The rise of GLP-1 agonists: a scientific response to the challenges of diabetes and obesity

Understanding GLP-1 and its analogues: mechanisms and distinctive properties

Glucagon-like peptide 1 (GLP-1) has established itself as a pivotal player in metabolic research and the pharmacological treatment of type 2 diabetes and obesity. This incretin hormone, secreted by intestinal L cells after each food intake, modulates blood glucose levels by stimulating insulin release from beta cells and inhibiting glucagon secretion, depending on circulating sugar levels. However, the physiological effect of GLP-1 is fleeting, as it is rapidly eliminated by the DPP4 enzyme. It could be said that nature sometimes does things too fast: “endogenous” GLP-1 has only a very limited time to act, hence the need for innovation.

To circumvent this rapid degradation, researchers have developed GLP-1 analogues capable of mimicking the natural hormone while resisting the action of DPP4. These GLP-1 receptor agonists differ in their molecular structure and duration of action:

• Exenatide (Byetta, Bydureon): derived from exendin-4 from the Gila lizard, it is used on a daily or weekly schedule.

• Liraglutide (Victoza, Saxenda): its architecture mimics that of human GLP-1, administered daily, and it was the first approved for weight management.

• Dulaglutide (Trulicity), semaglutide (Ozempic, Wegovy, Rybelsus, in oral format), finally tirzepatide (Mounjaro): mainly injected weekly, they have high target affinity and prolonged persistence.

Their mechanism of action encompasses:

• increased stimulation of insulin release in the presence of glycemic elevation;

• a decrease in hepatic glucose synthesis, following glucagon inhibition;

• a slowing of the passage of food from the stomach to the intestine;

• a marked effect on the sensation of satiety and appetite reduction.

In use, this translates into improved blood glucose control, progressive reduction in body weight and positive effects on several cardiometabolic parameters. The main differences between these molecules are their half-life, frequency of administration and the extent of weight loss. In the field, many patients report an almost immediate reduction in appetite – the “appetite suppressant” effect of GLP-1 is sometimes the talk of the clinic.

Comparative table of the main GLP-1 agonists:

View interactive diagram of GLP-1 agonist mechanisms of action.

In practice, preference is now given to:

• Subcutaneous injectable forms, which fit in well with the chronic dimension of management and promote therapeutic adherence, sometimes complex to maintain over the long term, especially in patients with a history of failed diets.

• Enzyme stability, the key to sustained efficacy and a guarantee of less volatility in blood concentrations.

• The speed of action and extent of weight loss vary notoriously depending on the analogue chosen and the situation: it’s not uncommon for semaglutide to hold the top spot for weight management, particularly in specialist hospital group practices.

We also note a gradual adaptation of doses to limit digestive effects, which requires active patient involvement in follow-up.

Clinical perspectives: indications, benefits and levels of scientific evidence

In common diabetes care, GLP-1 agonists are proposed as second- or third-line therapy when traditional oral antidiabetic agents (metformin, sulfonamides) are no longer sufficient to maintain glucose control. Since the extension of European marketing authorization to include obesity (BMI ≥30, or ≥27 with complications such as high blood pressure or sleep apnea), their use is expanding; in France, dispensing by any doctor will be possible from June 2025. This development is the result of discussions between the Haute Autorité de Santé (HAS), the European Medicines Agency (EMA), and the Académie Nationale de Médecine, each contributing its own criteria for integration and monitoring.

Large clinical trials have shown major benefits, validated by several international bodies:

• Reduction of HbA1c by around 1 to 1.5%

• Real weight loss: the STEP (semaglutide) and SURPASS (tirzepatide) trials document a loss that can exceed 15% depending on duration, follow-up and dose. The difference with older treatments is sometimes notable, even spectacular (some reference diabetologists evoke weight-loss profiles yet difficult to achieve by other means).

• Lower incidence of acute cardiovascular events (heart attack, stroke, cardiovascular mortality)

• Improved hepatic steatosis, reduced waist circumference, slower unfavorable evolution of certain metabolic complications, and even hopes for longevity.

List of major indications:

• Malstabilized type 2 diabetes on tablets.

• Overweight or obesity (BMI ≥30), or BMI ≥27 with comorbidities.

• Cardiovascular prevention for subjects at proven risk.

• Integration into a comprehensive care circuit, combining medical procedures, nutrition and sometimes rehabilitation.

In practice, some patients and users gathered in advocacy groups are asking questions: equitable access to treatment remains an issue, a source of inequalities depending on the territory and the local pharmacy.

Regulatory agencies (HAS, EMA, FDA, CDC) are gradually adjusting their recommendations to integrate these drugs into guidelines, while recommending close monitoring. Recommendations often evolve in the light of pharmacovigilance data transmitted by the CRPVs, and feedback from the field (or even from meetings of the Temporary Scientific Committee – CST, which is occasionally called upon).

Consult the tables of updated recommendations and the results of STEP/SURPASS studies.

Weight loss efficacy results from the STEP and SURPASS studies:

Our opinion

While therapeutic approaches are breaking new ground, GLP-1 agonists are breaking new ground by tackling the root cause of metabolic imbalances in diabetes and obesity. Linking prescriptions to a rethought lifestyle and therapeutic education opens the way to more comprehensive treatment paths for patients who are sometimes left without prospects. The results are encouraging, but we must remain vigilant with regard to misuse and accessibility issues: many professionals, including hospital diabetologists, insist on the need for careful monitoring to make the collective health benefits tangible. On the patient side, the social motivation or fear of stigmatization linked to weight loss with medication continues to fuel reflection: this is a point of medical ethics that remains topical.

Safety, monitoring and pharmacovigilance issues

The tolerability of GLP-1 agonists is based on an arsenal of data from real-life and controlled trials. Side effects, generally digestive, are frequent at the start of treatment, but, in most cases, of moderate and transient intensity.

Main adverse effects noted:

• Common digestive manifestations: nausea, retching, diarrhea, sometimes constipation, the severity of which often appears dose-related.

• Rare acute inflammation of the pancreas.

• Increased risk of gallstones.

• Rare thyroid gland damage (nodules or specific forms of cancer).

• Simultaneous loss of muscle mass, requiring monitoring of the patient’s nutritional status.

The benefit/risk ratio is assessed through notifications to the ANSM and CRPV. Some diabetologists note that monitoring of weight and lean body mass is becoming almost systematic, particularly when patients combine a low-calorie diet with physical activity.

Regional pharmacovigilance centers under the aegis of the ANSM centralize incident reports, alerting in the event of unusual signals. In France, the issue is a sensitive one, in view of increasingly visible off-label use and the resulting tensions in the supply chain: in 2024, several establishments reported major stock-outs, impacting the management of priority patients.

• It’s worth noting that stopping treatment often leads to rapid weight regain, which argues in favor of in-depth support aligned over time.

• Diversion for cosmetic purposes or with no recognized indication continues to motivate caution and a reminder to caregivers to be vigilant, in line with official instructions from the authorities (HAS, EMA, FDA).

Key points of follow-up:

• Regular weighing and HbA1c dosage.

• Evaluation of digestive tolerance, especially in the start-up phase, and then at each dose change – in the field, patients sometimes report unforeseen problems after adapting too quickly.

• Adaptation of the therapeutic regimen if adverse effects occur.

• Systematic reporting of any side effects to the relevant authorities (ANSM/CRPV).

Access the practical guide to monitoring side effects and the ANSM report.

Mesusage, social acceptability and public health issues

The extent of the media coverage surrounding these analogues has generated a completely unprecedented craze – and sometimes difficulties of access for the target audiences. Out-of-framework prescriptions, motivated by fashion, are generating increasing pressure on the availability of the drug, a phenomenon observed both in France and abroad. The relationship between media coverage and supply tensions is now under scrutiny by public health organizations.

Overview of the main risks:

• Misuse by bypassing regulated circuits or overprescribing outside validated indications, very often under the influence of social networks.

• Fragilization of logistics (delays, stock-outs, inequalities in access depending on territory – some patients sometimes have to change pharmacies or wait several weeks).

• The need for learned societies and health agencies (HAS, Académie Nationale de Médecine, EMA) to refocus official messages, reminding patients of the protocols to be followed.

Patient information and support remain decisive levers: conveying the keys to optimal treatment use, explaining how to integrate it into an overall program, and preventing drifts are all essential relays for improving care. Several patient groups are calling on the media and advising the general public to be cautious.

• The question of the acceptability of weight loss on medication, between public expectations and the risk of stigmatization, is a matter of debate: it’s a situation that’s still far from clear-cut, with some patients reluctant to reveal the drug-induced origin of their weight loss.

• It remains useful to organize prolonged follow-up in order to check the stability of results and guide public health choices, even if it means sometimes wondering whether medicalizing weight loss might not be going too far.

Subscribe to the information webinar on best practices and therapeutic education.

Towards precision medicine: individualization, perspectives and innovations

The trajectory of GLP-1 agonists is part of a logic of continuous improvement and individualized pathways. The personalized approach is already based on a detailed analysis of age, gender, metabolic profile and weight trends. Combining an adjusted diet, physical exercise and psychological support is now becoming the norm for consolidating weight-loss benefits and boosting therapeutic outcomes.

Prospects are emerging through:

• The evaluation of possible neuroprotective and anti-addictive effects, mentioned in a few recent trials (notably on bulimia or food addiction).

• The creation of more complex biotherapies, such as dual GLP-1/GIP agonists, promising better performance, and which should enter the debate at forthcoming meetings of the Académie de Médecine.

• The refinement of recommendations in line with data compiled in real-world practice (real-world evidence, notably from the Univadis or Qare.fr networks).

• The greater emphasis placed on the patient experience, to prevent weight regain and strengthen collaboration throughout the management process – some therapeutic adherence devices are actually making their appearance in nursing homes.

The preventive medicine model is gradually gaining ground, with the idea, promoted by several diabetologists and institutions, that better management of diabetes and overweight will reduce long-term morbidity and mortality, and lower the cost to the healthcare system. Chrononutrition and the intestinal microbiota remain subjects of investigation for the future.

Find out about the clinical perspectives soon to be available and the avenues of research into personalized medicine.