GLP-1 Drugs - Weight Loss Indications

• GLP-1 Drug Weight Loss Principle

The results of a study published in the International Journal of Endocrinology showed that obese patients do not secrete enough GLP-1 when eating, so GLP-1 deficiency is one of the pathophysiological mechanisms of obesity. Currently, GLP-1 drugs are used for weight loss management mainly based on the following mechanisms: On the one hand, GLP-1 directly acts on the GLP-1 receptors in the hypothalamic feeding center and other central parts of the brain that directly affect appetite, making the human body feel full and reducing hunger, thus controlling food intake; on the other hand, GLP-1 can act on the GLP-1 receptors in the gastrointestinal tract and the vagus nerve, inhibiting gastrointestinal motility and gastric juice secretion, delaying the absorption of substances and gastric emptying, increasing satiety, and reducing food intake.

The vagus nerve pathway plays a key role in signal transduction in the GLP-1 weight loss process. The gastroduodenal afferents of the vagus nerve can be functionally divided into mechanosensitive afferents and chemosensitive afferents. Mechanosensitive vagus nerve afferents can sense mechanical stimulation, including mucosal expansion and contraction caused by food entering the gastrointestinal tract.

It includes the mechanosensitive mucosal endings IGLE located in the intermuscular myenteric plexus and the IMA distributed in the muscularis. Studies have shown that the glucagon-like peptide 1 receptor (GLP-1R) expressing IGLEs in the stomach and the oxytocin receptor (Oxtr) expressing IGLEs in the duodenum are the main mechanosensitive vagal inputs (2019, Cell 179, 1129–1143); the peripheral terminals of chemosensitive vagal afferents can sense chemical stimuli, including nutrients, hormones, pH, and immune stimuli (pathogens, food allergies, and microbiota); the central terminals of gastroduodenal vagal afferents terminate in the dorsal vagal complex in the brainstem, mainly in the nucleus tractus solitarius (NTS), but also in the posterior zone, the dorsal motor nucleus of the vagus (DMV), and the trigeminal insula. Neurons in the nucleus tractus solitarius (NTS) have ascending axonal projections to a large number of brain regions, including food intake regulatory centers such as the hypothalamus and amygdala. Neurons in the nucleus tractus solitarius (NTS) also have nerve fibers that project directly or indirectly to the vagal efferent neurons in the dorsal motor nucleus of the vagus (DMV), forming a pathway for reflex feedback to the gastrointestinal tract, regulating intestinal function through the vagal efferent pathway.

Currently, physical weight loss balloons also use their stomach volume to physically expand the gastrointestinal tract, relying on the mechanically sensitive vagus nerve to transmit information to the feeding center of the hypothalamus, thereby producing a sense of fullness and reducing appetite to achieve the purpose of weight loss, such as Apollo Endosurgery's Orbera and Allurion Technologies' Eclipse balloons.

• GLP-1 Drug Weight Loss Features

(1)?? Weight rebound after drug withdrawal:

On December 11, 2023, Weill Cornell Medical College, University of Glasgow, McGovern Medical School at the University of Texas and other research institutions jointly with Eli Lilly published a clinical research paper entitled: Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial in the Journal of the American Medical Association (JAMA). In obese or overweight participants (but without diabetes), a weekly injection of tirzepatide can effectively lose weight, but stopping the drug will cause a significant rebound in the weight lost previously. At week 88, people using the placebo regained almost half of their previously lost weight, and their final weight was 9.9% lower than their baseline. Continuing the drug was able to maintain and further enhance the weight loss effect, and the final weight loss was 25.3% lower than the baseline.

Currently, there is no article that comprehensively analyzes the reasons for weight rebound after discontinuation of medication, but in essence, discontinuation of GLP-1 is similar to the rebound of other hormonal drugs because the continuous stimulation is lost and the originally saturated GLP-1R occupancy cannot be maintained, thereby no longer being able to control weight regulation mechanisms such as satiety and gastric emptying.

(2)?? Muscle loss:

GLP-1 drugs are not perfect. According to the STEP 1 and SUSTAIN 8 clinical trials of semaglutide, GLP-1 drugs significantly reduce lean body mass, the main components of which are bones and muscles. In the STEP 1 and SUSTAIN 8 clinical trials, about 39% and 40% of the weight loss of patients enrolled in semaglutide came from the loss of lean body mass, respectively.

Therefore, how to avoid muscle loss after using GLP-1 drugs has become a potential direction. At present, weight loss drug giants Eli Lilly, LaChem, Veru, BioAge, etc. are all making arrangements in the direction of muscle-building drugs, which is expected to bring new clinical and investment opportunities.