GLP-1 at the Center of Modern Medicine

Until a few years ago, GLP-1 was a term encountered mainly in textbooks on physiology, endocrinology, and diabetes.

Today, it is discussed far beyond scientific circles.

The reason is a class of drugs that target the GLP-1 receptor and have changed the treatment options available for type 2 diabetes and obesity. But the story of GLP-1 did not begin with a drug.

It begins with a question about normal human physiology:

How does the body know that food has arrived?

What Is GLP-1?

GLP-1 stands for glucagon-like peptide-1.

After a meal, specialized enteroendocrine cells in the gut release GLP-1 in response to incoming nutrients. The hormone forms part of the complex communication between the digestive system and the rest of the body.

One of its best-established effects is on the pancreas.

When glucose concentrations are elevated, GLP-1 enhances insulin secretion from pancreatic beta cells. It also helps regulate glucagon.

This is part of the so-called incretin effect: oral glucose elicits a stronger insulin response than glucose administered intravenously, even when blood glucose concentrations are matched.

This difference shows that the gut is not merely a passage through which nutrients reach the blood.

It plays an active part in preparing the body for what follows a meal.

One Hormone, More Than One Function

GLP-1 does more than affect insulin secretion.

It helps regulate gastric emptying and communication between the digestive and nervous systems. GLP-1 receptors and associated neural pathways also contribute to the control of food intake and satiety.

This system, however, is more complex than the popular explanation that GLP-1 simply ‘switches off hunger.’

Some signals may be transmitted through neural pathways, and GLP-1 is also produced by certain neurons in the brainstem. Its various physiological effects cannot be reduced to a single hormone released from the gut and traveling directly to every target.

There is another important feature.

Active endogenous GLP-1 does not remain in the circulation for long.

A Signal That Disappears Quickly

Once released, active GLP-1 is rapidly inactivated, with the enzyme DPP-4—dipeptidyl peptidase-4—playing an important role.

This means that endogenous GLP-1 is a short-lived physiological signal.

And this is precisely where physiology begins to meet pharmacology.

If activating the GLP-1 receptor has beneficial effects on glucose regulation and food intake, could this receptor be used as a therapeutic target?

Over time, the answer proved to be yes.

But the solution was not simply to provide more natural GLP-1.

It required molecules capable of activating the GLP-1 receptor for long enough to produce a therapeutic effect. This distinction between a short-lived endogenous signal and sustained pharmacological activation underlies the development of GLP-1 receptor agonists.

From Physiology to Therapy

GLP-1 receptor agonists are drugs that activate the GLP-1 receptor.

They are not simply ‘natural GLP-1 at a higher dose.’

Different molecules have different structures and pharmacokinetic properties, and they are designed to act for substantially longer than active endogenous GLP-1.

One of the best-known examples today is semaglutide.

It was initially developed for type 2 diabetes, but the effect of GLP-1 receptor activation on food intake and body weight opened another therapeutic possibility: treating obesity.

Here, we have more than a physiological hypothesis: we have large randomized clinical trials.

What Have the Semaglutide Trials Shown?

In STEP 1, published in 2021 in The New England Journal of Medicine, 1,961 adults with obesity or with overweight and at least one weight-related comorbidity, but without diabetes, were randomized to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo, alongside a lifestyle intervention, for 68 weeks.

The mean change in body weight was approximately −14.9% with semaglutide, compared with −2.4% with placebo.

This is a large effect for a pharmacological intervention in obesity and one reason GLP-1 receptor agonists have attracted so much attention.

But weight loss is not the only reason GLP-1 has moved to the center of medical attention.

SELECT asked a different question.

From Weight Loss to Health Outcomes

SELECT enrolled 17,604 people aged 45 or older with overweight or obesity and established cardiovascular disease, but without diabetes.

Participants received semaglutide 2.4 mg once weekly or placebo.

Over a mean follow-up of 39.8 months, the primary composite cardiovascular outcome—cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke—occurred in 6.5% of the semaglutide group and 8.0% of the placebo group.

This corresponds to an approximately 20% relative reduction in risk for the primary composite outcome in this particular high-risk population.

That qualification matters.

SELECT does not show that semaglutide prevents cardiovascular events in everyone with overweight.

The trial examined a specific group: people with overweight or obesity, established cardiovascular disease, and no diabetes.

This distinction—between an impressive result and the precise population to which it applies—is essential when discussing drug evidence.

Effective Treatment Can Still Have Adverse Effects

Pharmacological activation of the GLP-1 receptor affects several physiological systems, and treatment is not free of adverse reactions.

The most common are gastrointestinal symptoms such as nausea, vomiting, diarrhea, and constipation. Large clinical trials also show a higher rate of treatment discontinuation because of adverse effects than in placebo groups.

A more recent systematic review and network meta-analysis from 2025 also confirms the importance of gastrointestinal adverse events with GLP-1 receptor agonists used in people with overweight or obesity who do not have diabetes.

There are also rarer risks and specific contraindications that depend on the particular drug and the clinical context.

Their efficacy therefore does not make these drugs a universal solution for everyone who wants to lose weight.

They are medical therapies.

And What About Muscle?

When someone loses a substantial amount of body weight, the loss generally does not come entirely from adipose tissue.

Fat-free mass can also be lost.

This is not unique to GLP-1 therapies—it also occurs with other forms of substantial weight loss—but it becomes an especially important consideration when medications enable greater weight reduction.

In the STEP 1 DXA substudy, the reduction in fat mass was greater than the reduction in fat-free mass.

That does not mean fat-free mass can be disregarded.

Contemporary research increasingly considers not only how much weight is lost, but also how body composition, muscle function, and physical capacity change.

This is particularly important for people who already have low muscle mass or functional limitations before treatment.

Endogenous GLP-1 and Drug Treatment Are Not the Same

The popularity of GLP-1 therapies has also led to another interesting trend: the idea that certain foods can ‘increase GLP-1 naturally’ and thereby produce the same effect.

Nutrients can indeed stimulate the release of endogenous GLP-1.

But that does not make food pharmacologically equivalent to a long-acting GLP-1 receptor agonist.

Endogenous GLP-1 is part of a short-lived physiological system that is integrated locally and through neural signaling. The drugs produce much more sustained receptor activation and were developed precisely to overcome the limitations of the endogenous hormone.

Diet and GLP-1 pharmacology can therefore engage the same biological system without being interchangeable.

Why Has GLP-1 Become So Important?

The story of GLP-1 shows how fundamental physiology can become a therapeutic strategy.

First, we recognize that the gut plays an active part in regulating the metabolic response to food.

Then we identify one of the signals in this system.

Next, we understand the receptor, the limitations of the endogenous hormone, and how the receptor can be activated pharmacologically.

Finally, large clinical trials show that, in certain patients, this strategy can change not only blood glucose or the number on the scale, but also important health outcomes.

This explains why GLP-1 is now at the center of so many scientific and medical conversations.

Not because we have discovered a ‘weight-loss hormone.’

But because a physiological system that coordinates the body’s response to food has proved to be a therapeutic target with unusually broad potential.

And the science around it is still developing.