The Mystique of Ozempic Is Growing

There’s no such thing as a miracle cure for weight loss, but the latest obesity drugs seem to come pretty close. People who take Ozempic or other weekly shots belonging to a class known as GLP-1 agonists, after the gut hormone they mimic, can lose a fifth or more of their body weight in a year. Incessant “food noise” fueling the urge to eat suddenly goes silent.

In recent months, the mystique of these drugs has only grown. Both semaglutide (sold under the brand names Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound) were initially developed for diabetes and then repurposed for weight loss. But they apparently can do so much more than that. Studies showing the heart benefits of semaglutide have already led the FDA to approve Wegovy as a way to reduce the risk of major cardiac events, including stroke, heart attack, and death, in certain patients. The drug has also shown clear benefits for sleep apnea, kidney disease, liver disease—and can potentially help with fertility issues, Alzheimer’s, Parkinson’s, colorectal cancer, alcohol overuse, and even nail-biting. These days, a new use for GLP-1s seems to emerge every week.

With each new breakthrough, GLP-1s look more and more like the Swiss Army knife of medications. As Vox asked last year: “Is there anything Ozempic can’t do?” But GLP-1s can’t take all the credit. Obesity is linked to so many ailments that losing huge amounts of weight from these drugs is destined to have “a pretty dominant effect” on health outcomes, Randy Seeley, an obesity researcher at the University of Michigan, told me. Teasing out exactly what is causing these secondary benefits will be difficult. But the future of these drugs may hinge on it.

Some of the additional health effects of GLP-1s do seem in line with a drug that can lead to dramatic weight loss. People with obesity are at a much higher risk for heart attacks and liver disease; excessive weight can restrict breathing at night, leading to sleep apnea. Of course obesity drugs would help. Even reports of “Ozempic babies”—people unexpectedly conceiving while on GLP-1s—make sense considering that fertility tends to improve when people lose weight. But weight loss alone isn’t always the only explanation. A major trial tracking the heart health of people on semaglutide suggested that patients can have cardiovascular improvements even if they don’t lose much weight. “It is quite clear that there are benefits to these drugs that are beyond weight loss,” Seeley said.

GLP-1s improve health outcomes through three mechanisms, Daniel Drucker, a professor of medicine at the University of Toronto who co-discovered GLP-1 in the 1980s, told me. (Both Drucker and Seeley have consulted with GLP-1 manufacturers, as have many prominent obesity researchers.) The first mechanism involves the main functions of the drug: controlling blood sugar and inducing weight loss. That the drug coaxes the pancreas into secreting insulin led to its development for diabetes. Weight loss mostly happens through a separate process affecting the brain and gut that prompts a waning appetite and a lingering feeling of fullness. Disentangling their effects is difficult because high blood sugar can lead to weight gain, and is linked to many of the same chronic illnesses as obesity, including heart disease and cancer. The significant reductions in the risk of cardiovascular disease and death from chronic kidney disease seen by people on GLP-1 drugs “certainly reflect” both changes in blood sugar and weight, Drucker said.

A second mechanism that could explain some of these health effects is that the drugs act directly on certain organs. GLP-1 receptors exist on tissues all over the body: throughout the lungs, kidneys, cardiovascular system, gut, skin, and central nervous system. The drugs’ heart benefits, for example, might involve GLP-1 receptors in the heart and blood vessels, Steven Heymsfield, a professor who studies obesity at Louisiana State University, told me.

Beyond affecting individual organs, GLP-1s likely spur wide-ranging effects across the body through a third, more generalized process: reducing inflammation. Chronic diseases associated with obesity and diabetes, such as liver, kidney, and cardiovascular disease, are “all driven in part by increased inflammation,” which GLP-1s can help reduce, Drucker said.

In some situations, these mechanisms may work hand in hand, as in the case of Alzheimer’s. An older GLP-1 drug called liraglutide has shown potential as a treatment for Alzheimer’s, and semaglutide’s effect on early stages of the disease is being tested in a Phase 3 trial. The brain is littered with GLP-1 receptors, inflammation is known to be a central driver of neurodegeneration, and losing weight and having lower blood sugar “will probably help reduce the rate of cognitive decline,” Drucker said.

More complex effects will be harder to disentangle. The drugs are thought to curb addictive and compulsive behaviors, such as alcohol overuse, impulse shopping, and gambling. In animals, GLP-1s have been shown to affect the brain’s reward circuitry—a handy explanation, but perhaps an overly simplistic one. “Reward isn’t just one thing,” Seeley said. The mechanism that makes eating rewarding may differ slightly from that of smoking or gambling. If that’s the case, it wouldn’t make sense for a single drug to tamp down all of those behaviors.

Still other benefits of GLP-1s have yet to be explained. In a large study of people with diabetes published in February, those who took GLP-1s had a lower risk of colorectal cancer than those who didn’t—and weight didn’t seem to be a factor. One possible explanation for the link is that the drugs reduce inflammation that could lead to cancer. Yet recent research in mice suggests that blocking the GLP-1 receptor—that is, doing the opposite of what the drugs do—is what triggers the immune system to fight colorectal cancer.

Some of the ancillary effects being observed now will prove to be legitimate; others won’t. “This happens every time we discover a new molecule,” Seeley said. At first, a drug proves to be amazingly effective against the condition it’s designed to treat. As more people use it, new effects come to light; before long, it begins to seem like a cure-all. Research ensues. Then, the comedown: The studies, when completed, show that it can treat some conditions but not others. In the 1980s, statins emerged as a powerful treatment for high cholesterol, and excitement then mounted about their additional benefits on kidney disease and cognitive decline. Now statins are largely used for their original purpose.

Each new discovery about what GLP-1s can do seems like a lucky surprise—a bonus effect of already miraculous drugs. But people don’t want drugs that are surprising. They want ones that are effective: not medications that might lower their risk of other illnesses, but those that will. To make those drugs, manufacturers need to know what’s actually happening in the body—to what degree the health effects can be attributed to more than just weight loss. To prescribe those drugs, health-care providers need to know the same thing. Doing so will become even harder as GLP-1s themselves become more complicated, targeting multiple other metabolic pathways, each with their own downstream effects. Tirzepatide already targets an additional hormone on top of GLP-1, and a drug that targets three hormones is on its way.

A fuller picture of the potential of GLP-1s may begin to emerge soon. Some of the trials investigating their effects on early Alzheimer’s and Parkinson’s are expected to have results before the end of 2025, offering “a glimpse of whether or not they work,” Drucker said. Eventually, studies may reveal how they work—for these and all the other ancillary benefits. Drug companies are in a furious battle to develop new kinds of obesity drugs, and as it’s shaping up, the future of these medications may not entirely be about obesity. As new kinds of drugs are developed, drugmakers will have to consider whether they maintain, improve upon, or weaken the other benefits, according to Drucker. Competition will likely give rise to a wide range of drugs, each specific to a certain condition or combination of them. GLP-1s might follow the trajectory of blood-pressure medications, which come in more than 200 types to suit all kinds of patients.

New benefits will propel GLP-1 further into the mainstream—not just by opening them up to new subsets of people, but by adding pressure on insurance providers to cover them. Medicare doesn’t pay for obesity drugs, in part because the federal government has historically considered weight loss to be a cosmetic issue, not a medical one. But in March, after the FDA extended Wegovy’s approval to include reducing cardiovascular risk in people with obesity, some Medicare plans began to offer coverage to patients with both weight and heart problems. That GLP-1s have multiple uses is not in itself miraculous. But it would be a small miracle if all of their additional effects, whether separate from or downstream of weight loss, are what help obesity drugs become as widely available as so many other life-changing treatments.

The Atlantic

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