GLP-1 receptor agonists: Did anyone really see this coming?

by Ujwal Pyati, PhD, Chief Medical Officer

Working in healthcare provides no end to excitement, particularly when we partner with companies who are generating amazing new ways to deploy established therapeutic approaches. The best example of this is with GLP-1 receptor agonists. All the recent news on different uses got me thinking: How did this happen? And how could these molecules function in all these different disease states?

Stating the obvious

Unless you’ve been living on a deserted island or simply refuse to think about pharmaceutical innovation, you’re fully aware by this point that GLP-1 receptor agonists (GLP-1 RAs or GLP-1s as commonly known) have fundamentally changed the intersection of medicine and culture. We’re bombarded with ads, influencers, and friends who have touted the glorious benefits of this medication class, displaying remarkable self-control in their dietary and vice-related habits and making many of us, frankly, jealous.

Going beyond blood sugar reduction and weight loss, specific GLP-1–based and incretin therapies now have US product-specific indications for broader cardiometabolic benefit, including cardiovascular risk reduction, noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with F2–F3 fibrosis, reduction of CKD progression risk in adults with T2D and CKD, and moderate-to-severe obstructive sleep apnea in adults with obesity, and they are being researched in a wide array of conditions from substance use disorders to mental health conditions to oncology, rheumatology, and even neurodegenerative conditions. Being a biochemist by training who thinks constantly about signaling pathways and related mechanisms of action, I began to wonder: How exactly does this all work?

How it started

I bet you don’t think of the Gila monster much. Neither do I. But it turns out that this strange little creature is pivotal to the story of modern GLP-1 RAs. Original experiments in the early 1900s first described the concept of a hormone sent from the gut to distant organs, potentially affecting their function. Researchers over subsequent decades then worked toward the discovery of incretins, the hormone class GLP-1 RAs are designed to mimic, and observed their impact on GLP-1 receptors, with broad metabolic effects.

Despite this discovery, there was a fundamental problem; the native form of human GLP-1 is rapidly degraded (within minutes) by an enzyme called DPP-4, making it unsuitable for medical purposes. Enter our buddy the Gila monster. In 1992, as many of us were trading grunge CDs, John Eng, a researcher in New York’s Veteran Affairs Medical Center, analyzed Gila monster venom and discovered exendin-4, a 39-amino acid peptide with around 50% similarity to human GLP-1. The most relevant part turned out to be something exendin-4 was actually missing—a cleavage site for DPP-4.

As a result, this Gila monster peptide could actually be active in the human body and produce lasting effects similar to what earlier researchers had envisioned. This initiated the development of synthetic exendin-4, called exenatide, and resulted in the launch of Byetta (exenatide) by Amylin Pharmaceuticals as the first GLP-1 RA, approved for the treatment of type 2 diabetes mellitus. The explosion of pharmaceutical-led innovation in the space was underway.

How it’s going

As we know, large pharmaceutical companies including Eli Lilly and Novo Nordisk developed other injectable GLP-1 RAs such as dulaglutide (Lilly), liraglutide (Novo Nordisk), and semaglutide (Novo Nordisk), with a much closer relation to human GLP-1, a greater half-life, and different pharmacokinetic profiles and generally more convenient dosing than exenatide, with tolerability varying by agent and dose. These molecules were shown to drive meaningful blood sugar reductions in eligible T2DM patients.

But another consistent effect was, of course, weight loss. Not just a few pounds, but highly clinically significant weight loss in some patients. In an effort to study weight loss effects in particular, the STEP-1 study of 1,961 adults with overweight or obesity without diabetes demonstrated that semaglutide 2.4 mg weekly achieved a mean weight loss of 14.9% vs 2.4% with placebo over 68 weeks—outcomes narrowing the gap with bariatric surgery, which had been a standard for patients needing rapid and sustained weight loss at these levels.

A dual GIP receptor and GLP-1 receptor agonist called tirzepatide (Eli Lilly) was developed to produce synergistic metabolic effects through GLP-1 and GIP (glucose-dependent insulinotropic peptide). The SURMOUNT-1 study demonstrated mean weight loss of 22.5% (efficacy estimand) at the highest dose, which was unprecedented.

And now the resulting products, Zepbound (tirzepatide) and Wegovy (semaglutide), are household names and transforming outcomes. And not just in diabetes and obesity.

What came next

The effects of GLP-1 RAs have subsequently been shown to go beyond sugar and weight. Cardioprotective effects have been shown in multiple studies in patients with or at high risk of atherosclerotic cardiovascular disease. These seminal studies moved the GLP-1 RAs beyond the realm of glucose-lowering and weight loss agents and into the cardio-renal-metabolic therapeutic category.

Up next was sleep apnea with approval of Zepbound in patients with obesity struggling with this condition. This was followed by MASH, with approval of semaglutide marking only the second approval in this very challenging disease space (under accelerated approval, contingent on confirmatory evidence of clinical benefit).

The next wave of studies is varied and very intriguing. GLP-1–based therapies are being studied across a wide range of conditions, including liver disease, chronic kidney disease, osteoarthritis, substance use disorders, neurodegenerative disease, oncology, and psychiatric disorders. The studies are in different stages and the strength of evidence varies widely, with some negative results in Alzheimer’s and Parkinson’s disease in particular, but there are promising signals across a number of these conditions regardless.

But how?

Importantly, GLP-1 receptors, the targets of these molecules, are not only expressed in the gut. Another key area is the pancreatic beta cells, where GLP-1 RAs can trigger insulin release, as well as other areas that can suppress glucagon production among other effects.

In the central nervous system, GLP-1 receptors are widely expressed in the hypothalamus, brainstem, and many other areas of the brain. While studies are ongoing, it is believed that both an indirect effect via the gut-brain axis and hormone signaling, as well as direct effects when these molecules partially cross the blood brain barrier, could be responsible for effects in psychiatric and neurological conditions.

Beyond these areas, GLP-1 receptors are expressed in the heart, vasculature, kidneys, lungs, immune cells, bone, and some skin cells, opening up potential in myriad disease states. The relative contributions of direct receptor-mediated effects versus indirect metabolic mechanisms vary by organ and condition, and remain an active area of investigation.

I could write another whole article on individual mechanisms within relevant diseases, but suffice it to say these molecules could be optimized for usage in many different conditions based on the widespread expression of the target. While in some conditions like MASH, there may be indirect effects on the diseased organ (in this case the liver) through changes in metabolism, there are likely direct effects implicated as well in the case of cardioprotective benefits and neurobiological impacts.

While we have yet to see whether GLP-1 RAs are approved for use in all these indications, the potential is incredible and as wide-ranging as anything we’ve seen in healthcare. I’m excited to read about every new development, and I welcome discussion on people’s perspectives about the scientific and societal impact of these amazing molecules.

Where we go from here

As healthcare communicators, the key is to always keep the science at the heart of the conversation. That means following the data even where there is hype and expectation. Each study should be carefully analyzed and assessed with caveats in mind including risk vs benefits, advantages vs standards of care, and of course, cost.

With oral agents now approved for weight loss—and in some cases CV risk reduction—in addition to a prior oral option for type 2 diabetes + CV risk reduction, there are multiple dosing and administration options, and this trend will certainly continue. It is our job to ensure that everyone has the right information to decide if a GLP-1 RA could be beneficial, whether for blood sugar regulation, weight management, or any of the emerging conditions for which these medications are or will be approved.

Regardless, the future is bright—and I look forward to what’s to come.

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