart failure were associated with increased intra-cardiac pressure and LVEF ≥ 50%. By performing a matched analysis on BMI, it was shown that patients who developed heart failure with preserved LVEF also presented degraded renal function, and higher estimated plasma volumes [25] indicating cardio-renal dysfunction.

While the incidence of cardiovascular events (heart attack, stroke) has fallen in both the diabetic and the general population over the past 20 years, thanks to better control of cardiovascular risk factors, the incidence of heart failure in the diabetic population has stagnated [24]. In particular, there is a profile of young patients
<figure><img src="image_4.png" /><figcaption>Fig. 1. Figure adapted from the AACE 2023 Consensus.</figcaption></figure>

with obesity developing type-2 diabetes, at a high risk of developing heart failure. These same profiles are less medically treated regarding their cardiovascular risk factors [26].

## 3.2. Screening for heart failure in the population with excess adiposity therefore seems essential

Diagnosis of heart failure with preserved LVEF in the population with obesity is difficult. In particular, the clinical picture of effort/rest dyspnea linked to hypervolemia may arise in this setting, or be linked to physical deconditioning or an underlying respiratory pathology (obesity-hypoventilation syndrome, asthma). At this stage, precise analysis of echocardiographic parameters is required (left atrial size, pulmonary pressures, filling pressures) [27]; echocardiography, however, may have limited visibility. Moreover, natriuretic peptide thresholds are lower than in the general population [28]. A stress test or even right heart catheterization (rest and stress) can help establish diagnosis [20].

Effective treatments are available for this population, targeting obesity and heart failure: GLP1 analogues, in particular semaglutide [29] and iSGLT2 [30], which can reduce the number of hospital admissions. Bariatric surgery is also an option worth discussing: it relieves heart failure symptoms, with an effect on left ventricular volume and improved relaxation [31]. Combining these treatments with physical activity, whether moderate or high-intensity, has an additive beneficial effect [32]. Follow-up of a cardiac rehabilitation program is particularly relevant in this indication [33].

## 3.3. Which target for which complications? How to get there?

Assessment of complications enables a weight target to be set, as weight loss has a dose-response effect on complications. 5-10% weight loss in diabetic patients with obesity improves glycemic control (HbA1c -0.5%) [34]. 10% weight loss maintained over time helps prevent diabetes in subjects with pre-diabetes (30% reduction in diabetes incidence at 15 years [35]), significantly reduces the apnea hypopnea index in subjects with sleep apnea syndrome [36], limits inflammation and fibrosis in steatopathy (MAFLD: Metabolic-Associated Fatty Liver Disease) [37]. Losing more than

10% of body weight [38] reduces mortality and cardiovascular events [39]. The treatment decision is influenced by the goals to achieve and the anticipated response to different therapies.

Lifestyle changes involving a balanced diet with reduced intake during the weight loss phase, and increased physical activity during the weight stabilization phase, are associated with a fairly modest weight loss of 5-7% [17]. Drug treatments for obesity, such as GLP1 analogues (e.g., semaglutide), dual agonists (e.g., GLP1-GIP, tirzepatide) or triple agonists (e.g., GLP1-GIP-glucagon, retatrutide) promote satiation by acting on the hypothalamus [40] and slow gastric emptying, resulting in a loss of 15% [29] to 24% [41,42] of body weight. This is close to the average weight loss achieved by bariatric surgery [43], which is around 25%. These treatments are prescribed when nutritional management has failed. As expected in a chronic disease, discontinuation of drug treatment is associated with weight regain: 1 year after discontinuation of semaglutide, absolute weight loss was only 5% [44].

A major pitfall of treatment is the variable response to the various treatments [17], with discrepancy between the results of randomized studies and real-life experience. A real-life study in a cohort of 539 patients, for example, showed that the average weight loss at 12 months with semaglutide was only 4% in the non-diabetic population (dosage range 0.25 mg to 2 mg/week) [43].

## 3.4. Phenotyping benefits and focuses

Characterizing the individual pathophysiological determinants of obesity enables adaptation of therapeutic proposals. In particular, precise phenotyping [45], with analysis of eating behavior, food sensations (hunger, satiety, fullness) in relation to the intestine-brain axis, emotional eating and energy expenditure parameters, distinguished 4 profiles in an American cohort of 450 patients who then underwent adapted treatment, available in the USA. Subjects with low energy expenditure ("hypometabolics", 21% of subjects) received resistance training combined with phentermine treatment, which induces noradrenaline release, and increases energy expenditure. Subjects with a low level of satiation during meals ("hungry brains", analyzed during an all-you-can-eat buffet: 32% of subjects consumed 1,224 ± 25 kcal
versus 919 ± 16 kcal) received phentermine-topiramate (mode of action of topiramate not elucidated [18]). Subjects with a low level of satiety ("hungry stomachs", analyzed by gastric emptying scintigraphy; 32% of subjects) received GLP1 analogues. Subjects with a high level of emotional eating ("emotional eaters", analyzed by depression-anxiety questionnaires; 21% of subjects) received treatment aimed at addictions (naltrexone-bupropion: bupropion is a dopamine and noradrenaline reuptake inhibitor that stimulates the activity of pro-opiomelanocortin (POMC) neurons in the hypothalamus, while naltrexone blocks inhibition of POMC neurons by opioid receptors, the combination resulting in a lasting reduction in appetite [18]). After 12 months' treatment, weight loss was greater (16% at one year) in the phenotyped group, with 79% of subjects showing weight loss of more than 10% than in the non-phenotyped group (9% weight loss at 1 year; 35% of subjects lost more than 10%), while the pharmacopoeia used was the same in both groups. These results need to be confirmed by a randomized study.

It has also been proposed to study gene variants linked to adipose tissue metabolism in order to predict responses to lifestyle interventions, since interaction between genes and environment contributes to the onset of obesity [46]. This is particularly true of variants in the FTO (fat mass and obesity-associated protein) gene. Certain variants could lead to differences in weight response [47] to dietary intervention (diets modulated on lipid-carbohydrate-protein distribution) [46] or after bariatric surgery [48]. Polygenic scores linked to BMI are associated with variability in the rate of weight loss. However, these differences do not appear to be clinically significant [49]. On the other hand, genetic diagnoses of rare obesity, whether monogenic (biallelic loss of POMC, PCSK1, leptin receptor), syndromic (Bardet-Biedl syndrome) or hypothalamic (linked to craniopharyngioma, for example), are essential, as the MC4R agonist setmelanotide is an effective treatment [50–52].

Given the interaction between diet and intestinal microbiota, and the dysbiosis [53] described in patients with obesity, an initial characterization of the metabolic profile enriched by metagenomic analysis of the microbiota could enable the development of individualized precision-medicine dietary interventions [54,55] in terms of dietary fiber intake, animal or vegetable protein composition and addition of prebiotics (such as polyphenols) or probiotics [55,56]. Fiber, for example, is at the origin of a fermentation process producing short-chain fatty acids in the colon, which can positively modulate metabolism and promote satiety [55]. In the future, this research may lead to fecal transplants [57] for certain metabolic/metagenomic patient profiles.

## 4. New pharmacological approaches

Obesity is a chronic, relapsing pathology: developing new drug treatments that can be combined or used sequentially (e.g., in preparation for bariatric surgery, as an adjuvant to surgery, in the event of failure of the above-mentioned molecules) is essential and the focus of intense research.

### 4.1. A new target: activin receptor antagonist-mediated lean mass development during weight loss phases

The major challenge in weight loss phases is to target adipose tissue while conserving lean body mass, to limit the risk of weight regain and sarcopenia and conserve functional capacity. In addition, there is resistance to weight loss due to metabolic adaptation, partly linked to the loss of lean body mass [58]. This contributes to the risk of weight regain. After bariatric surgery, during the weight loss phase, lean body mass accounts for around 20% of the total weight lost [59]. This proportion is roughly equivalent with low-calorie diets [60]. Protein supplementation after surgery, com-

bined with resistance exercise, has no effect on conserving lean body mass [61]. There is considerable interest in therapeutics to limit loss of lean body mass. The myostatin-activin pathway is currently the focus of particular attention. Myostatin and activin A are TGFβ-like ligands that bind activin type II receptors (ActRII), limiting muscle growth by reducing IGF1 signaling via Akt [62]. Sarcopenic patients have high levels of myostatin, limiting muscle development [63]. Moreover, elevated myostatin levels correlate positively with insulin resistance and BMI [64]. ActRII antagonists are currently under investigation, including bimagrumab, an ActRII monoclonal antibody that binds to both ActRIIA and ActRIIB receptors. Its combination with semaglutide increases fat loss while conserving muscle mass in mice, and also improves exercise performance [65]. In a randomized 48-week phase 2 trial in 75 overweight patients with type-2 diabetes [18], monthly injections of bimagrumab combined with dietary support and physical activity advice resulted in 6% loss of initial weight, with 7 kg loss of body fat, 1.7 kg increase in lean body mass and improvement in HBA1c (−0.8%). Adverse events included moderate diarrhea, muscle spasms and acute pancreatitis. A modulation of this pathway during the dynamic phases of weight loss, particularly in patients with sarcopenic obesity, is promising.

Another avenue of interest under development is to target leptin resistance, seen in subjects with obesity: i.e., attenuated response to leptin despite increased leptin levels [66]. Histone deacetylase HDAC 6 has been identified as a contributor to leptin resistance [67,68], with expression in the hypothalamus and adipose tissue. In obese mice, HDAC 6 inhibitors contribute to weight loss by reducing ingestion. HDAC 6 inhibitors target the leptin receptor signaling pathway, restoring gene expression at hypothalamic level downstream of the receptor [68]. This pathway has not yet been explored for the treatment of obesity in humans.

## 5. Conclusion

At a time when 1 in 8 adults worldwide is living with obesity according to BMI criteria, redefining obesity beyond weight must include pathophysiological characteristics (dietary behavior, energy expenditure, genetics, metabolic and mechanical impact), in order to individualize care proposals (weight loss targets, treatments). The exploration of new drug targets aims in particular at conserving lean body mass during weight loss phases. Beyond the pharmacological or surgical approach to obesity, lifestyle interventions (promotion of physical activity, environment, diet) are central throughout life to improve quality of life and limit the risks associated with excess adiposity.

## Disclosure of interest

BS: links with Novonordisk, Lilly, Rhythm, Abbott, Amryt. BGC: links with Novonordisk, Lilly, Rhythm.

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