The pounds tumble under incretin-based therapies

Antiadiposita can effectively support the success of lifestyle interventions and thus close a treatment gap. In Switzerland, the GLP-1 RAs liraglutide and semaglutide are currently the most effective in the indication area of obesity. Although tirzepatide has even stronger weight-reducing effects, it is currently only approved in Germany for type 2 diabetics. Bariatric surgery is usually only considered in cases of severe obesity.

Obesity is a complex chronic disease whose prevalence is increasing, particularly in industrialized countries. In Switzerland, around 43 percent of the adult population is overweight or obese; around 12 percent are affected by obesity [1]. According to the WHO classification, a body mass index (BMI) between 25–29.9 kg/m² is overweight and a BMI ≥30 is considered obesity (Table 1) [2]. The complex etiology of overweight and obesity requires a multifactorial therapeutic approach. It is known from population-based studies that BMI is a predictor of morbidity and mortality in obese patients [3]. As part of a multimodal therapy approach, drug treatment has recently gained in importance alongside dietary changes, physical activity and counseling/behavioral therapy, thus closing a therapy gap, explained Prof. Dr. Christian Rust, Chief Physician of the Clinic for Internal Medicine I at the Hospital of the Brothers of Mercy, Munich [4]. Bariatric surgery is generally only used from a BMI of >40 kg/m² or type 2 diabetes and BMI >35 ^kg/m2 [5].

Semaglutide outperforms liraglutide in terms of weight reduction

Incretin analogs are currently among the pioneering drug therapy options for reducing overweight and obesity. The lipase inhibitor orlistat is also approved, but in view of the comparatively low weight reduction, this drug is rarely used nowadays. “The minimum target we want to achieve to have an impact on hard medical outcomes is at least 5%,” said the speaker, adding: “More weight loss brings more” [4]. Liraglutide, semaglutide and tirzepatide fulfill this requirement. Liraglutide (Saxenda®) was the first approved long-acting GLP-1 (glucagon-like peptide-1) agonist in the indication of obesity and is administered once daily. In the SCALE study program, liraglutide (3 mg, s.c., 1×/d) resulted in an average weight loss of 5.7-8.0% of the initial weight within one year [6]. The speaker pointed out that the lifestyle intervention, which the placebo and verum groups had received, obviously also showed some effectiveness. After about one year, a plateau effect was observed with liraglutide [6]. It is now known that semaglutide 2.4 mg (Wegovy®) has also been approved for the treatment of obesity. This medication only needs to be given once a week. In the STEP-5 study, a weight reduction of 12.6% was achieved in non-diabetic obese patients (n=304) compared to placebo, although a plateau effect was also observed here after around one year [7]. In this study, the participants of both study arms also received a lifestyle intervention (in addition to 150 minutes of physical activity per week, this included a diet reduced by 500 kcal). Liraglutide and semaglutide have similar side effect profiles, it appears to be a class effect. Initially in particular, gastrointestinal complaints such as nausea, vomiting, constipation and diarrhea are relatively common, the speaker reported [4]. To reduce the side effects, a slow increase in dosage is recommended.

Even more effective weight loss with tirzepatide

The dual GLP-1/GIP agonist tirzepatide (Mounjaro®), which is currently only approved for diabetes therapy in Switzerland (status of information: 28.05.2024) , achieved a weight loss of 15-21% of the initial weight in the SURMOUNT-1 obesity study [8]. Compared to liraglutide and semaglutide, this is a significantly better weight-reducing effect, although a plateau effect can also be observed with tirzepatide after one year. In the EU, the dual GLP-1/GIP agonist has now been given an indication extension for obesity [9]. Like GLP-1, GIP (glucose-dependent insulinotropic polypeptide) is a gastrointestinal peptide hormone from the incretin family. In summary, semaglutide and tirzepatide are particularly convincing due to their highly significant weight reduction, which persists under therapy. This reduces the cardiovascular risk, as we know from diabetes studies, emphasized Prof. Rust [4]. Since patients put on weight again after discontinuing incretin analogs (rebound effect), both liraglutide and semaglutide as well as tirzepatide must be used permanently. Among other things, oral semaglutide is currently in the research pipeline, reported the speaker [4,10]. The bioavailability of orally ingested semaglutide is only around 1%, so it must be taken on an empty stomach to further optimize its efficacy [11]. With retatrutide, a novel triple hormone receptor agonist that activates the glucagon receptor in addition to GLP-1 and GIP, research also has another pillar in its quiver. In a phase II study published in the New England Journal of Medicine, subjects taking the highest dosage (retatrutide 12 mg) had lost an average of 17.5% of their initial weight after 24 weeks [10].

Congress: DGIM Annual Conference

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