2023-10-05 11:10:52
GLP-1 agonists are commonly used in the treatment of type 2 diabetes. Two of them, liraglutide and semaglutide, have also obtained marketing authorization in Europe in recent years for weight loss in certain obese non-diabetic patients, in addition to hygienic-dietary measures.
In France, liraglutide (Saxenda) has been marketed since 2021, indicated in patients with a BMI ≥ 30 mg/m2, or ≥ 27 mg/m2 with comorbidities (hypertension, dyslipidemia or sleep apnea), in addition to a hypocaloric diet and physical activity, but it is not reimbursed in this indication. Semaglutide (Wegovy) obtained early access authorization in 2022 for obese patients (BMI ≥ 40 mg/m2) with comorbidities, but it was withdrawn in September 2023.
Due to the galenic form of these currently available specialties (injectable solutions), Oral alternatives, easier to use, are being studied. This was the subject of a recent trial whose results have just been published in the NEJM
.
It’s regarding a randomized, double-blind phase II studywho recruited 272 adults overweight or obese but without diabetes (average age: 54.2 years; 59% women), in Canada, the United States and Hungary. Participants, aged 18 to 75, had to be at least one comorbidity linked to obesity to be included (hypertension, dyslipidemia, cardiovascular pathologies or sleep apnea). They must also have had a stable weight over the 3 months preceding the start of the study (≤ 5% weight gain or loss). At inclusion, the average weight was 108.7 kg and the average BMI was 37.9 mg/m2.
Participants were randomly assigned to receive eitherorforglipron per us
once a day (at different doses: 12, 24, 36 or 45 mg) or a placebo, for 36 weeks. All groups received the usual health and diet and physical activity advice at the same time. Change in weight was assessed at week 26 (primary endpoint) and at week 36 (secondary endpoint).
Results: Taking orforglipron was associated with greater weight loss than with placebo, which depended on the dose. Thus, at S26, average change in weight of participants who took the drug ranged from -8.6% to -12.6%, compared to -2% in those who received the placebo. At week 36, these percentages ranged from -9.4% to -14.7% in the treated groups, versus -2.3% in the control group. Finally, at week 36, 46 to 75% of treated patients had lost at least 10% of their weight, compared to only 9% of patients in the control group. Orforglipron use was also associated with clinically significant improvement in cardiometabolic parameters associated with weight (SBP, triglycerides, cholesterol).
Adverse effects – mainly gastrointestinal (nausea, vomiting, constipation, diarrhea, belching, etc.) – were more common in the orforglipron group than in the placebo. Mild to moderate in intensity, and temporary in the majority of cases, they led to treatment discontinuation in 10 to 17% of participants depending on the group. They were occurring especially during the initial phase of gradual dose increase and even more so when the initial dose was higher (but beyond 3 mg their frequency did not increase with the highest doses), suggesting that starting treatment at low doses and increasing them slowly might help reduce these side effects.
These results show that orforglipron per os might have a effectiveness in weight loss similar to that observed with other GLP-1 agonists (liraglutide and semaglutide, associated in phase III trials with weight reductions ranging from -9% to -17% over longer follow-up periods), with a similar safety profile. Furthermore, the weight loss induced by this molecule did not seem to have reached a plateau at the end of follow-up (W36), which suggests that there might be longer-term effects by prolonging the treatment, but further studies need to be carried out to confirm these effects and especially assess security.
However, regarding the use of GLP-1 agonists for the purpose of weight loss, the French Society of Pharmacology and Therapeutics recently called for caution, recalling that the weight losses observed are transient, with a resumption when treatment is stopped, and that an effect on morbidity and mortality linked to treatment has not yet been demonstrated. obesity, while the adverse effects linked to their use are potentially serious (acute pancreatitis, severe constipation, etc.).
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