Casey Arnold, who lives in a suburb of Houston, spent years trying to quit smoking. She’d tried nicotine patches. That failed. She tried quitting cold turkey but that made her short tempered. On other occasions the idea of quitting made her so anxious, she smoked more to ease her fears.
By the time she permanently gave up cigarettes in the winter of 2023, at age 55, she’d been smoking for four decades and was up to two packs a day. But this time it was a new type of weight loss drug that helped her quit.
GLP-1, short for glucagon-like peptide 1, is a natural hormone that stimulates the production and release of insulin, slows digestion, curbs appetite, and blunts the brain’s focus on food. GLP-1 agonist drugs, like exanetide, tirzepatide and semaglutide, mimic this hormone. They were originally developed as diabetes treatments, but as more people began taking them, researchers observed these medications are effective for many more conditions than just diabetes and weight loss.
The FDA recently approved semaglutide, the active ingredient of Wegovy, for the treatment of obesity and for reducing the risk of heart attack and stroke in patients with obesity and heart disease. But as the number of people taking these drugs grows, physicians and researchers are learning about unanticipated health benefits for conditions where treatments have been limited, such as addiction, heart failure, and kidney disease.
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Arnold quit smoking while participating in a clinical trial examining the potential of GLP-1 agonists as a treatment for smoking addiction.
“It was totally opposite of when I tried to quit in my previous years,” Arnold says. “I was shocked at how calm I was, compared to how I used to think about quitting.” Instead of anxiety and rage, she felt at peace, and her cravings faded.
“It’s just been an avalanche across the different patient populations,” says Mark Petrie, a cardiologist at the University of Glasgow, whose research focuses on the use of GLP-1 agonists in patients with heart failure. “It’s just good news all around.”
Heart failure with preserved ejection fraction
More than six million Americans are living with heart failure, a condition where the heart progressively loses the ability to pump enough blood to the rest of the body. Of these patients, approximately half have a type known as heart failure with preserved ejection fraction, in which the heart can pump normally but is too stiff to fill up with blood.
In a study published last year, researchers tested semaglutide as a treatment for heart failure with preserved ejection fraction in patients who were not diabetic. The result: patients who received the drug showed fewer symptoms and reported a better quality of life, compared to those who received the placebo. Patients who received the drug had lower levels of C-reactive protein, which is a marker for inflammation.
“This is a big finding,” says James de Lemos, a cardiologist at UT Southwestern Medical Center, in Dallas, Texas, who was not associated with the study. The study was too small to determine if semaglutide can reduce the risk of hospitalization or death but given the stark improvement in patient quality of life, it’s promising.
Although some of these benefits are likely due to weight loss, that’s just part of what makes this treatment effective.
These medications are also cardioprotective and reduce inflammation, which is known to be a driver of heart failure, says Amanda Vest, a cardiologist at the Cleveland Clinic, who specializes in treating patients with heart failure. “We must continue to think more expansively than just about the number on the scale,” Vest says.
For patients with the other major type of heart failure—heart failure with reduced ejection fraction—there is less evidence, so far, that these drugs are effective. More trials are in the works to determine which types of patients will benefit from the use of these medications.
Kidney disease
An estimated 850 million people worldwide are living with chronic kidney disease, but there are few effective treatments. Historically, the main strategy has been to stall kidney failure for as long as possible and then move the patient to dialysis or wait for a kidney transplant. But nine out of 10 patients die of complications before reaching that point.
For patients with severe chronic kidney disease, “you are looking at a mortality rate that’s 10 to 20 percent a year,” says Katherine Tuttle, a nephrologist at the University of Washington Medicine. “This is on par with the worst malignancies.”
As a couple of recent studies have shown, the GLP-1 agonist dulaglutide helps patients who suffer from chronic kidney disease and diabetes. In a recent trial looking at the effect of semaglutide on patients with chronic kidney disease and type 2 diabetes, the treatment was so effective at delaying the progression of chronic kidney disease that the clinical trial was stopped early so that all the trial patients could benefit from the drug.
“It’s the only semaglutide trial that was stopped early for efficacy,” says Tuttle, who is on the executive committee for the trial. “To stop a trial early for efficacy, the bar is set really high,” which includes strong enough evidence for its efficacy that it would be no longer considered ethical to continue giving patients the placebo.
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As Tuttle notes, the effects on the kidneys is only partially due to reductions in risk factors such as blood pressure, blood sugar, and weight. Other benefits are likely to result from reduced inflammation.
“They have a profound anti-inflammatory effect,” Tuttle says. “Our field is really under recognizing the importance of inflammation, particularly in kidney damage caused by diabetes.”
Results from the trial will be published later this year.
Effects on fertility
For a growing number of patients on GLP-1 agonists, such as Ozempic or Mounjaro, one surprising side effect has been unexpected pregnancy, which for some patients, has come after years of struggling with infertility. Although more research is needed to explore the link between GLP-1 agonists and pregnancy, it’s become enough of a phenomenon that ‘Ozempic babies’ has become a trending phrase. Meanwhile, experts think there are several factors responsible.
The first factor is the fact that GLP-1 agonists cause a delayed gastric emptying, which can cause oral contraception pills to be absorbed by the body at a slower rate. “These drugs are altering that particular part of the drug absorption phase,” says Archana Sadhu, an endocrinologist at Houston Methodist Hospital, adding that this effect can be particularly prominent during dosage increases. This means that oral birth control may not be as effective.
The second factor is the link between polycystic ovarian syndrome (PCOS)—the leading cause of infertility in women—and insulin resistance.
“Insulin resistance will dysregulate the ovarian cycle,” Sadhu says. Insulin resistance can lead to infertility by disrupting hormones such as estrogen and testosterone, which are related to fertility; and it can affect the release of eggs from the ovaries. When patients start taking GLP-1 agonists, this reduces their insulin resistance, which boosts fertility.
However, the effects of these drugs on pregnancy are still unknown, which means that it’s important for patients to talk with their doctors about any plans for becoming pregnant, as well as strategies for contraception, which may include adding in a second method to augment oral contraceptive pills, or switching to a different method.
Treating addiction
Since Ozempic and Mounjaro have been become more common, patients have been reporting several unexpected side effects, such as a diminished desire to smoke or drink. Although more research is needed, it’s thought that the part of the brain that is responsible for food cravings overlaps with the part of the brain that is responsible for cravings for substances of abuse, says Luba Yammine, an addiction researcher at UTHealth Houston.
For doctors working in the field, earlier versions of these GLP-1 drugs showed tremendous potential as anti-addiction medications.
“We have far fewer medications available” for treating addiction and many patients report difficulties accessing these, says Christian Hendershot, an addiction researcher at the University of North Carolina School of Medicine. The field also receives less research funding compared with other diseases.
For Yammine, she first became interested in studying the effect of GLP-1 agonists on addiction while working in primary care, where she had several patients who were smokers with diabetes. Yammine would counsel her patients on quitting smoking, prescribing nicotine patches or the medication buproprion, to help them quit. But most of the time these strategies failed.
“It’s hard to quit smoking, period,” Yammine says. “The vast majority of smokers want to quit, but even with the use of these therapies, many of them are not successful.”
To help these smokers with their diabetes she would prescribe GLP-1 agonist medications, only to discover when they returned for a follow-up that they had quit smoking. When she asked them what happened, their answer was that suddenly their cravings vanished. “That was a very interesting finding,” Yammine says.
This happened often enough that Yammine decided to explore the impact of these GLP-1 receptor agonists on addiction through a clinical trial.
Yammine and her collaborators led a pilot study, in which 46 percent of the participants who received exanetide, plus nicotine patches and smoking cessation counseling, were able to quit, compared to 26 percent of participants who received nicotine patches, counseling, and a placebo. Yammine and her collaborators are now following up with a larger trial. They are also planning a separate trial with semaglutide.
For the patients in the study who received exanetide, their post-cessation weight was 5.6 pounds lower than those who received the placebo, a side effect that can help offset the weight gain that is often associated with quitting smoking.
“This weight gain is very problematic,” Yammine says, adding that many patients are either afraid to quit or relapse due to concerns about weight gain, while it can also put them at heightened risk for developing weight-related conditions, such as type 2 diabetes.
For Arnold, who was enrolled in a follow up trial that Yammine is conducting, the months in which she was participating in the trial was characterized both by a calmness surrounding her efforts to quit, as well as minimal weight gain. Since the trial has ended, she’s been able to maintain her efforts to quit smoking, although she gained a little weight. “I don’t have cravings,” Arnold says. “It’s this weight gain that is bothering me.”
Arnold, who works for an HVAC company, would really like to go back on exanetide, but as is the case with so many other patients who have experienced benefits from GLP-1 receptor agonists, she’s finding that it’s too expensive to do so. Just one month’s supply costs about $1,000, and without FDA approval for its use as an anti-addiction drug, most health insurance companies won’t pay for it.
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