The Skinny on GLP-1s
Janel L. Davis, PhD | Freelance Science Writer
Over the last few years, glucagon-like peptide-1 agonists (GLP-1s) have emerged as a promising solution for tackling obesity. In particular, Novo Nordisk’s (NOVO) semaglutide, marketed under the brand names Wegovy and Ozempic, has garnered unprecedented attention, leading to shortages within the diabetic community. To fully grasp the excitement surrounding semaglutide and other obesity therapies, it is essential to understand the current and potential market for these treatments, review the supporting data to date, and explore the future direction of the obesity treatment landscape.
What are GLP-1s
GLP-1s are therapies designed to mimic the function of a naturally produced gut protein called incretin. While GLP-1s, initially developed to treat Type-2 Diabetes, are not new, their popularity has surged since 2020. This rise in interest followed the readout of Novo Nordisk’s STEP trials in 2020. The trials showed that patients treated with semaglutide lost approximately 18% of their initial body weight. Consequently, semaglutide, which was already FDA-approved for managing diabetes in 2017, gained additional approval at a higher dose and was branded as Wegovy in 2021 for obesity management. In 2024, the approved treatment group was expanded to include obese adults with heart disease.
To be effective in these patient groups, the activity of GLP-1s typically outlasts the naturally produced proteins. By simply persisting, these therapies can:
Slow the movement of food through the digestive system
Delay brain activity signaling hunger
Reduce impulses to graze
Lower blood sugar levels by increasing the production of the blood-regulating hormone insulin
Like everything in life, there are consequences to these benefits. Some of the major concerns with this class of therapies include:
Muscle loss due to the rapid weight loss effect of the therapy
Gastrointestinal distress: vomiting, diarrhea, nausea, etc.
Increased hunger and weight gain after discontinuing the therapy
The market has continued to grow with Eli Lilly (LLY) entering the arena with their GLP-1/GIP dual agonist (tirzepatide), branded as Mounjaro for diabetes and Zepbound for obesity and associated comorbidities. In addition to the action of GLP-1, tirzepatide also mimics the naturally produced hormone GIP (glucose-dependent insulinotropic polypeptide), which lowers blood sugar and reduces brain signals related to hunger. Based on Lilly’s SURMOUNT trial, it was shown that patients lost approximately 25% of their initial body weight, and the side effects were similar to those of semaglutide. Real-world data has supported this, showing that patients on the dual therapy were three times as likely to achieve a 15% weight loss compared to those on semaglutide.
The approved GLP-1s are included below:
Why Just About Everyone Cares?
The hype around GLP-1s stems from the staggering size of the potential treatment group for these therapies. A 2018 study showed that approximately 42% of Americans are obese. Obesity is identified by comparing a person’s weight relative to their height using the body mass index (BMI), with obesity characterized by a BMI over 30. Additionally, data from 2019 indicates that around 48% of the population has cardiovascular disease, and a 2021 study found that about 11% of Americans have type 2 diabetes. Based on these potential groups, over 100 million Americans could already be eligible for a GLP-1 therapy in some form. Further, there are ongoing studies of GLP-1s in multiple other treatment groups, including individuals with chronic kidney disease, sleep apnea, fatty liver disease, and arthritis.
While the potential market for these therapies is large, adoption has been limited due to undercoverage by insurance and supply shortages. Additionally, the high price points of the branded therapies (approximately $1,000 per month) and availability challenges have led to the popularity of compounded versions (custom-made by pharmacists). While compounded therapies are cheaper (around $150 per month), the specific formulations have not been FDA-approved. Despite these challenges, analysts from Goldman Sachs predict that by 2028, the number of Americans using GLP-1s could increase from 10 million to 30 million.
Even though the potential treatment group for GLP-1s is already massive, there has also been significant interest in these therapies from individuals who do not meet the treatment criteria. The CDC found that between 2013 and 2016, 50% of the population attempted to lose weight for health or perception reasons. This is not surprising since, in the Western world and beyond, the ideal body type is often based on the fashion industry, where a 2020 study found that the average BMI was 15.6 for females and 17.3 for males. For reference, a normal BMI falls between 18.5 and 25, while BMIs below 16.5 are classified as severely underweight.
Forging ahead, without considering whether our beauty standards are healthy or unhealthy, the most common approaches for achieving the desired look include:
Winning the Genetic Lottery: The easiest and also the most elusive option.
Diet & Exercise: Probably the most accessible and potentially healthy option, but there is significant discord regarding the ideal approach.
Juice Cleanses and Supplements: While the depth of the rabbit hole is endless, most have not been studied for safety or effectiveness.
Given the constraints of the alternatives, the limits for therapies that “magically” help you lose weight are seemingly non-existent. As a result, GLP-1 supplements, as well as diets and other supplements geared towards GLP-1 users, are already available to consumers. Furthermore, numerous GLP-1 therapies, including novel combinations, are currently under development.
What’s Next?
The developmental approaches that are furthest along are included below:
Oral GLP-1s: While next-generation subcutaneous GLP-1 agonists continue to advance, there is also significant interest in developing an oral form of these therapies, which could potentially be less effective but have fewer side effects than the approved injectable options. Eli Lilly is currently leading the field with a Phase 3 trial underway for their oral GLP-1 approach. Meanwhile, Pfizer (PFE) has announced the development of a daily oral GLP-1 based on their danuglipron, which has completed Phase 2 trials (NCT04617275 & NCT04707313). This formulation was previously studied at a twice-daily dose.
GLP-1/GIP Dual Agonists: This approach targets both GLP-1 and GIP receptors and has already shown effectiveness with Eli Lilly’s Zepbound. Viking Therapeutics is also developing a therapy with a similar mechanism of action.
GLP-1 Agonist + GIP Antagonist: Amgen’s (AMGN) maridebart cafraglutide combines GLP-1 agonism with GIP antagonism. Preclinical studies have shown that blocking the GIP receptor can improve metabolic profiles and reduce food consumption. However, there is some concern with this approach, as it opposes the mechanism used by Eli Lilly’s Zepbound, which activates both GLP-1 and GIP receptors. Despite this, Amgen’s Phase 1 results were promising, leading to a Phase 2 trial.
GLP-1 Agonist + Glucagon Co-Agonist: Glucagon is a hormone associated with reducing hunger signals and increasing energy expenditure. Several companies are developing therapies that combine glucagon with GLP-1 agonists. Among these, Boehringer Ingelheim’s survodutide and Innovent/Eli Lilly’s mazdutide are the furthest along.
GLP-1 + GIP + Glucagon Triple Agonist: Eli Lilly is also developing a triple therapy that combines the activation of GLP-1, GIP, and glucagon. This approach aims to leverage the benefits of all three mechanisms to potentially result in a more effective treatment.
GLP-1 + Amylin: Amylin is a hormone that helps signal to the body that it no longer needs food. Novo Nordisk is in late-stage development of a weekly therapy that combines amylin with a GLP-1 agonist.
In addition to the therapies highlighted above, there are currently 61 therapies in Phase 1 and 45 in Phase 2 for obesity under development, with the field showing no signs of thinning. As a result, GLP-1s and other obesity therapies will likely maintain their grip on the public’s attention.
About the Author: Janel Davis is a science communicator specializing in pharma/biotech and medtech content. As a note, her thesis was on spectroscopic super-resolution microscopy so questions related to stochastically emitting fluorophores are always welcome.
