GLP-1-based drugs close the treatment gap

The WHO has declared obesity to be a global health problem and weight reduction is an important measure in the prevention and treatment of metabolic diseases such as type 2 diabetes. Until recently, bariatric surgery was often the only way to help severely obese patients reach their target weight. In the meantime, the marketing authorization of semaglutide and liraglutide has led to a breakthrough in the field of drug treatment options for obesity, and studies on tirzepatide show that this dual GIP/GLP-1 receptor agonist can achieve even better effects in terms of weight reduction.

“Obesity is one of the main risk factors for the development of type 2 diabetes,” reported Prof. Dr. med. Medical Director, Tübingen University Hospital and member of the board and spokesperson of the German Diabetes Association (DDG) [1]. It has been shown that there is a linear relationship between BMI and the prevalence of type 2 diabetes (T2D) in all age groups [2]. It therefore makes sense to also address obesity with regard to diabetes prevention, emphasized the speaker [1]. In recent decades, the prevalence of overweight and obesity has increased worldwide, making it a major public health issue. Epidemiological analyses of data from 200 countries show that the prevalence of obesity in the male population rose from 3.2% to 10.8% in the period 1975-2014, while the prevalence of obesity in women rose from 6.4% to 14.9% in the same period [3]. The World Health Organization (WHO) now classifies obesity (BMI>30 ^kg/m2) as a disease in its own right and it is well known that morbid obesity is a risk factor for chronic diseases such as type 2 diabetes mellitus, cardiovascular disease and non-alcoholic fatty liver disease (NAFLD) [4–6]. Obesity is now also common in children and adolescents, Prof. Gallwitz pointed out and emphasized the importance of creating ways to implement the treatment of morbid obesity at an early stage [1]. After a long dry spell in the field of drug therapy options, the introduction of GLP-1-based drugs brought a long-awaited turnaround.

GLP-1 and GIP – gut hormones with a broad spectrum of action
Glucagon-like peptide-1 (GLP-1) is a peptide hormone that is produced in the intestine (L-cells of the ileum and colon) and plays an important role in controlling glucose metabolism. In addition to stimulating glucose-dependent insulin secretion in the pancreas and improving insulin sensitivity, GLP-1 causes a glucose-dependent reduction in glucagon levels, a delay in gastric emptying and an inhibition of gastric juice secretion.
The glucose-dependent insulinotropic peptide (GIP) is formed in the K cells of the duodenum and jejunum, binds to GIP receptors on the cell membrane of pancreatic beta cells and thus promotes the release of insulin. In higher concentrations, GIP also inhibits gastric motor activity and the secretion of gastric juice. As GIP receptors are also found in the central nervous system, it is assumed that the peptide has a central effect on the feeling of appetite and satiety.

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Weight reduction with liraglutide, semaglutide or tirzepatide

In the recommendations of European and North American specialist societies, weight reduction has gained in importance in the management of T2D compared to the past. According to the German national care guidelines for T2D, GLP-1-RA is also used very early and independently of _HbA1c, especially in patients with previous cardiovascular disease, in order to avoid complications, explained Prof. Gallwitz [1,7]. In diabetes studies and in everyday clinical practice, GLP-1-RA showed very beneficial effects on weight loss. In the meantime, liraglutide (Saxenda®) and semaglutide (Wegovy®) have also overcome the approval hurdles in the area of obesity. In some countries, the dual GIP/GLP-1 receptor agonist tirzepatide (CH trade name: Mounjaro®) has also already received an indication extension for obesity, but in Switzerland approval has so far** been limited to T2D [8]. Semaglutide and tirzepatide have so far shown the best efficacy in terms of weight reduction, with the effects of tirzepatide being the strongest due to its dual agonism. In addition, study data are available that attest to the favorable effects of semaglutide and liraglutide on an obese liver. The speaker explained that these are not just surrogate parameters, but that liver histological changes can be detected [1].

** Status of information: 23.04.24

Alternative to bariatric surgery?

For many years, pharmacologically induced weight loss of more than 10% at tolerable doses seemed to be an insurmountable obstacle. Against this background, the latest results of the latest generation of GLP-1 mimetics are impressive. Both semaglutide 2.4 mg and tirzepatide reduced body weight by around 15-20% in clinical trials with a tolerable safety profile, as shown by data from the SURPASS and STEP study programs [9]. In the SURPASS studies, tirzepatide was compared at different doses (5 mg, 10 mg, 15 mg) with other active substances or placebo. In order to keep initial gastrointestinal side effects in check, the dose of tirzepatide was gradually increased. A dose-dependent reduction in the _HbA1c value was shown and around a quarter to a third of the T2D patients treated with tirzepatide achieved diabetes remission (=normal HbA1c _value). In the SURMOUNT 1 study, tirzepatide achieved a dose-dependent weight loss of 16% (5 mg), 21.4% (10 mg) and 22.5% (15 mg) in overweight patients without diabetes over a period of 72 weeks [14].

In summary, GLP-1-based substances offer significantly better chances of achieving the target weight through drug therapy than in the past and may represent an alternative for obese patients who wish to avoid surgery with the associated risks. A body mass index (BMI) of ≥35 ^kg/m2 is usually a prerequisite for bariatric surgery. Nowadays, sleeve gastrectomy and gastric bypass (Roux-en-Y gastric bypass, RYGB) are the most commonly used bariatric procedures [10]. The weight loss achieved by an RYGB ranges from 12% of the initial weight after 6 months to 45% after 3 years, with a considerable range of variation due to differences in comorbidities and lifestyle factors, among other things [11].

Congress: Diabetologie grenzenlos

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