The Evolution of GLP-1 Receptor Agonists: From Diabetes Treatment toNext-Generation Metabolic Therapies
Queens Pharmaceutical Sciences
Research Director Cullan Wheeler
Research Executives Elena Rastani and Momena Hasnain
Editors Ava Ditiero and Emily Kim
October 19th, 2026
GLP-1 receptor agonists have become one of the most important and rapidly
evolving drug classes in modern medicine, especially in recent years. This raises the
question of why they became so popular in such a short period of time.
Originally developed to improve blood glucose control in patients with type 2
diabetes, these drugs are now also widely recognized for their role in chronic weight
management, as well as for their cardiovascular and kidney benefits. Their growing impact,
particularly with drugs such as semaglutide, has shifted GLP-1 receptor agonists from
primarily being diabetes medications to therapies with much broader applications in
metabolic disease, including obesity and weight management. At the same time, their
increasing use has raised important questions surrounding long-term treatment, adverse
effects, accessibility, and what happens when the treatment is discontinued.
The development of this drug class is especially interesting because of how much it
has changed since the initial discovery of glucagon-like peptide-1 (GLP-1) as a hormone
involved in glucose regulation. Understanding the biology of GLP-1 and the limitations of the
naturally occurring hormone eventually led to the development of GLP-1 receptor agonists,
beginning with exenatide and followed by longer-acting therapies such as liraglutide and,
more recently, semaglutide (Knudsen & Lau, 2019). Each of these developments helped
address the limitations of earlier therapies and contributed to the expanding role that GLP-1
receptor agonists have today.
This paper will first examine the discovery of GLP-1 and the development of early
GLP-1 receptor agonists, including how researchers transformed a naturally occurring
biological pathway into an effective therapeutic strategy. It will then explore the current state
of the drug class, including its use in type 2 diabetes, obesity, and cardiovascular risk
reduction, as well as its major limitations. Finally, it will look at where the field is heading,including oral and longer-lasting therapies and the development of multi-receptor drugs such
as tirzepatide.
The Discovery and Early Development of GLP-1 Receptor Agonists: From Natural
Hormones to Longer-Acting Therapies
The development of GLP-1 receptor agonists began with research into how the body
naturally regulates blood glucose after eating. Researchers discovered that glucose taken
orally produced a greater insulin response than the same amount of glucose given
intravenously, suggesting that hormones released from the gastrointestinal tract contributed
to insulin secretion. This phenomenon became known as the incretin effect, and
glucagon-like peptide-1 (GLP-1) was eventually identified as one of the hormones
responsible (Friedman, 2024). GLP-1 is released from the intestine following food intake and
helps regulate blood glucose by stimulating insulin secretion from pancreatic β-cells while
also reducing glucagon, which is a hormone that promotes glucose production by the liver.
An important feature of GLP-1 is that it stimulates insulin in a glucose-dependent manner,
meaning that its effect increases when blood glucose is high and decreases as glucose
levels fall (Meloni et al., 2013). This made GLP-1 a promising option for the treatment of type
2 diabetes. However, there was one major problem with using the natural hormone as a
drug: GLP-1 is quickly broken down by the enzyme DPP-4, giving it a half-life of only around
one to two minutes, meaning that half of the hormone is eliminated from the body within this
short period. As a result, researchers needed to develop a way to produce the same effects
as GLP-1 while allowing it to remain active in the body for much longer.
A major breakthrough then came from the discovery of exendin-4 in 1990, a peptide
isolated from the saliva of the Gila monster, a type of lizard. Exendin-4 was structurally
different from human GLP-1, but it was still found to activate the same GLP-1 receptor andproduce similar effects on glucose regulation. More importantly, it remained active much
longer than natural GLP-1. Although its duration of action was not long enough to become
the final treatment, it was an improvement over the natural GLP-1. These properties led to
the development of exenatide, a synthetic form of exendin-4 that became the first GLP-1
receptor agonist approved for the treatment of type 2 diabetes in 2005 (Drucker, 2024).
Exenatide therefore demonstrated that the beneficial actions of GLP-1 could be transformed
into an effective drug, but its relatively short duration still required twice-daily injections.
Although exenatide was a major step forward, it still had a short duration of action
compared with what was needed for a more convenient treatment. The original formulation
still required two injections daily, which encouraged researchers to develop longer-lasting
GLP-1 receptor agonists. This eventually led to liraglutide, which unlike exenatide, was
developed using a human GLP-1 as its starting point. Researchers tested different fatty-acid
modifications and found that attaching a fatty acid allowed the drug to reversibly bind to
albumin (a protein found in blood plasma made by the liver), protecting it from rapid
breakdown and helping it remain in the body for longer periods of time (Knudsen & Lau,
2019). Liraglutide was ultimately selected because it maintained strong activity at the GLP-1
receptor, while lasting long enough for once-a-day administration. The progression from
natural GLP-1 to exenatide and then liraglutide illustrates how researchers advanced this
drug class by addressing the limitations of earlier treatments and making administration
more convenient.
The Evolution of GLP-1 Receptor Agonists: Current Clinical Applications, Benefits,
and LimitationsWhat began as treatment designed primarily to improve glycemic control in patients
diagnosed with type 2 diabetes has developed into a drug class with many applications
including: obesity, inflammation, cardiovascular disease and even sleep apnea. With
emerging research exploring the multitude of benefits that GLP-1 agonists can provide to the
body, the three main applications they are used for are type 2 diabetes, chronic weight
management and cardiovascular risk reduction. The most commonly used medications are
semaglutide, liraglutide, dulaglutide and exenatide. The dosing frequency of GLP-1 receptor
agonists varies between medications, ranging from twice-daily administration with exenatide
to once-daily dosing with lixisenatide and liraglutide, and once-weekly dosing with
extended-release exenatide, dulaglutide, and semaglutide. Semaglutide is also available as
an oral formulation that is taken once daily (Latif et al., 2024).
Although GLP-1 receptor agonists were initially developed to improve blood glucose
control in patients with type 2 diabetes, the significant weight loss observed during treatment
led researchers to explore their use for obesity, ultimately expanding the drug class from
primarily diabetes management to chronic weight management (Friedman, 2024). GLP-1
agonists are similar to the hormone GLP-1, which occurs naturally in the body. When these
medications are administered, they stimulate insulin release when needed and slow
digestion, allowing food to leave the stomach more slowly. These effects stabilize blood
glucose levels and allow the body to feel satiated for longer periods of time. These effects
make GLP-1 receptor agonists particularly beneficial for individuals undergoing weight
management, as increased satiety and reduced food intake can make it easier to maintain a
reduced caloric intake over time. While diet, exercise, and behavioural modifications remain
important components of obesity management, lifestyle changes alone can make it difficult
for some individuals to achieve and maintain adequate weight loss over time, which is why
GLP-1 receptor agonists may be used alongside these lifestyle changes (Gul et al., 2024).Semaglutide is a major example of a GLP-1 receptor agonist used for weight
management. In the STEP 1 trial, adults with overweight or obesity who received 2.4 mg of
semaglutide weekly lost an average of 14.9% of their body weight over 68 weeks, compared
with 2.4% in the placebo group. Additionally, 86.4% of participants receiving semaglutide
achieved at least 5% weight loss, compared with 31.5% receiving placebo (Fornes et al.,
2022). The benefits of semaglutide may also extend beyond weight loss. In the SELECT
trial, semaglutide reduced the risk of major cardiovascular events by 20% in adults with
overweight or obesity and pre-existing cardiovascular disease who did not have diabetes
(Lincoff et al., 2023). More recent research has also explored the effects of semaglutide on
obstructive sleep apnea in patients with obesity, with research reporting significant
improvements in this condition (Wu et al., 2026).
Despite these long-term benefits, GLP-1 receptor agonists also have several
limitations, particularly their gastrointestinal (GI) side effects. The most common adverse
effects include: nausea, diarrhea, vomiting, constipation and a decreased appetite, which
may cause some patients to discontinue treatment (Xie et al., 2025). A recent meta-analysis
of 48 randomized controlled trials involving 27,729 participants found that nausea was the
most frequently reported gastrointestinal adverse effect, followed by diarrhea and vomiting.
These adverse effects also differ between medications; for example, semaglutide was
associated with a higher risk of diarrhea compared with several other GLP-1 receptor
agonists.
Loss of lean muscle mass is also a potential limitation, as muscle contributes to
metabolic health and immune function. Some other limitations include weight gain after
stopping the medications, the monthly cost of the medication, and the fact that some
insurance companies do not cover these costs. Other potential adverse effects include
irritation occurring at the injection site, and, in rare cases, pancreatitis. It is important forphysicians to consider a patient’s history when prescribing medications such as Ozempic,
particularly for those who have difficulty tolerating gastrointestinal side effects.
Despite these limitations, the success of GLP-1 receptor agonists has encouraged
researchers to explore how this drug class can be further improved to increase tolerability,
accessibility and effectiveness. Rather than targeting the GLP-1 receptor alone, emerging
therapies are beginning to target multiple metabolic pathways at the same time, representing
the next stage in the evolution of this drug class.
The Future of GLP-1-Based Therapies: Multi-Receptor Agonists, Emerging
Applications, and Long-Term Challenges
Although GLP-1 receptor agonists have been extremely successful, researchers are
still looking for ways to decrease the number of limitations and increase the efficacy of the
medication. More specifically, researchers are investigating whether targeting multiple
metabolic hormone pathways at the same time could produce greater metabolic effects
instead of just targeting GLP-1 alone. One of the most significant developments
demonstrating where this drug class may be heading is tirzepatide, a medication that targets
more than one receptor. Tirzepatide is a dual agonist that activates both GLP-1 and
glucose-dependent insulinotropic polypeptide (GIP) receptors. Similar to GLP-1, GIP is an
incretin hormone involved in the body's response to food and contributes to the release of
insulin following a meal. By targeting both of these incretin pathways simultaneously,
tirzepatide can improve glycemic control while also encouraging weight loss (Lin et al.,
2023).
The potential benefit of this dual-receptor approach can be seen in clinical research
comparing tirzepatide with existing treatments. A systematic review and meta-analysis of 10randomized controlled trials involving 9,873 participants found that tirzepatide significantly
reduced both body weight and HbA1c levels, demonstrating the potential metabolic benefits
of simultaneously targeting more than one incretin pathway. Compared with other GLP-1
receptor agonists, including semaglutide and dulaglutide, tirzepatide was associated with an
additional average reduction in body weight of approximately 1.05 kg (Lin et al., 2023).
These findings suggest that the future of this drug class may extend beyond GLP-1 receptor
agonism alone, with multi-receptor therapies offering another approach to improving both
glycemic control and weight management.
The success of dual-receptor agonists such as tirzepatide has encouraged
researchers to investigate whether targeting additional metabolic pathways could produce
even greater effects. One emerging approach involves triple agonists that simultaneously
target GLP-1, GIP, and glucagon receptors, with the goal of combining the metabolic effects
of all three hormones into a single treatment (Jakubowska et al., 2024). One example is
retatrutide, a GLP-1/GIP/glucagon receptor triagonist that produced an average weight loss
of 24.2% after 48 weeks at the highest dose tested in a phase 2 trial. In addition to weight
loss, participants experienced improvements in waist circumference, blood pressure,
glycemic control, and lipid levels (Jakubowska et al., 2024).
Beyond developing drugs that target multiple hormone receptors, researchers are
also working to make GLP-1 therapies more convenient and accessible for patients.
Although many current treatments require injections, recent research has focused on
developing oral alternatives that may reduce barriers associated with needle aversion,
storage, and administration (Santulli, 2025). Two recent phase 3 trials demonstrated the
potential of this approach. In the ATTAIN-1 trial, the oral GLP-1 receptor agonist orforglipron
produced an average weight loss of 11.2% after 72 weeks, while the OASIS-4 trial found that
oral semaglutide produced an average weight loss of 13.6% after 64 weeks (Santulli, 2025).These findings demonstrate the potential of oral GLP-1 therapies to produce similar benefits
without requiring injections.
Researchers are also investigating whether the effects of GLP-1 receptor agonists
could extend beyond metabolic diseases and potentially be used in the treatment of
addictive disorders. GLP-1 receptors are found in several areas of the brain involved in
reward and addiction, leading researchers to investigate whether these medications may
influence behaviours associated with alcohol and substance use disorders (Klausen et al.,
2022). Preclinical studies have shown reductions in the intake of substances such as
alcohol, nicotine, cocaine, and opioids following GLP-1 receptor stimulation, with
researchers suggesting that some of these effects may involve changes in dopamine
signalling within the brain.
Despite the expanding potential of GLP-1-based therapies, several important
questions surrounding their long-term use remain unanswered. As these medications may
require chronic treatment to maintain their benefits, further research is needed to understand
their safety and effectiveness when used over many years. This is particularly important as
newer medications target multiple hormone pathways simultaneously, potentially increasing
their effectiveness while also introducing new considerations surrounding tolerability and
long-term safety.
The continued development of multi-receptor agonists also raises the question of
whether traditional GLP-1 receptor agonists, such as semaglutide, will remain the dominant
approach or whether medications targeting multiple pathways will eventually become
preferred. While drugs such as tirzepatide and emerging triple agonists demonstrate the
potential for greater metabolic and weight-loss effects, increased effectiveness alone will not
determine the future of this drug class. Researchers and health-care systems must alsoconsider whether these increasingly complex therapies can remain safe, tolerable,
affordable, and accessible to the patients who could benefit from them.
Conclusion
The evolution of GLP-1 receptor agonists demonstrates how understanding a
biological pathway can eventually lead to increasingly sophisticated and effective therapies.
What began with the discovery of GLP-1 and its role in glucose regulation eventually led
researchers to overcome the hormone’s extremely short half-life through the development of
drugs such as exenatide and later, longer-acting GLP-1 receptor agonists such as liraglutide
(Knudsen & Lau, 2019). As these medications continued to improve, drugs such as
semaglutide expanded the role of GLP-1 receptor agonists beyond type 2 diabetes and into
chronic weight management and cardiovascular risk reduction. The STEP 1 trial, for
example, demonstrated the significant effects that semaglutide can have on weight loss,
while the SELECT trial demonstrated that its benefits may also extend to reducing major
cardiovascular events in certain patients with overweight or obesity (Fornes et al., 2022;
Lincoff et al., 2023).
However, the evolution of this drug class is still continuing. The development of
tirzepatide, which targets both GLP-1 and GIP receptors, and emerging triple agonists such
as retatrutide suggest that the future of these therapies may move toward targeting multiple
metabolic pathways at the same time (Lin et al., 2023; Jakubowska et al., 2024). At the
same time, limitations surrounding gastrointestinal side effects, long-term treatment,
accessibility, cost, and weight regain after discontinuation show that there is still room for
these therapies to improve. Overall, the evolution of GLP-1 receptor agonists demonstrates
how understanding a biological pathway can provide the foundation for an entire drug class
that continues to change as researchers identify new limitations and therapeutic
opportunities. From a naturally occurring hormone involved in glucose regulation to drugsnow being investigated across multiple receptors and diseases, GLP-1-based therapies
demonstrate how scientific discoveries can be continuously built upon to create increasingly
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