GLP-1-based polyagonists: A promising weight loss alternative to bariatric surgery

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Jul 28 2024

In a recent review published in the journal Cell, researchers collate and elucidate recent research and clinical trials highlighting the mechanistic underpinnings and beneficial outcomes of glucagon-like peptide-1 (GLP-1)-based polyagonists. First developed as anti-type 2 diabetes (T2D) interventions, these biochemically engineered drug interventions have presented extraordinary success in the pharmacological treatment of excess body fat, with reductions of 20-30% observed in some cases.

Additionally, their associated benefits of reduced blood glucose content (glycemia), kidney disease, fatty liver, and improved cardiovascular functioning make them a viable alternative to conventional bariatric surgery and underscore significant medical advances in combatting obesity.

Review: Transforming obesity: The advancement of multi-receptor drugs. Image Credit: MillaF / Shutterstock

Background

Obesity, clinically defined as a body mass index (BMI) > 35 kg/m², is characterized by excessive body fat and presents one of the most pressing public health concerns of the world today. The World Health Organization (WHO) estimates a current global prevalence of 16% in adults aged 18 and over. In recent decades, the incidence of the condition has been rising at alarming rates –  from 4% to 13% of the global population between 1975 and 2014.

Obesity has been associated with a significantly increased risk of chronic, non-transmittable diseases, including type 2 diabetes (T2D), cancers, cardiovascular diseases (CVDs), dyslipidemia, and overall mortality. Research has further highlighted its role in exacerbating complications of infectious diseases such as the coronavirus disease 2019 (COVID-19). Hence, population-scale weight modulation is an imperative goal of the public health system.

Despite decades of research, until recently, 5-8% short-term weight reductions were considered the gold standard in pharmacological stand-alone weight loss interventions. Unfortunately, as highlighted in recent meta-analyses, more than 50% and 75% of weight lost in conventional pharmacological and lifestyle interventions are regained in two and five years, mainly due to the body’s intrinsic desire to defend weight and preserve energy. Consequently, patients with excessive BMIs were often administered 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 management

As early as 1906, clinicians observed that blood glucose uptake is significantly higher when glucose is absorbed through the gut than intravenous infusion. This suggested the presence and potency of intestine-secreted insulinotropic hormones (incretins). Still, it was not until 1973 and 1987 that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were discovered and characterized.

GIP has hence been shown to play an integral role in adipose tissue blood flow, lipid deposition, and insulin-induced glucose uptake. GLP-1, in turn, has been revealed to modulate insulin secretion, enhance gastric motility, inhibit food intake, and inhibit glucagon secretion. Glucagon, first discovered in 1923 but only chemically characterized in the early 1970s, has now been established as a regulatory hormone capable of countering the effects of insulin.

“The physiological action of the GLP-1/GIP axis hence rendered these gut hormones as attractive medicinal targets to treat T2D and, subsequently, obesity. In particular, GLP-1R agonism not only emerged as a powerful tool in the treatment of T2D and excess adiposity but also displayed favorable effects on the cardiovascular system and neurodegenerative diseases.”

Research and development of GLP-1R agonists – single receptor interventions

Despite its substantial in vitro and in vivo benefits, native GLP-1’s use in pharmacological interventions was hampered by its extremely limited half-life (~2-3 min), with studies estimating that even in sustained administration, only 10% of active GLP-1 enters general circulation, and even less reaches its target organ – the brain.

Chemical modifications of native GLP-1 have since overcome this challenge, with several pharmacological GLP-1-derived drugs, including exenatide, liraglutide, lixisenatide, and most recently, semaglutide receiving regulatory approval for the treatment of T2D and obesity. Notably, these drugs have been observed to achieve weight loss between 6.8% and 14.9% or more, with transient nausea as a common side effect of this class of interventions.

Development of multi-receptor agonists

Following the success of single-receptor GLP-1R interventions, in vivo models discovered that unimolecular multi-receptor agonists can exploit glucagon’s biology to achieve substantial weight loss and glucose modulatory improvements at significantly lower dosages, addressing GLP-1R’s gastrointestinal side effects.

“Multiple gut-hormone combinations have been explored preclinically, with an appreciable number having advanced to clinical studies, with unimolecular peptides possessing varying degrees of GLP-1R, GIPR, and GCGR activity constituting the clinically most matured set of drug candidates.”

Notable examples and future research

GLP-1R/GCGR coagonists represented the first generation of multi-receptor interventions, including SAR425899, Mazdutide, Cotadutide, NN9277, and ALT-801. Simultaneously, GLP-1R/GIPR coagonists such as MAR709 and the ‘second generation’ of multi-receptor agonists such as Tirzepatide were developed. Clinical trials on Tirzepatide revealed unprecedented weight loss levels at 20.9% in up to 92% of patients.

In addition to fine-tuning the chemical composition and dosages of the dual-receptor agonists covered above, current research explores the potential of GLP-1R/GIPR/GCGR triagonists as the next step in anti-obesity pharmacological research. Four triagonists have been developed (MAR423, retatrutide, SAR441225, and HM15211) and are currently undergoing preclinical trials to verify their potency and biological safety.

Conclusions

The discovery and application of the incretin hypothesis and the associated pharmacological development of multi-receptor agonists have resulted in unprecedented advancements in anti-obesity interventions. Trizepatide, a GLP-1R/GIPR coagonist, has achieved ~20.9% long-term weight reductions, comparable to the gold standard of 25-30% attained through bariatric surgery. The current development of triagonists may initiate an era wherein pharmacological interventions effectively replace the need for surgery, even in severely obese patients.