By Alexandre Duparc, Olivier Lairez, and Philippe Ter

Paris- The fight against obesity is one of the major challenges of 21st century medicine.

This chronic disease, with its numerous physical, psychological, and social complications, has seen its global prevalence double between 1990 and 2022, at which point it affects, according to the World Health Organisation (WHO), more than one billion people (880 million adults and 160 million children).

France is not spared. It is estimated that approximately 8 million French men and women are currently affected by obesity. Its prevalence increased from 8.5% in 1997 to 15% in 2012, then to 17% in 2020, and this trend is expected to continue in the coming years.

Recently, new drugs - analogs of the gut hormone glucagon-like peptide-1 (GLP-1) - have been added to the therapeutic arsenal, raising new hopes. However, they alone will not be enough to conquer obesity. Here's why.

New effective molecules

The WHO defines overweight and obesity as an abnormal or excessive accumulation of fat that poses a risk to health. A person is considered overweight if their body mass index (BMI) is greater than 25, and obese if it exceeds 30.

Historically, the therapeutic management of this disease has been structured around a multidisciplinary and comprehensive approach combining lifestyle advice (physical activity, diet), psychological support, and the prevention and treatment of complications. For the most severe cases, bariatric surgery may be considered.

Drug therapies were long relegated to the sidelines. We remember the failure of dexfenfluramine (brand name Isomeride, authorized in France from 1985 to 1997), then of benfluorex (brand name Mediator, authorized from 1976 to 2009).

Both were withdrawn from the market due to their dramatic side effects, particularly cardiac (heart valve damage) and pulmonary (pulmonary arterial hypertension) problems. Mediator remains associated with one of the most resounding health scandals of recent decades.

Recently, a new class of molecules has become available to the medical community to combat obesity: glucagon-like peptide-1 (GLP-1) analogs. This small hormone increases insulin production, thus improving glucose absorption. It has a beneficial effect on satiety and delays gastric emptying.

Among these new medications are liraglutide (marketed under the brand names Saxenda for obesity and Victoza for diabetes), semaglutide (brand names Wegovy for obesity and Ozempic for diabetes), and tirzepatide (Mounjaro).

Prescribed as weekly injections, these molecules were already routinely used in the management of type 2 diabetes. Several large-scale clinical trials in obese or overweight subjects without diabetes have demonstrated the effectiveness of these medications when used in conjunction with a management plan combining diet and physical activity.

The benefit appears to extend beyond weight loss alone, as improvements in certain cardiovascular and metabolic parameters have also been observed.

The marketing authorization currently allows them to be prescribed as a supplement to a low-calorie diet and increased physical activity in adults with a body mass index (BMI) greater than 30 kg/m2 or greater than 27 in cases of weight-related comorbidities. However, they are not reimbursed by the national health insurance.

These treatments, which appear simple, effective, and less invasive than surgery, have generated legitimate enthusiasm. However, it is unrealistic to imagine that the fight against obesity can be reduced to a weekly injection of medication.

Indeed, the causes of obesity and being overweight are multifactorial and go beyond the issue of a simple imbalance between calorie intake and expenditure.

Obesity, overweight: multiple causes

Research has revealed that the risks of overweight and obesity depend on several determinants: genetic (and epigenetic), endocrine (in other words, hormonal), drug-related (some treatments increase the risk), psychological, sociological, and environmental factors.

Regarding this last point, we now know that many substances ubiquitous in the environment are classified as obesogenic. They can disrupt our hormonal metabolism (endocrine disruptors ), alter our gut microbiota, or act at the genetic and epigenetic level.

In this context, the concept of the exposome, defined as“the sum total of environmental exposures throughout life, including lifestyle factors, from the prenatal period onwards”, takes on its full meaning.

In some cases, the effects of the factors involved in obesity can remain latent for many years, and the consequences may only manifest later, even in subsequent generations. Diethylstilbestrol (better known by its trade name Distilbene) is a prime example of these transgenerational metabolic effects, not only in terms of overweight and obesity, but also with regard to cancer risk.

It is to account for these causal phenomena that the concept of developmental origins of health and disease (DOHaD) was forged.

Once the complexity of obesity has been exposed, it becomes clear that the targets on which GLP-1 analogues act (insulin production, satiety) are far from being the only ones involved in the disease.

Furthermore, it is observed that the sources of obesity mostly have negative health consequences that go beyond mere weight gain. Thus, excessive consumption of refined sugars, ultra-processed foods, red meat, processed meats, lack of fibre, exposure to toxins, and a sedentary lifestyle are all risk factors for poor health.

Molecules that don't work miracles

GLP-1 analogues cannot“cure” obesity. This is not what the authors of the studies that tested their effectiveness claim.

According to the results of the STEP3 study, weight loss with semaglutide was 15% after 68 weeks of treatment (compared to 5% in the placebo group). Considering the“typical” profile of patients included in this study, individuals with an average BMI of 37 (corresponding to a weight of 100 kg for a height of 1.65 m), a 15% weight loss would bring their BMI down to 31.

They would then move from severe to moderate obesity. While the health benefits are considerable, these individuals would still present a significant increased medical risk.

It is also important to consider the treatment's tolerability and adherence in patients whose prescriptions may be very long due to multiple comorbidities. Furthermore, the long-term maintenance of efficacy remains to be determined, especially if all the underlying causes are not eliminated.

There are also issues of weight gain after stopping treatment, as well as sarcopenia, that is, muscle loss, whether qualitative or quantitative. Indeed, weight loss is never solely a loss of fat mass, but is also accompanied by a loss of lean mass, particularly muscle. This phenomenon could be prevented or offset through physical exercise.

The importance of prevention

To date, GLP-1 analogs are considered as a treatment for obesity once it has developed. This is therefore a curative approach. Scientific articles assume that preventive measures, known as“lifestyle and dietary” measures, are insufficient, while the methods used to develop these measures are rarely questioned, nor is the possibility of addressing the numerous factors that hinder their implementation.

Advice given to the general public is primarily disseminated as messages or injunctions to modify individual behaviours. This implicitly places the responsibility on each individual and is, in this sense, potentially guilt-inducing. At the same time, it most often overlooks the other causal factors that shape our overall exposure.

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