The Benefits of Ozempic Are Multiplying
You’ve heard the dramatic weight loss stories. Semaglutide, the active ingredient in Ozempic and Wegovy, can help people lose 15 percent of their body weight. Tirzepatide, sold under the brand names Mounjaro and Zepbound, may be even more effective at shedding pounds.
Known as GLP-1 agonists, these drugs were originally developed to help control diabetes. But there’s increasing evidence that they have other health benefits, beyond controlling weight. They seem to boost heart health, protect the kidneys, improve sleep apnea, and lower the risk of certain obesity-related cancers. Recent studies have also hinted at their potential to treat addiction and even slow the cognitive decline that comes with dementia. As researchers test these drugs for various conditions, they’re trying to untangle the mysteries behind how exactly they’re working in the body—and they have a few theories.
“Many of us in the medical community are really beginning to think about these drugs as health promotion drugs, not just weight loss drugs or even anti-obesity drugs,” says Harlan Krumholz, a cardiologist and professor at Yale University School of Medicine.
In March, Novo Nordisk’s Wegovy became the first weight loss medication to also gain approval to help prevent serious heart problems in people with cardiovascular disease. In an international trial of more than 17,600 people with excess weight, weekly injections of Wegovy significantly reduced the risk of a major cardiac event. Researchers followed participants for an average of three years and found that those who took Wegovy were 20 percent less likely to die of a heart attack, stroke, or other cardiovascular cause.
Eli Lilly, which makes tirzepatide, is also looking to expand Zepbound’s uses. The company announced this month that its weight-loss drug improved symptoms in heart failure patients with obesity and led to a 38 percent reduction in hospitalizations.
One in every four deaths each year in the United States is due to heart disease, and obesity is increasingly a factor. Excess weight can cause high blood pressure and cholesterol, which increases the risk of heart attack and stroke. Weight gain can also affect how the heart muscle functions, increasing the risk of failure. It’s perhaps no wonder then that a drug that helps people lose weight would also improve heart health. But there are reasons to think there are other factors at play beyond weight loss.
“When we first saw the results, we wondered, is this simply about weight loss?” Krumholz says. “But what we’re seeing is that having more weight loss doesn’t necessarily translate into more benefit.”
In the trial of people with heart disease, Wegovy lowered blood pressure, cholesterol levels, heart rate, and heart inflammation before participants reached their maximum weight loss. What’s more, the drug seemed to reduce major cardiac events regardless of how much weight they lost. The same was true for heart failure patients. This all suggests to Krumholz that the drug is, at least in part, working on the cardiovascular system in some other way. “This is the big question,” he says. “What is the exact mechanism of benefit?”
Semaglutide and tirzepatide work by mimicking the action of GLP-1, a hormone found naturally in the body. These drugs act on GLP-1 receptors in the pancreas to trigger the release of insulin after eating, which helps control blood sugar levels in people with diabetes. They also bind to GLP-1 receptors in the brain to make people feel full, leading them to eat less.
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Scientists are still trying to understand the other knock-on effects of these drugs, including the cardiovascular benefits. One explanation is that GLP-1 receptors also exist on cells in the heart, blood vessels, liver, and kidney, so these drugs may act directly on these organs. “It turns out that these receptors are present in many parts of the body,” says Katherine Tuttle, a clinical professor of nephrology at the University of Washington School of Medicine.
A recent trial led by Tuttle was stopped early due to overwhelming evidence that semaglutide has protective effects on the kidney. The study included more than 3,500 people with both type 2 diabetes and kidney disease. About half of the participants took a weekly injection of semaglutide while the other half got a placebo shot. After an average of three and a half years, the semaglutide group had a 24 percent lower likelihood of having a major kidney disease event—such as needing dialysis or a kidney transplant.
Clinical trials aren’t usually designed to determine the mechanism of a drug—and in fact, the mechanisms of many drugs on the market aren’t entirely known. But Tuttle has her own theory for how semaglutide is protecting the kidney: by shutting down inflammation.
GLP-1 drugs may even calm inflammation in the brain, raising hope that they could be used to treat conditions like dementia and Parkinson’s disease. Inflammation is thought to play a role in the development of both conditions.
In a UK trial of 200 people with mild Alzheimer’s disease, an older GLP-1 drug called liraglutide appeared to slow shrinking of the parts of the brain that control memory, learning, language, and decisionmaking by as much as 50 percent. Those who received weekly injections of liraglutide over 52 weeks also had an 18 percent slower decline in cognitive function after a year compared to those who got the placebo. Obesity is a known risk factor for developing Alzheimer’s disease, but the study didn’t specifically include people with obesity, which suggests that the drug is helping through another means.
The authors, who presented the findings last month at the Alzheimer’s Association annual conference, think liraglutide could be working in a few different ways—including reducing inflammation in the brain and lowering insulin resistance.
Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association, says the results are exciting, although larger trials will be needed to confirm this protective effect. “This is really the first study where we’ve seen a hint of this benefit for individuals,” she says.
And the neuroprotective effects may extend to Parkinson’s disease as well. An older diabetes drug in the GLP-1 family, lixisenatide, seemed to slow the progression of Parkinson’s symptoms in a small study of 156 patients in France. In results published in April, participants with early-stage Parkinson’s who took the drug for a year saw no worsening of motor symptoms such as tremors, balance problems, slowness, and stiffness. Those who received a placebo, meanwhile, experienced a decline over the same period.
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Because GLP-1 drugs interact with the brain and seem to curb food cravings, scientists wonder if these medications could also curb cravings for addictive substances. Parts of the brain involved in eating behaviors are also involved in the use of alcohol and drugs. In mice, semaglutide has been shown to reduce alcohol consumption and binge-like drinking, and some people who have taken semaglutide and other GLP-1 drugs have self-reported less drinking and smoking.
In 2019, researchers at Penn State wanted to see if this class of drugs could help reduce cravings in people with opioid use disorder. In experiments with rats, they showed that GLP-1 drugs could reduce fentanyl-seeking behavior and relapse to heroin. The group launched a pilot study of 20 participants who were living at a residential treatment facility. Half were given the GLP-1 drug liraglutide, and the other half received a placebo. Measuring cravings can be tricky, so researchers used a smartphone app that pinged people four times a day to ask about their craving as well as their mood and stress levels.
When the three-week study ended, researchers found that those who received the GLP-1 drug reported a 40 percent reduction in opioid craving compared to those who got the placebo. The study didn’t follow participants after they left the residential facility, so it’s not known whether the drug actually curbed their opioid use. That, of course, is the important outcome, since many people who initially recover from addiction experience a relapse.
Patricia Grigson, a professor of neural and behavioral sciences at Penn State College of Medicine who led the study, says GLP-1 drugs seem to block the signal in the brain that gets released after eating or taking an addictive substance. “It would appear that they’re just knocking down that reward signal,” she says. Grigson presented the findings at the American Association for the Advancement of Science conference earlier this year. Her group will test semaglutide next in 200 people getting treatment for opioid addiction, and they plan to start recruiting participants for that study this fall.
With so many people turning to GLP-1 drugs to lose weight, their other health benefits may soon become clearer—and so could the answers about how exactly they’re working. Grigson says newer drugs like tirzepatide, as well as ones still in development, may work even better than previous GLP-1 medications. “If they look safe, they need to be tested,” she says. “And the sooner, the better.”