In a recent review published in the journal Cell, Researchers summarize and clarify recent research and clinical trials that highlight the mechanistic underpinnings and beneficial effects of glucagon-like peptide-1 (GLP-1)-based polyagonists. Originally developed as type 2 diabetes (T2D) interventions, these drug interventions have shown excellent 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 (glycemia), kidney disease, fatty liver, and improved cardiovascular function make them a viable alternative to conventional bariatric surgery and highlight important medical advances in the fight against obesity.
Review: Transforming obesity: The progress of multi-receptor drugs. Image credit: MillaF / Shutterstock
Record
Obesity, clinically defined as body mass index (BMI) > 35 kg/m2, is characterized by excess body fat and is one of the most pressing public health concerns in the world today. The World Health Organization (WHO) estimates a current global prevalence of 16% in adults aged 18 years and older. In recent decades, the incidence of the condition has been increasing at an alarming rate – from 4% to 13% of the world’s population between 1975 and 2014.
Obesity has been associated with a significantly increased risk of chronic, noncommunicable diseases, including type 2 diabetes (T2D), cancers, cardiovascular diseases (CVDs), dyslipidemia, and total mortality. Research has further pointed to its role in exacerbating complications of infectious diseases such as coronavirus disease 2019 (COVID-19). Therefore, population-scale weight modeling is an imperative goal of the public health system.
Despite decades of research, until recently, short-term weight reductions of 5-8% 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 with conventional pharmacological and lifestyle interventions is regained within two and five years, mainly due to the body’s innate desire to defend the weight and conserve energy. Consequently, patients with excess 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 management
As early as 1906, clinicians observed that blood glucose uptake is significantly higher when glucose is absorbed through the gut than by intravenous infusion. This indicates the presence and strength of insulinotropic hormones secreted by the gut (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.
Therefore, GIP has 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 shown to regulate insulin secretion, enhance gastric motility, inhibit food intake, and inhibit glucagon secretion. Glucagon, first discovered in 1923 but chemically characterized only in the early 1970s, is now established as a regulatory hormone capable of counteracting the effects of insulin.
Therefore, the physiological action of the GLP-1/GIP axis has made these gut hormones attractive medical targets for the treatment of T2D and subsequently obesity. In particular, the GLP-1R agonist not only emerged as a powerful tool for the treatment of T2D and obesity, but also demonstrated favorable effects on the cardiovascular system and neurodegenerative diseases.”
Research and development of GLP-1R agonists – single receptor interventions
Despite its noun in vitro and in vivo benefits, the use of native GLP-1 in pharmacological interventions has been hampered by its extremely limited half-life (~2–3 min), with studies estimating that even with prolonged administration, only 10% of active GLP-1 enters the 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 drugs derived from GLP-1, such as exenatide, liraglutide, lixisenatide, and more recently, semaglutide receiving regulatory approval for the treatment of T2D and obesity. Specifically, 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 have found that single-molecule multireceptor agonists can exploit glucagon biology to achieve significant weight loss and improvements in glucose regulation at significantly lower doses, counteracting the gastrointestinal side effects of the GLP-1R.
“Multiple gut-hormone combinations have been investigated preclinically, with a significant number progressing to clinical studies, with single-molecule peptides possessing varying degrees of GLP-1R, GIPR, and GCGR activity constituting the most clinically mature set of drug candidates.”
Notable examples and future research
GLP-1R/GCGR agonists represented the first generation of multireceptor interventions, including SAR425899, Mazdutide, Cotadutide, NN9277, and ALT-801. At the same time, GLP-1R/GIPR agonists such as MAR709 and “second generation” multi-receptor agonists such as Tirzepatide were developed. Clinical trials for Tirzepatide revealed unprecedented levels of weight loss in 20.9% to 92% of patients.
In addition to fine-tuning the chemical composition and doses of the dual receptor agonists covered above, current research explores the potential of GLP-1R/GIPR/GCGR triads as the next step in antiobesity pharmacological research. Four triangulants have been developed (MAR423, retatrutide, SAR441225, and HM15211) and are currently undergoing preclinical testing 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 led to unprecedented advances in anti-obesity interventions. Trizepatide, a GLP-1R/GIPR agonist, has achieved ∼20.9% long-term weight reductions, comparable to the gold standard of 25–30% achieved through bariatric surgery. The current development of triangulators may usher in an era where pharmacological interventions effectively replace the need for surgery, even in severely obese patients.
