GLP-1 receptor agonist

Based on Wikipedia: GLP-1 receptor agonist

In the early 1980s, a researcher named Jean-Pierre Raufman became curious about a peculiar fact: the Gila monster, a venomous lizard native to the American Southwest, only eats once or twice per year. What biological machinery allows a creature to go months between meals? Raufman was working at the National Institutes of Health, hunting through animal venoms for molecules that might affect human physiology. When he injected Gila monster venom into test animals, their pancreases became inflamed.

That discovery sat dormant for nearly a decade.

Then in 1992, a scientist named John Eng at the Veterans Administration Medical Center in New York City picked up the thread. Using techniques he'd learned from Nobel laureate Rosalyn Sussman Yalow, Eng isolated a novel substance from Gila monster venom. He called it exendin-4. It looked remarkably similar to a hormone the human body produces naturally—glucagon-like peptide-1, or GLP-1—but with one crucial difference: while natural GLP-1 breaks down in the bloodstream within two minutes, exendin-4 stuck around long enough to actually work as a drug.

When Eng tried to get his employer, the U.S. Department of Veterans Affairs, to patent the discovery, they declined. So he filed the patent himself in 1993 and spent three years searching for a pharmaceutical company interested in developing it.

That molecule from lizard venom would eventually become the foundation for a class of medications that has transformed how we treat diabetes and obesity—drugs you've probably heard of by their brand names: Ozempic, Wegovy, Mounjaro, Zepbound.

What GLP-1 Actually Does in Your Body

To understand why these drugs work, you need to understand what happens when you eat a meal.

Your small intestine releases a hormone called GLP-1—that's short for glucagon-like peptide-1, which is a mouthful even for scientists. This hormone does several things simultaneously. It signals your pancreas to release more insulin, the hormone that helps cells absorb sugar from your blood. It tells your pancreas to stop releasing glucagon, a different hormone that would otherwise raise your blood sugar. And it slows down how quickly food leaves your stomach, creating a more gradual rise in blood sugar rather than a spike.

There's a catch, though. Your body destroys natural GLP-1 almost immediately. An enzyme called dipeptidyl peptidase-4—mercifully abbreviated to DPP-4—breaks it down within about two minutes. This makes evolutionary sense: you don't want your appetite suppressed for hours after a small snack. But it also means you can't simply inject natural GLP-1 as a medicine. It would disappear before it could do anything useful.

The synthetic versions solve this problem. Pharmaceutical companies have modified the GLP-1 molecule in various ways to resist that enzymatic breakdown. Some versions last a day. Others last a week. The result is that you can maintain elevated GLP-1 activity continuously, producing effects that go far beyond what a normal meal would trigger.

The Brain Connection

Here's where things get interesting. GLP-1 receptors aren't just in your pancreas. They're scattered throughout your body, including in your brain.

When GLP-1 agonists cross the blood-brain barrier—either by slipping through passively or by hitching a ride on specialized transport proteins—they activate receptors in the hypothalamus. This is the part of your brain that regulates hunger and satiety. The drugs essentially turn up the volume on "I'm full" signals and turn down the volume on "I'm hungry" signals.

People taking these medications often describe a fundamental shift in their relationship with food. The constant background noise of appetite quiets. The compelling urge to finish everything on the plate fades. Food becomes something you think about less.

This is different from most weight-loss approaches that require willpower to override biological signals. GLP-1 agonists change the signals themselves.

Beyond Diabetes: The Expanding List of Uses

These medications started as diabetes drugs. The first, exenatide—that molecule derived from Gila monster venom—was approved by the Food and Drug Administration in 2005. For people with type 2 diabetes, GLP-1 agonists offered a meaningful improvement over older medications. They lowered blood sugar effectively, but unlike sulfonylureas and other insulin-stimulating drugs, they rarely caused dangerous drops in blood sugar. They didn't cause weight gain like insulin does. And increasingly, studies showed they protected the heart and kidneys.

A 2021 analysis of multiple studies found that people with type 2 diabetes taking GLP-1 agonists had a 12 percent reduction in death from any cause compared to those not taking the drugs. That's not a subtle effect.

Then came the weight-loss applications. The same mechanism that helps diabetics control their blood sugar—reduced appetite and slower stomach emptying—turns out to be remarkably effective for weight management. Clinical trials of semaglutide (sold as Wegovy for weight loss) and tirzepatide (sold as Zepbound) showed weight reductions of 16 to 20 percent. For someone weighing 250 pounds, that could mean losing 40 to 50 pounds.

To put this in perspective: most weight-loss medications barely outperform placebo. Diet and exercise programs typically produce modest, often temporary results. Bariatric surgery remains the most effective intervention but requires going under the knife. GLP-1 agonists have landed in a previously empty space—genuinely effective, non-surgical weight loss.

The applications keep expanding. In August 2025, the FDA approved semaglutide for treating a liver condition called MASH—metabolic dysfunction-associated steatohepatitis. This is a more severe form of fatty liver disease that can progress to cirrhosis. Clinical trials showed a 60 percent reduction in liver inflammation. Researchers are also investigating these drugs for polycystic ovary syndrome, and intriguingly, for addiction and other conditions affecting the brain's reward system.

How You Take Them

Most GLP-1 agonists are injected under the skin, typically once a week. The drugs come in auto-injector pens, similar to the devices used for insulin. You press the pen against your thigh or abdomen, click a button, and the needle does its work.

For many people, this is a dealbreaker. Weekly self-injection requires comfort with needles and manual dexterity. Type 2 diabetes commonly causes vision problems and nerve damage in the hands, making injection more difficult for precisely the population that needs these drugs most.

There is one oral option: semaglutide is sold under the brand name Rybelsus as a daily pill. Getting a peptide drug to survive the digestive system and absorb through the gut wall is no small feat—most proteins simply get broken down like any other food. The oral version works, though it requires taking the pill on an empty stomach with minimal water and waiting before eating.

Pharmaceutical companies are working on inhaled versions, skin patches, and other delivery methods. The ideal would be something as simple as taking a vitamin.

The Side Effects

The most common side effects are gastrointestinal. Nausea, vomiting, diarrhea, constipation. This makes sense when you understand the mechanism: slowing stomach emptying means food sits longer, which can feel uncomfortable. Up to three-quarters of people taking short-acting GLP-1 agonists report nausea. The long-acting weekly injections cause fewer problems, and symptoms often improve over time as the body adjusts.

Doctors typically start patients on a low dose and gradually increase it. This titration period helps minimize side effects, though it means the full benefits take weeks to materialize.

There are more serious concerns. Case reports have described pancreatitis—inflammation of the pancreas—though large studies haven't found a consistent association. The risk of gallstones increases, especially with rapid weight loss. The drugs slow stomach emptying enough that anesthesiologists have raised concerns about aspiration during surgery; the American Society of Anesthesiologists now recommends stopping GLP-1 agonists at least a day before procedures, or potentially a week.

One concerning finding needs context. In rodent studies, long-term use of GLP-1 agonists caused thyroid C-cell tumors, a type of thyroid cancer. The FDA requires a boxed warning—the most serious type—on all these medications, and they're contraindicated in people with a personal or family history of medullary thyroid cancer. However, the mechanism that causes these tumors in rodents—increased calcitonin secretion—hasn't been observed in humans. A large French study found increased thyroid cancer risk after one to three years of use, but other studies with more than ten years of follow-up found no association. The jury remains out.

Early concerns about suicide risk have not been borne out. A 2024 study of over 54,000 adolescents actually found a 33 percent reduction in suicidal thoughts and attempts among those using the drugs.

What Happens When You Stop

There's no gentle way to say this: the weight comes back.

Studies consistently show that people regain 50 to 70 percent of lost weight within a year of stopping GLP-1 agonists. This shouldn't be surprising. The drugs work by changing biological signals—hunger, satiety, insulin response. Stop the drug, and the signals return to their previous state. Your body still has the same set point it was defending before.

This has profound implications for how we think about these medications. They're not a course of treatment you complete, like antibiotics. They're more like blood pressure medication or statins—ongoing therapy for a chronic condition. For many people, that means taking a weekly injection for the rest of their lives.

Whether this is acceptable depends on your perspective. If you view obesity as a chronic disease, then chronic treatment makes sense. If you view weight loss as something you should be able to maintain through willpower alone, the need for lifelong medication feels like failure.

The Economics of It All

These drugs are expensive. In the United States, list prices run around $1,000 or more per month. Insurance coverage varies widely. For diabetes, many plans cover the medications, though often with prior authorization requirements. For weight loss, coverage is much spottier—many insurers explicitly exclude weight-management drugs.

Cost is the primary reason people stop taking GLP-1 agonists. A study found that nearly half of discontinuations were due to cost. This creates a disparity: people with good insurance or substantial means can access medications that produce significant health benefits, while others cannot.

A cost-effectiveness analysis in Taiwan found that for people with existing cardiovascular disease, GLP-1 agonists actually saved money overall by preventing expensive heart attacks and strokes. For those without cardiovascular disease, the cost worked out to about $9,000 per quality-adjusted life year—well below the typical threshold for what healthcare systems consider worthwhile.

But those calculations assume the drug is actually affordable enough to take. In practice, the expense creates barriers that undermine the theoretical benefits.

The Shortage and the Gray Market

When celebrities and influencers began talking about using Ozempic for weight loss in the early 2020s, demand exploded. Pharmaceutical manufacturing couldn't keep up. The FDA declared shortages of injectable semaglutide, tirzepatide, and several other GLP-1 agonists in 2022.

This created opportunities for gray-market sellers. Some compounding pharmacies—facilities that custom-mix medications—began producing their own versions of the drugs during the shortage. This is legal under specific circumstances, but an estimated 95 percent of online pharmacies were operating illegally in 2024. Buyers face risks from counterfeit or substandard products, but some turn to unauthorized sources after being denied insurance coverage and finding name-brand prices unaffordable.

The tirzepatide shortage ended in 2024, but the underlying tension remains. Demand for these medications far exceeds what the healthcare system is prepared to supply and pay for.

The Cast of Characters

Several GLP-1 agonists are currently available:

• Liraglutide, sold as Victoza for diabetes and Saxenda for weight management, was approved in 2010 and 2014 respectively. It's a daily injection made by Novo Nordisk.
• Dulaglutide, sold as Trulicity, is a weekly injection made by Eli Lilly, approved in 2014.
• Semaglutide is the molecule behind Ozempic and Rybelsus (for diabetes) and Wegovy (for weight management). Made by Novo Nordisk, it's become the most prominent GLP-1 agonist, approved between 2019 and 2021 depending on formulation.
• Tirzepatide is something of a hybrid—it activates both the GLP-1 receptor and another receptor called GIP, which may enhance its weight-loss effects. Sold as Mounjaro for diabetes and Zepbound for weight management, it's made by Eli Lilly.

Several older GLP-1 agonists have been discontinued. Exenatide—the original, descended from Gila monster venom—was pulled from the market in 2024. Albiglutide lasted only three years before being discontinued in 2017. The field is evolving rapidly.

What Comes Next

Pharmaceutical companies are pursuing several directions. Dual and triple agonists—drugs that hit multiple receptors simultaneously—promise even greater weight loss. Tirzepatide already does this with GLP-1 and GIP receptors. Others are adding glucagon receptor activation or targeting the amylin receptor.

Oral formulations remain a priority. A once-weekly pill would be far more convenient than injection and might improve adherence. Small-molecule drugs that activate GLP-1 receptors without being peptides could potentially be easier to manufacture and administer.

The applications keep multiplying. Researchers are investigating whether these drugs could help with addiction, given the brain reward circuitry they affect. Trials are underway for conditions from sleep apnea to Alzheimer's disease.

A Different Relationship with Food

Perhaps what's most striking about GLP-1 agonists is how they've changed the conversation about weight.

For decades, the dominant narrative held that weight was fundamentally a matter of choices—calories in, calories out, willpower and discipline. People who couldn't maintain weight loss were seen as having failed, as lacking sufficient self-control. The existence of a medication that produces substantial weight loss by changing biological signals challenges that narrative.

If a drug can quiet the incessant drive to eat, was that drive really something people could have overcome through sheer determination? If hunger is a biological signal as powerful as pain or fatigue, should we expect people to simply ignore it indefinitely?

These medications haven't settled those debates, but they've forced a reckoning. Weight, it turns out, is regulated by complex hormonal systems that resist attempts to override them. GLP-1 agonists don't require willpower to work. They change the underlying biology that willpower was supposed to control.

That's a profound shift—one that started with a curious researcher wondering how a desert lizard manages to eat so infrequently, and ended with millions of people experiencing, perhaps for the first time, what it feels like when food isn't constantly on their minds.