Obesity: Why new medications are not miracle cures

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Both were withdrawn from the market due to their dramatic side effects, particularly cardiac (heart valve damage) and pulmonary (pulmonary arterial hypertension) problems.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.

Factors that hinder prevention include: -- the ease of access to foods that promote obesity (sweet, salty, ultra-processed), cheap, touted by advertising, little regulated and little taxed, even though their harmful nature is proven; -- the obstruction to the generalisation of tools which are nevertheless widely validated such as the Nutri-Score, illustrating the fact that health issues generally come after economic interests, both at the French and European levels; -- the unfavourable environmental context exposes individuals to multiple pollutants. Many of these promote obesity, particularly through hormonal mechanisms; -- the shortcomings of land-use planning policies which should promote active mobility and access to physical and sporting activity infrastructure across the entire territory (urban, semi-urban and rural) and thus combat sedentary lifestyles and lack of physical activity; -- the impact of socio-economic or psychological factors that make it difficult to implement virtuous behaviours in terms of diet and physical activity.

Let us recall the weight of inequalities (socio-economic, gender, ethno-racial, territorial, etc.) on health in general and particularly on issues relating to obesity. In France, 17% of individuals whose standard of living is below the first quartile of the distribution are obese, compared to 10% for those whose standard of living falls within the upper quartile.

The increase in poverty, precariousness and the widening of social inequalities are therefore worrying, as they can only worsen the health conditions of the most disadvantaged populations.

Prevention is cheaper than cure

Let us conclude with a point impossible not to consider: the cost of treatment with GLP-1 analogues, estimated at around 300 euros per month per patient.

Without reimbursement, this treatment will only be accessible to the wealthiest. If it is covered by health insurance, the potential cost appears staggering. The WHO predicts that by 2030, nearly 30% of the French population could be affected by obesity.

In conclusion, the healthcare community, along with the patient community, cannot rely excessively on this class of medications.

To combat obesity, it is essential to continue promoting a multidisciplinary approach, combining academic knowledge from various scientific disciplines with knowledge often described as "experiential": that of patients, health education and prevention professionals, health policy decision-makers, and so on.

This approach is certainly less spectacular and less easily publicised than the sensational announcements that accompany the discovery of innovative therapies, but it is essential. Prevention is not opposed to curative treatment: it precedes and accompanies it.

We can only hope to significantly and sustainably reduce the prevalence of obesity by targeting all the underlying factors that contribute to it: individual, social, and environmental. This implies the development and implementation of broad, ambitious public health policies that respect democratic participation in healthcare.

We must recognise that this will likely go against short-term economic interests. But public health is undoubtedly worth it.