Drug therapies were long relegated to the sidelines
The fight against obesity is one of the
major challenges of 21st century medicine.
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.
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Both were withdrawn from the market due to their dramatic side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.