GLP-1 and incretins: physiological bases and mechanisms of action

GLP-1 (glucagon-like peptide-1) belongs to the large family of incretins: these are digestive hormones, of which GLP-1 is distinguished by its production within the L cells of the intestine as soon as nutrients are detected. It should not be forgotten that this mechanism takes place after virtually every meal, hence its daily involvement in the regulation of metabolism.

Its action, via the GLP-1R receptor, orchestrated in particular on the pancreas (beta cells), manifests itself through several effects:

• Activation of insulin production as soon as blood sugar rises (classic but effective)

• Brake on glucagon release – and thus control of hepatic glucose

• Dampening of gastric emptying : the post-prandial rise in sugar is smoothed

• Stimulation of the central nervous system to amplify the sensation of satiety and regulate appetite

Alongside “natural” GLP-1, medicated analogues mimic or exceed its effects: they have an adapted structure that slows down their degradation by DPP-4 and prolongs their half-life, a major breakthrough resulting from work by companies such as Novo Nordisk and Amylin Pharmaceuticals. This pharmacological extension supports the ongoing management of type 2 diabetes and obesity, where treatment stability makes all the difference in the field.

Latest research (Institut Cochin, CNRS, INSERM, Université Paris Cité, Froguel, Jockers, Bonnefond teams) has shown how GLP-1R receptor mutations modify the metabolic response: among 60 variants, 56 reduce the effectiveness of GLP-1 on insulin production or glucose regulation. This genetic impact – sometimes invisible in practice – is beginning to point the way towards personalized medicine: soon, pharmacogenetics and identification of the metabolic phenotype will make it possible to fine-tune the regimen for each patient.

We’ll remember:

• GLP-1, hormone secreted by intestinal L cells on food ingestion

• Area of action: pancreas (beta cells), glucagon inhibition, effect on gastric slowing, intervention on central regulation (brain)

• Analogues : prolonged half-life thanks to enzymatic resistance (DPP-4), enhanced efficacy (accompanied by better therapeutic adherence)

• Individual variability: response depends on genetics, hence the importance of personalized treatment

We now need to refine how each GLP-1 modulation actually adapts to the individual: clinicians’ experience shows that this field is in full mutation, even if everything in the field is not yet settled.

Panorama of treatments: clinical efficacy, authorized molecules and target population

Recommended molecules, efficacy and conditions of administration

• Presence of a GLP-1R receptor mutation: the protocol may require adaptations, sometimes necessitating the advice of specialized centers such as PRECIDIAB

• Elderly, polymedicated subjects, or a history of pancreatic disease (pharmacovigilance has insisted on this point since 2023)

Health agencies (ANSM, HAS, FDA, EMA) remind us of the importance of:

• Report every adverse reaction via official systems and, on this point, an information campaign for caregivers started in 2024

• Respect validated indications and contraindications

• Educate on the risk of detour for non-medical use: this also concerns the social impact around the “slimming pill” that circulates on forums and among certain media

In practice:

• Main adverse effects reported: digestive, pancreatic, exceptionally neurological

• Population to watch out for: GLP-1R receptor mutations, polytherapy, history of pancreatitis

Continuous medical monitoring recommended

Systematic pharmacovigilance reporting (even for symptoms considered mild)

In case of doubt, contact a doctor or pharmacist immediately to report an unusual effect and receive the appropriate instructions: the official procedure has been strengthened in summer 2024.

Regulations and prescribing practices in 2024-2025

Supervision, access and legal developments: France and internationally

In France, until 2025, initial prescription remains reserved for specialists (endocrinologists, diabetologists, registered nutritionists), with possible transfer of follow-up to the general practitioner, in line with new HAS and ANSM opinions. Access for obese patients (excluding diabetics) is free: Wegovy (semaglutide) and Mounjaro (tirzepatide) have been marketed without reimbursement since November/October 2024.

Overseas, legality and coverage vary:

• Europe: EMA centralizes authorization, but reimbursement remains rare for isolated obesity – each country sets its limits

• United States : the FDA has more systematically authorized the “obesity” indication since 2024, giving prescribers greater latitude, at least on paper; some states have even launched campaigns against detour and the social acceptability of the drug

• In France, recurring shortages (2023-2024) have forced pharmacies, supported by the ANSM, to redirect patients to alternative treatments (sulfonylureas or glitazones)

==Before taking any action, remember to consult a healthcare professional to check the current regulations: a change can occur quite quickly following annual revisions or occasional shortages==

Misuse, resistance and the future of GLP-1 analogues

New issues: misuse, innovation, translational medicine

The rapid popularization of GLP-1 analogues led, unexpectedly, to a sharp increase in misuse for cosmetic or social purposes. As early as 2023, the media relayed warnings of shortage periods affecting several major French cities and accounts of massive detour – not only in medical circles but also on social networks (which the ANSM confirmed at its most recent meetings).

To overcome these new challenges, research is focusing on several areas:

• Development of oral forms for GLP-1 (in trial at Novo Nordisk), which are better accepted (and sometimes less anxiety-provoking for patients reluctant to take injections)

• Work on positive allosteric modulators (PAMs), delayed formulation and molecules with enhanced metabolic stability (AC2993/new-generation exenatide)

• Very thorough individualization : UK Biobank-type cohorts enable early detection of genetic profiles at risk of poor response or resistance, and adaptation of dosage or molecular regimen (even if psychological management remains difficult to integrate into standard protocols)

• Coordinated translational approach (endocrinologists, geneticists, pharmacists, educators and sometimes psychologists): “resistant” patients are sometimes redirected to multidisciplinary consultations, a phenomenon that has increased markedly since 2024

Scientific societies and authorities (HAS, ANSM, Universcience, PRECIDIAB) are now mobilized around two pillars:

• Combating the trivialization or even massive misuse of drugs: information campaigns for caregivers and the public are underway

• Encouraging the exploration of innovative molecules for non-responder or intolerant patients, while remaining vigilant about the benefit/risk balance

Keep in mind:

• Scarcity and diversion: access tensions, tighter regulation

• Molecular advances: oral administration, modulators or high-stability analogues

• Personalized strategies : genetic analysis and adaptation of treatment to metabolic phenotype

• Interdisciplinary cooperation: increasing the competence of all players, from prescribing to psychological support

Stay informed about drug developments: innovation is ongoing, and each medical team adjusts its practices in line with new data, sometimes from one week to the next.

In the current pharmacopoeia, several GLP-1 agonists are employed, mainly from laboratories such as Novo Nordisk or Amylin Pharmaceuticals. Over the years, we’ve seen the arrival of:

• Liraglutide (Saxenda, Victoza)

• Semaglutide (Ozempic, Wegovy)

• Tirzepatide (Mounjaro)

Exenatide (Byetta, Bydureon, AC2993 in formulation)

• Dulaglutide (Trulicity)

Results validated by the ADA, Nature Metabolism or Jean-Pierre Riveline in Philadelphia:

1. Glycemic control (HbA1c): reduction of up to 1% in 1 month for exenatide versus placebo, which is clearly not negligible.

2. Weight loss: from 2% to 15% depending on the molecule, with peaks sometimes exceeding 15% in obese or high-BMI patients (≥ 35 kg/m²).

3. Cardiovascular effect: reduced risk of major accidents, particularly with recent generations; cardiologists see this as a real breakthrough.

4. Drug safety: low rate of hypoglycemia in monotherapy, digestive disorders to watch out for (nausea especially), good overall tolerance but variable acceptability depending on the patient.

In France, reimbursement and prescription schemes have tightened:

• Growing number of type 2 diabetic patients (after metformin or micro-polytherapy failure)

• Obesive patients: BMI ≥ 30 kg/m², or ≥ 27 kg/m² in case of metabolic complications, but financial coverage remains absent outside diabetes (free price for Wegovy, Mounjaro since end 2024)

In practice, we find that the recommendations need to be refined: some patients, particularly overweight patients with comorbid conditions, react in unexpected ways. And during the latest exchanges at the scientific committee (ANSM 2024), this heterogeneity of response was one of the major concerns.

Our opinion

GLP-1 analogues have brought about a profound change in the treatment of diabetes and obesity, on a scale comparable to the arrival of metformin in the past. Today, the use of pharmacogenetics, coupled with metabolic phenotype analysis, is leading to ultra-targeted management: each patient becomes a case apart, or almost. It’s not just a question of prescribing, but also of rigorous educational support to limit misuse – the recent craze for rapid loss (see the waves on social networks) is clearly not without danger. Tension over stocks, the pressure of a standardized body image and aesthetic misappropriation call for ongoing debate, mobilizing both health authorities (HAS, ANSM, EMA, FDA) and professionals in the field.

Safety of use: adverse effects, pharmacovigilance and surveillance

Side effects, clinical monitoring and benefit-risk balance

The majority of patients tolerate these drugs well – but, in clinical trials, some side effects remain non-negligible:

• Digestive disorders (nausea, diarrhea, vomiting): around 10% discontinuation during studies, especially at the start of treatment, and sometimes depending on the molecule or titrated dose

• Possibility of acute pancreatitis : any suspicious sign should lead to discontinuation of the drug, a reflex that often avoids the worst

• Rareful (but watchful) optic nerve neuropathy: reported for prolonged exposure, mainly in polymediated patients

• Drug interactions: cases of pharmacological interaction have been cited, notably with glitazones and insulin aspart or glargine; caution is therefore advised in multi-treated patients

Clinical monitoring is intensified in certain cases:

• Presence of a GLP-1R receptor mutation: the protocol may require adaptations, sometimes necessitating the advice of specialized centers such as PRECIDIAB

• Elderly, polymedicated subjects, or a history of pancreatic disease (pharmacovigilance has insisted on this point since 2023)

Health agencies (ANSM, HAS, FDA, EMA) remind us of the importance of:

• Report every adverse reaction via official systems and, on this point, an information campaign for caregivers started in 2024

• Respect validated indications and contraindications

• Educate on the risk of detour for non-medical use: this also concerns the social impact around the “slimming pill” that circulates on forums and among certain media

In practice:

• Main adverse effects reported: digestive, pancreatic, exceptionally neurological

• Population to watch out for: GLP-1R receptor mutations, polytherapy, history of pancreatitis

Continuous medical monitoring recommended

Systematic pharmacovigilance reporting (even for symptoms considered mild)

In case of doubt, contact a doctor or pharmacist immediately to report an unusual effect and receive the appropriate instructions: the official procedure has been strengthened in summer 2024.

Regulations and prescribing practices in 2024-2025

Supervision, access and legal developments: France and internationally

In France, until 2025, initial prescription remains reserved for specialists (endocrinologists, diabetologists, registered nutritionists), with possible transfer of follow-up to the general practitioner, in line with new HAS and ANSM opinions. Access for obese patients (excluding diabetics) is free: Wegovy (semaglutide) and Mounjaro (tirzepatide) have been marketed without reimbursement since November/October 2024.

Overseas, legality and coverage vary:

• Europe: EMA centralizes authorization, but reimbursement remains rare for isolated obesity – each country sets its limits

• United States : the FDA has more systematically authorized the “obesity” indication since 2024, giving prescribers greater latitude, at least on paper; some states have even launched campaigns against detour and the social acceptability of the drug

• In France, recurring shortages (2023-2024) have forced pharmacies, supported by the ANSM, to redirect patients to alternative treatments (sulfonylureas or glitazones)

==Before taking any action, remember to consult a healthcare professional to check the current regulations: a change can occur quite quickly following annual revisions or occasional shortages==

Misuse, resistance and the future of GLP-1 analogues

New issues: misuse, innovation, translational medicine

The rapid popularization of GLP-1 analogues led, unexpectedly, to a sharp increase in misuse for cosmetic or social purposes. As early as 2023, the media relayed warnings of shortage periods affecting several major French cities and accounts of massive detour – not only in medical circles but also on social networks (which the ANSM confirmed at its most recent meetings).

To overcome these new challenges, research is focusing on several areas:

• Development of oral forms for GLP-1 (in trial at Novo Nordisk), which are better accepted (and sometimes less anxiety-provoking for patients reluctant to take injections)

• Work on positive allosteric modulators (PAMs), delayed formulation and molecules with enhanced metabolic stability (AC2993/new-generation exenatide)

• Very thorough individualization : UK Biobank-type cohorts enable early detection of genetic profiles at risk of poor response or resistance, and adaptation of dosage or molecular regimen (even if psychological management remains difficult to integrate into standard protocols)

• Coordinated translational approach (endocrinologists, geneticists, pharmacists, educators and sometimes psychologists): “resistant” patients are sometimes redirected to multidisciplinary consultations, a phenomenon that has increased markedly since 2024

Scientific societies and authorities (HAS, ANSM, Universcience, PRECIDIAB) are now mobilized around two pillars:

• Combating the trivialization or even massive misuse of drugs: information campaigns for caregivers and the public are underway

• Encouraging the exploration of innovative molecules for non-responder or intolerant patients, while remaining vigilant about the benefit/risk balance

Keep in mind:

• Scarcity and diversion: access tensions, tighter regulation

• Molecular advances: oral administration, modulators or high-stability analogues

• Personalized strategies : genetic analysis and adaptation of treatment to metabolic phenotype

• Interdisciplinary cooperation: increasing the competence of all players, from prescribing to psychological support

Stay informed about drug developments: innovation is ongoing, and each medical team adjusts its practices in line with new data, sometimes from one week to the next.