A promising weight loss alternative to bariatric surgery

A recent review published in the journal cell, Researchers have collected and elucidated recent studies and clinical trials that highlight the mechanistic basis and beneficial outcomes of glucagon-like peptide-1 (GLP-1)-based polyagonists. Initially developed as interventions for type 2 diabetes (T2D), these biochemically engineered drug interventions have shown phenomenal success in the pharmacological treatment of excess body fat, with 20-30% reductions observed in some cases.

Additionally, associated benefits such as lowering blood sugar levels (glycemia) and improving kidney disease, fatty liver and cardiovascular function make it a viable alternative to traditional bariatric surgery and a major testament to medical advances in the fight against obesity.

review: Transforming Obesity: Advances in Multi-Receptor DrugsImage credit: MillaF / Shutterstock

background

Obesity is clinically defined as a body mass index (BMI) greater than 35 kg/m .²Obesity, characterized by excess body fat, is currently one of the world's most pressing public health concerns. The World Health Organization (WHO) estimates its current global prevalence at 16% among adults aged 18 years and older. In recent decades, the incidence of the disease has increased at an alarming rate, increasing from 4% to 13% of the world's population between 1975 and 2014.

Obesity is associated with a significantly increased risk of chronic non-communicable diseases, including type 2 diabetes (T2D), cancer, cardiovascular disease (CVD), dyslipidemia, and all-cause mortality. Studies have further highlighted its role in exacerbating infectious disease complications, such as coronavirus disease 2019 (COVID-19). Therefore, population-wide weight regulation is an essential goal of public health systems.

Despite decades of research, until recently, short-term weight loss of 5-8% was considered the gold standard for pharmacological-only weight loss interventions. Unfortunately, as highlighted in a recent meta-analysis, over 50% and 75% of weight lost with traditional pharmacological and lifestyle interventions is regained within 2 and 5 years, respectively, primarily due to the body's innate desire to protect weight and conserve energy. As a result, patients with excessive BMI were often offered bariatric surgery (weight loss/metabolic surgery) as a last resort to achieve clinical weight management goals.

The role of glucagon and incretin hormones in weight control

As early as 1906, clinicians observed that glucose absorption from the intestine resulted in significantly higher blood glucose absorption than intravenous infusion, suggesting the existence and potency of gut-secreted insulinotropic hormones (incretins). However, it was not until 1973 and 1987 that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were discovered and characterized.

Thus, GIP has been shown to play an important role in adipose tissue blood flow, lipid deposition, and insulin-induced glucose uptake, whereas GLP-1 has been shown to regulate insulin secretion, increase gastric motility, inhibit food intake, and suppress glucagon secretion. Glucagon was first discovered in 1923 but was not chemically characterized until the early 1970s and is now established as a regulatory hormone capable of opposing the effects of insulin.

“The physiological actions of the GLP-1/GIP axis have made these gut hormones attractive therapeutic targets in the treatment of type 2 diabetes and, therefore, obesity. In particular, GLP-1R agonists have not only emerged as powerful tools in the treatment of type 2 diabetes and excess adiposity, but also showed favorable effects on the cardiovascular system and neurodegenerative diseases.”

GLP-1R Agonist Research and Development – Single Receptor Intervention

Pretty In vitro and alive Despite the advantages of native GLP-1, its extremely short half-life (approximately 2–3 min) precludes its use in pharmacological interventions, and studies estimate that even with continuous administration, only 10% of active GLP-1 enters the systemic circulation, and even less reaches its target organ, the brain.

Subsequently, chemical modifications of native GLP-1 have overcome this challenge, and several pharmacological GLP-1-derived agents, including exenatide, liraglutide, lixisenatide, and more recently semaglutide, have received regulatory approval for the treatment of type 2 diabetes and obesity. Notably, these agents have been observed to achieve weight loss ranging from 6.8% to over 14.9%, with transient nausea being a common side effect of this class of intervention.

Development of multi-receptor agonists

Following the success of single receptor GLP-1R intervention, alive Models have discovered that single-molecule multi-receptor agonists can exploit the biological properties of glucagon to achieve significant weight loss and improved glycemic control at significantly lower doses, while addressing the gastrointestinal side effects of GLP-1R.

“Multiple gut hormone combinations have been studied preclinically, and a significant number have progressed into clinical trials. Single peptides with varying degrees of GLP-1R, GIPR and GCGR activity comprise the most clinically mature set of drug candidates.”

Notable cases and future research

GLP-1R/GCGR coagonists represented the first generation of multi-receptor interventions, such as SAR425899, mazdutide, cotadutide, NN9277, and ALT-801. Concurrently, a “second generation” of GLP-1R/GIPR coagonists, such as MAR709, and multi-receptor agonists, such as tirzepatide, were developed. Clinical trials of tirzepatide revealed unprecedented levels of weight loss of 20.9% in up to 92% of patients.

In addition to fine-tuning the chemical composition and dosage of the dual receptor agonists mentioned above, current studies are exploring the potential of GLP-1R/GIPR/GCGR triagonists as the next step in anti-obesity pharmacology research. Four triagonists (MAR423, retatortide, SAR441225, and HM15211) have been developed and are currently undergoing preclinical trials to confirm their efficacy and biological safety.

Conclusion

The discovery and application of the incretin hypothesis and the associated pharmacological development of multi-receptor agonists have led to unprecedented advances in anti-obesity interventions. Trizepatide, a GLP-1R/GIPR coagonist, achieved long-term weight loss of approximately 20.9%, which is comparable to the gold standard of 25-30% achieved with bariatric surgery. The current development of triagonists may usher in an era in which pharmacological interventions can effectively replace the need for surgery, even in severely obese patients.