Few drugs have captured public attention like Ozempic; many of us have even taken it. The type 2 diabetes medication, generically known as semaglutide, has received unprecedented attention in the press and the medical community for its ability to trigger profound weight loss. 

Although this popularity betrays a certain bias against people of higher weight, the reasons for these drugs’ media stardom isn’t hard to grasp: they work and they are safe with relatively few side effects for most people. Indeed, it's often described as a "wonder drug." That hasn’t stopped a torrent of fat phobia and often frankly hateful cultural attitudes towards weight the drugs have helped fuel, despite having benefits and risks like any other medication.

But diabetes management and weight loss are far from the most interesting things about semaglutide. In fact, the more we learn about biochemical pathways that this class of drug targets, the more it seems that we have opened the door to a dramatically improved understanding of metabolism and the many, often surprising, ways these pathways affect every aspect of our health. 

As a result, semaglutide and its fellow glucagon-like peptide-1 drugs are spawning a tremendous outpouring of research that often clarifies connections between health issues that have long been recognized, but previously not understood. Like why, for example, having diabetes can put you at higher risk of Alzheimer’s. Or the mysterious relationship between osteoarthritis and obesity.

Semaglutide mimics the action of the natural protein glucagon-like peptide 1(GLP-1), a hormone from a family of chemical messengers called the incretins, which Belgian physiologist Jean LaBarre first purified as an extract from the gut back in 1929. The substance stimulates the pancreas to release insulin, lowering glucose in the blood to keep blood sugar in balance. GLP-1, the second incretin to be identified, in the 1980s, is also found in the intestines, which release GLP-1 when you eat to help control your blood sugar. 

In the 1990s, Lotte Bjerre Knudsen, a Novo Nordisk researcher who previously studied detergent enzymes, was put on a type 2 diabetes drug development working group. Twenty years later (and with many other players and intermediate steps), Ozempic was born, and the game changed.

Svetlana Mojsov, a researcher at Rockefeller University whose work has been important in the characterization of GLP-1 and clarification of its role in glucose metabolism, explained in an interview with PNAS this September, “Once we solve obesity, I think a lot of other disorders will be taken care of …  As for all the other pathophysiological states in which GLP-1-based drugs appear to be beneficial, I think it may have something to do with the drugs’ central role in regulating glucose metabolism.”

But lowering glucose isn’t GLP-1’s only job, though as Mojsov said, the relationship with glucose metabolism may be a crucial central part in the many related conditions it seems to treat. Since Ozempic came on the market in 2017, we’ve seen that it can do far more than simply treat type 2 diabetes. The FDA approved Wegovy for chronic weight management in 2021.

The basic science around GLP-1

Think of the way things happen in our bodies as involving a lock and a key. The lock is a protein called a receptor  — in the case of GLP-1 and other G protein-coupled receptors, it’s a protein located on the surface of a cell. The key is the ligand  —  that’s the general word for whatever chemical messenger or signaling molecule attaches to the receptor, activating it. For GLP-1 receptors, it’s GLP-1. Ozempic, or semaglutide, is a GLP-1 agonist, meaning its molecules mimic the structure of GLP-1, binding to its receptor like a counterfeit key someone’s carved out of a bar of soap.

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“These are just natural gut peptides that everyone makes,” explained Dr. Andrea Coviello, a professor of medicine at University of North Carolina and medical director of the UNC Medical Weight Program, in a video interview with Salon. “And I think that’s why, to a large extent, you see a really good response.”

Ozempic and Wegovy do the same thing as GLP-1 would normally do for you — but to enable them to treat diabetes and obesity, not just the glucose impact of individual meals, they’ve been designed, largely thanks to Knudsen’s work, with slight changes to allow them to hang out in the blood longer than GLP-1 normally does.

GLP-1 briefly slows the rate food moves through the gut, which explains the most common side effects: bloating and constipation. Newer GLP-1 receptor agonists like tirzepatide, (which combines a GLP-1 mimic with the mimic of a different gut peptide) are designed to mitigate the effects on gut motility.

“The main side effects that we see are predictable when you understand the mechanism of action of these drugs,” Coviello told Salon.

We’ve learned GLP-1 receptors are found all over the place in the body  —  most notably in pancreatic beta cells, in the intestine, and in the central nervous system (the brain and spinal cord). They can also be found in blood vessels, in the peripheral nervous system, in the joints, the lungs, the heart, the alpha cells of the pancreas, and in the kidneys, giving them many different functions in the body: activating a protein here, lowering a different protein there, playing a role in intricate paths of cause and effect, getting things done. GLP-1 drugs like Ozempic are thus able to produce many surprising effects by activating the same pathways as GLP-1, pathways that we are beginning to understand in ever-greater levels of detail thanks to the research they’ve inspired.

Dr. Daniel Drucker is a clinician-researcher and professor at the University of Toronto, and holds the Canada Research Chair in Regulatory Peptides and the Banting and Best Diabetes Centre-Novo Nordisk chair in Incretin biology. He pointed Salon to a recent article in which he writes, “The initial chapter of GLP-1 innovation focused on glucose control, and later, weight loss. Subsequent waves seem likely to improve health outcomes in people with a range of chronic disorders.”

That’s because we’ve learned that insulin resistance and metabolism are important in ways we didn’t previously realize. And it’s because GLP-1 has roles in the body, beyond its role in the management of glucose, that weren’t previously appreciated.

“We don't fully understand the weight loss-independent mechanisms through which GLP-1 reduces inflammation  —  is it through the brain, or via T cells, or other pathways? A lot of work is ongoing to understand this,” Drucker told Salon in an email interview.

Dealing with sugar

But let’s start with insulin resistance. People with obesity have a tendency towards insulin resistance, when the hormone insulin stops effectively lowering glucose (sugar) levels in the blood. Ultimately, this can result in type 2 diabetes, a condition where insulin resistance becomes a chronic problem and blood sugar levels become too high as a result. But not everyone with diabetes is obese  —  in fact, in East Asian patients, type 2 diabetes develops at lower BMI, and fat accumulation tends to be in the viscera, such that patients may have more body fat at any given BMI.

Nevertheless, GLP-1 agonists like Ozempic are effective in these patients, suggesting that what is measured when we define obesity according to body mass index is not the aspect of overweight that is relevant to insulin resistance (likely because BMI was originally based on white European populations). More importantly, we need to focus on what GLP-1 does: trigger the pancreas’s beta cells to release insulin, which lowers blood sugar.

And when that doesn’t work, you get elevated blood sugar, or hyperglycemia. Since sugar, in the form of glucose, provides energy for every cell and system in the body, when there’s too much of it, all sorts of things get out of whack, with extra carbohydrates being stored as fat triglycerides in adipose tissue, in the liver and elsewhere. Improving insulin resistance with GLP-1 drugs turns out to be beneficial not just for obesity and diabetes, but also for the prevention of pancreatitis and non-alcoholic fatty liver disease.

The heart of the matter

Both type 2 diabetes and obesity put you at risk of cardiovascular disease, though we haven’t known exactly why. When the first clinical study of Ozempic came out, it was found that the once-weekly injection slashed rates of non-fatal heart attacks and strokes as well as cardiovascular deaths.

Making insulin work better (another way of describing good glycemic control) and weight loss are two of the indirect ways in which GLP-1 receptor agonists can improve cardiovascular health. Another is by reducing inflammation. In fact, says Coviello, under certain still unknown conditions or at a still-to-be-determined point, healthy adipose tissue acquires pathological qualities. As if responding to an injury, you get a rush of inflammatory proteins of various kinds into adipose (fat) tissue.

“Under the microscope you see a lot of inflammatory infiltrate in the adipose tissue,” Coviello said. “At some point, once that has reached sort of critical mass, you start to have insulin resistance, and you start to have the negative side effects of a lot of inflammation.”

Inflammation causes insulin resistance and insulin resistance causes poor sugar control and high blood sugar levels cause damage to the lining of your blood vessel. Ozempic may also act directly on the cardiovascular system. There are GLP-1 receptors in blood vessels and on the heart, including, Coviello said, on the sinoatrial nodes that controls the heart rate.

“So knowing that, it’s not perhaps surprising that there were cardiovascular benefits that were potentially even outside of the degree of weight loss that we see, or the degree of glycemic control that we see,” Coviello explained.

“It’s a more complex system”

Coviello’s patients receiving treatment for obesity have reported incidental improvements in their chronic inflammatory diseases such as osteoarthritis, rheumatoid arthritis or psoriatic arthritis.

We’ve long known of a link between osteoarthritis and metabolic syndrome related to obesity, but the nature of this link didn’t start to become clear until the discoveries of the past decade that underlie the invention of Ozempic, and more recently the anecdotal reports of patients like Coviello’s. It was just known that the biggest risk factor in getting osteoarthritis (OA) was having metabolic syndrome. Type 2 diabetes is also strongly associated with OA. And inflammation, associated with arthritis, is also an important risk factor for conditions ranging from heart disease to cancer to neurodegenerative diseases.

Now we’re learning that in osteoarthritis associated with obesity, metabolic syndrome causes inflammation by activating small proteins called cytokines that activate or calm down the immune system, right in the synovium area — the space in a joint, your knee for example, bringing white blood cells, or macrophages, rushing in, another sign of inflammation. (It’s rheumatoid rather than osteoarthritis that is more generally considered an inflammatory disease but inflammation is a factor in both.)

And guess what’s also found in joint tissues? GLP-1 receptors. So it turns out that GLP-1 drugs may be able to target and ease the low-grade local inflammation of the synovium that causes such misery in osteoarthritis patients. But so far, the studies of this and most other inflammation-related impact of GLP-1 drugs are restricted to animal (usually mouse or rat) models.

“Will this work in humans with a wide range of inflammation-driven disorders, independent of weight loss?” Drucker asked. “We don't yet know.”

A range of autoimmune diseases that affect various organ systems and cause muscle wasting may be good candidates (mouse and preliminary human studies suggest) for GLP-1 receptor agonist treatment because of their ability to reduce the expression and release of inflammatory cytokines. Other conditions that might be treated with the use of GLP-1 receptor medications include conditions that affect the optic nerve and the spinal cord, asthma and bone pathologies where GLP-1 is part of complex pathways involving the release or suppression of cytokines, those inflammatory proteins.

Coviello says that with such long and intricate biochemical pathways, there’s potential in new medications that incorporate more than one receptor agonist.

“I suspect that what we’ll learn is that it’s a more complex system. Many of the new drugs coming out are combinations, so they are mimicking many different hormones, and that, if you think about it, is going to be much more physiologic, because when you do eat … it sets off an entire cascade” of mostly peptide hormones as well as neurologic signals (such as signals in the brain telling you when you feel full) “to actually metabolize food and provide fuel,” Coviello said.

After all, GLP-1 is just one of the gut hormones that have multiple effects through the body. The closer we can mimic what’s actually supposed to be going on, the better they should work and the fewer side effects we should expect.

Can GLP-1 fight cancer?

“Obesity is associated with over ten different types of cancers,” said Coviello. These include hormonal cancers like uterine cancer, as well as epithelial cancers, such as some types of liver cancer.

Through further chains of biochemical interactions — key fitting into lock, upregulating one protein that causes the release of a different key to fit into a different lock, triggering downregulating some other molecule, and so on — GLP-1 seems to play a role in the progression or inhibition of cancer, perhaps explaining the risk associations of various cancers with obesity, and with systemic inflammation, and helping to elucidate the relationship between cancer and metabolic processes like blood sugar management. This offers hope that GLP-1 receptor agonist drugs may one day be able to treat cancers.

“It tackles these inflammatory pathways and reverses that process so you have less inflammation even at the tissue level,” Coviello explained. At the University of North Carolina, she says, three clinical trials are underway to see if the GLP-1 receptor class of medications might work.

Then there’s the brain

Most Alzheimer’s research in recent years has focused on the damning role of tau proteins and beta-amyloid deposits. But in the background, work on the role of glucose in the brain, and on insulin’s role in regulating it, has piled up, along with other possible mechanisms. We know that obesity and type 2 diabetes are both associated with Alzheimer’s disease. And Alzheimer’s definitely has a connection with insulin resistance — so much so that a 2005 paper proposed it be called type 3 diabetes, with actual insulin resistance in the brain demonstrated nearly a decade later.

Spraying insulin up the nose — where brain tissue reaches outside the brain, making up the olfactory bulb — improves cognition in people with early Alzheimer’s dementia and with mild cognitive impairment. So there’s reason to believe that if we could just improve insulin signalling in the brain, we could treat more severe cases as well. But until the first GLP-1 drugs came along, there was no medication that could get through the blood-brain barrier or last long enough without quickly breaking down, just as GLP-1 hormone itself does in the body. (After a meal, newly released GLP-1 has a half life of less than ten minutes. It does its job, then gets broken down in your stomach.)

Now we’re learning that GLP-1 in the brain plays important roles in metabolism there, just as GLP-1 in the gut and pancreas does in the rest of the body, including the brain. GLP-1’s functions inside our heads include regulating insulin signalling in the brain; promoting the differentiation of new neurons from precursor cells; and protecting the brain from injuries like stroke, Parkinson’s and some Alzheimer’s cases.

Associative learning, which takes place in the midbrain, can be impaired in some cases of obesity as a result of poor signaling to the brain from the GLP-1 peptides in the intestine. The ability to form sensory associations can be restored with the use of an early GLP-1 receptor agonist drug, liraglutide, a small study found last year.. Restoration of other normal functions of impaired GLP-1 signalling in the brain could have even more important effects.

As far as non-weight or diabetes-related benefits of GLP-1 drugs go, Drucker says “probably most exciting …is the potential for benefit in Alzheimer's disease. “Huge problem, large unmet need for a drug that works and is also safe,” Drucker said.

In fact, trials of oral semaglutide for Alzheimer’s Disease are underway and Drucker says that within a year we should know if it works.

Meanwhile, a paper published Monday in Nature Medicine provides further reason for hope. Researchers Yan Xie, Taeyoung Choid and Ziyad Al-Aly mapped associations between GLP-1 receptor drug use and a wide range of health outcomes, comparing such associations with health outcomes associated with usual care using non-GLP-1 treatment.

Over the 175 different positive and negative outcomes assessed, they found GLP-1 receptor agonists like semaglutide to be associated with reduced risk for dozens of conditions. These include neurocognitive disorders, including Alzheimer’s and other dementia; seizures; clotting disorders; a number of respiratory conditions; and various infectious illnesses. Unsurprisingly, there was also a reduced risk of cardiometabolic disorders. Another striking positive finding: reduced risks of substance use disorders and psychotic disorders.

Equally importantly, GLP-1 receptor agonist use was associated with some increased risks compared to usual care with other treatments. These risks include gastrointestinal disorders, low blood pressure, nephrolithiasis (kidney stone disease), interstitial nephritis, and drug-induced pancreatitis. Perhaps surprisingly, given the inflammatory pathways discussed above, the researchers also found a heightened risk of arthritic disorders in patients using GLP-1 drugs, compared to usual treatment. 

While it’s trendy to either feverishly promote Ozempic, Wegovy or their many knock-off versions, or to dump on the whole idea, dismissing it as the product of a sick and bigoted society and corporations eager to medicalize anything they can, there’s far more to it than that. Understanding better the complex pathways that get things done in the body — and that sometimes go awry — is like delicately unwrapping an intricately wrapped package until you can see with clarity just what’s inside and how it all works. For all the hype, semaglutide and similar drugs bring real substance in the hope they offer of doing just that.