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As a clinician, family nurse practitioner Luba Yammine, PhD, MSN, sees patients with substance use disorders, including many who smoke.

She couldn鈥檛 help but notice something surprising when she prescribed a particular class of medications to treat patients with type 2 diabetes.

鈥淎ll of a sudden they鈥檇 quit smoking,鈥� Yammine recalled in an interview. 鈥淭hat sort of prompted my dive into the literature.鈥�

Yammine, an associate professor in the department of psychiatry and behavioral sciences at UTHealth Houston, found some animal studies suggesting that glucagon-like peptide 1 (GLP-1) receptor agonists鈥攂etter known by such brand names as Ozempic and Wegovy (semaglutide), Victoza (liraglutide), and Byetta (exenatide)鈥攔educed nicotine-seeking behaviors.

That was a decade ago. Today, Yammine is leading trials of 2 GLP-1 receptor agonists in people who want to quit smoking. One , supported by the National Institute on Drug Abuse (NIDA), is comparing exenatide with a placebo. The other , funded by Novo Nordisk, is comparing that company鈥檚 semaglutide with a placebo.

Smoking cessation is only one of a variety of indications for which the popular drugs hold promise. They鈥檙e already approved by the US Food and Drug Administration (FDA) for treating type 2 diabetes and obesity, and, , protecting against cardiovascular death, myocardial infarction, and stroke.

GLP-1 is an incretin hormone, a gut peptide secreted in the lower digestive tract after nutrients are consumed. Among people with type 2 diabetes, stimulation of GLP-1 receptors with agonist drugs significantly reduces plasma glucose and improves glycemic control. GLP-1 also delays gastric emptying and, by acting on the hypothalamus, promotes satiety and reduces food intake.

Besides the pancreas, GLP-1 receptors are found in the brain, fat cells, heart, liver, and other organs. And animal and human studies have uncovered a host of possible uses for drugs that stimulate the ubiquitous receptors.

On average, people who previously smoked gain (3.6 to 5 kg) within 6 months after quitting鈥攁 prospect that鈥檚 enough to dissuade some from trying to snuff out their nicotine habit.

But what if a single medication could not only help people who smoke quit but also prevent them from adding weight? In 2021, Yammine coauthored an about a pilot study that suggested exenatide, to improve glycemic control in type 2 diabetes, could safely do just that.

Yammine鈥檚 team randomly assigned 84 people who smoked and were prediabetic, overweight, or both to receive weekly injections of exenatide or a placebo for 6 weeks. The trial excluded people with type 2 diabetes because most smoking cessation studies try to enroll relatively healthy people, Yammine explained.

Everyone in the trial also received nicotine replacement therapy patches and brief smoking cessation counseling. At the end of the study, about 46% of the participants who received exenatide had quit smoking, compared with 27% of the placebo group. Plus, participants in the exenatide group weighed about 5 lb (2.2 kg) less on average than those who got the placebo.

The pilot study led to the larger of exenatide, which aims to enroll 216 people who smoke and are overweight or have prediabetes. This time, study participants will receive injections of exenatide or a placebo for 14 weeks.

Novo Nordisk鈥檚 semaglutide trial, which is also enrolling adults who smoke cigarettes and are overweight or prediabetic, is focusing on changes in body weight, fat mass, and waist circumference from baseline to 28 weeks after the first injection.

Like Yammine, Lance Alan Sloan, MD, MSE, has had patients treated with GLP-1 receptor agonists for type 2 diabetes tell him that they鈥檙e smoking less. But Sloan, medical director of the Texas Institute for Kidney and Endocrine Disorders in Lufkin, said he counsels all his patients who smoke to quit. Without a clinical trial, he pointed out, it鈥檚 impossible to know whether his patients have quit smoking because of their medication, his counseling, or both.

The soaring use of GLP-1 receptor agonists for type 2 diabetes and obesity also has been accompanied by anecdotal reports of reductions in alcohol use, according to a recent .

Preclinical research into the drugs鈥� effects on alcohol consumption, which began more than a decade ago, consistently showed that they reduced the rewarding properties of alcohol and other addictive drugs, the authors wrote.

In addition, the authors noted, a that used data from nationwide registers in Denmark found that patients taking GLP-1 receptor agonists had fewer alcohol-related events than those taking dipeptidyl peptidase 4 inhibitors, or gliptins, another class of drugs used to treat type 2 diabetes. Alcohol-related events were defined as contact with a hospital for alcohol use disorder, alcoholism treatment, and the purchase of a medication used to treat alcohol withdrawal syndrome or alcohol dependence.

However, the only completed of a GLP-1 receptor agonist involving patients with alcohol use disorder found that exenatide was no better than placebo for reducing heavy drinking days, except in a subgroup of participants who also had obesity.

Despite the lack of clinical trial evidence, the study noted that there are anecdotal reports of patients getting semaglutide prescriptions to help reduce their use of alcohol or other substances. The authors emphasized the need to wait until trials are completed.

Christian Hendershot, PhD, who coauthored the recent commentary, is leading 2 clinical trials of semaglutide for treating substance use disorders. The studies, funded by the National Institutes of Health, each randomly assigned 48 participants to 9 weekly injections of semaglutide or a placebo.

In , Hendershot will investigate the effects of semaglutide on alcohol responses and consumption in the laboratory, alcohol consumption in the real world, and weight loss in people with alcohol use disorder.

鈥淚t is likely that people will have to stay on these treatments for a while if they prove effective,鈥� Hendershot said. 鈥淲e do have some reason to believe that stopping GLP-1s could lead to a rebound effect in terms of drinking.鈥�

The , which enrolled people who on average smoked at least 5 cigarettes a day for the previous year, will examine the effects of semaglutide on nicotine intake and cravings in laboratory tests and in the real world, as well as changes in body weight.

Although the for alcohol use disorder, 鈥渢he uptake is very low, especially in general medical settings,鈥� Hendershot said. That鈥檚 because of a reluctance to seek treatment, a lack of addiction training among health care professionals, and considerable stigma surrounding the condition and addiction in general, he and his coauthors explained.

GLP-1 receptor agonists potentially could overcome some of these barriers, Hendershot noted. 鈥淭hese medications are becoming increasingly normalized, and very quickly. We know that many physicians will be comfortable prescribing them.鈥�

As with other substance use disorders, preclinical research suggests that GLP-1 receptor agonists might help people who use cocaine, for whom 鈥渨e really have no pharmacotherapy,鈥� Yammine pointed out.

In the summer of 2023, Yammine coauthored a small about the feasibility of treating cocaine use disorder with exenatide. Three people with the condition were asked to attend a weekly clinic visit for 6 weeks, at which time they were to receive exenatide injections and individual drug counseling.

鈥淭his is a very difficult population to keep engaged,鈥� she noted, but the 3 people in her study attended every weekly clinic visit and received the exenatide injections. However, 2 participants continued to use cocaine through the study; the third stopped by the second half. Satisfaction ratings at the end were generally positive, and Yammine said she hopes eventually to conduct a randomized trial of a GLP-1 receptor agonist in people with cocaine use disorder.

Previously, a trial by researchers at Yale University and the University of Pennsylvania didn鈥檛 find evidence that exenatide altered cocaine use or the subjective effects of the illicit drug in people with cocaine use disorder. However, the authors noted, their trial randomized its 13 participants to only a single dose of exenatide or placebo, which precluded drawing firm conclusions about exenatide鈥檚 efficacy in treating cocaine use disorder.

Sloan, senior author of a 2022 about the potential uses of GLP-1 receptor agonists, predicts that the next new FDA-approved indication for the drugs will be to protect against worsening of chronic kidney disease in people with type 2 diabetes.

The initial evidence that GLP-1 receptor agonists might protect kidney function in patients with type 2 diabetes studying the drugs鈥� effects on cardiovascular disease. Those studies included people with and without chronic kidney disease.

Approximately 40% of people with type 2 diabetes have chronic kidney disease, according to Novo Nordisk. In a March press release, the company the results of an international that randomized 3533 people with both type 2 diabetes and chronic kidney disease to receive weekly injections of semaglutide or a placebo for approximately 5 years. Patients who received semaglutide were 24% less likely to experience progression of their kidney disease or kidney or cardiovascular death, according to the press release. Novo Nordisk the trial early after an interim analysis showed efficacy.

In general, participants in drug trials who are randomized to the active treatment are more likely to report adverse effects than those who receive a placebo.

But researchers noticed something unusual in the clinical trials of semaglutide for treating type 2 diabetes, Alireza Atri, MD, PhD, said in an interview. People who鈥檇 received the GLP-1 receptor agonist were less likely to report cognitive impairment or dementia, explained Atri, an Alzheimer disease clinician and researcher and director of the Banner Sun Health Research Institute in Arizona.

Intrigued, researchers looked at insurance databases to see if they could find a similar correlation. Every database they examined found a lower risk for cognitive impairment or dementia among people whose type 2 diabetes was treated with a GLP-1 receptor agonist, Atri said.

In addition, he noted, 鈥渢here was all this preclinical evidence going back 25 years鈥� about the drugs鈥� possible brain benefits. A few weeks after rats received injections of a GLP-1 receptor agonist into their peritoneum, they were found to have reduced inflammation in their brain. 鈥淭here were a lot of converging lines of evidence,鈥� Atri said.

鈥淲e know that insulin resistance in the brain certainly has an impact on the development of Alzheimer disease,鈥� Sloan posited as a potential mechanism.

Novo Nordisk, headquartered in Denmark, is funding 2 international phase 3 trials that have enrolled approximately 1840 participants each. The between the trials is that only was open to patients with significant small vessel pathology.

The trials randomly assigned participants to receive either semaglutide pills or placebo pills for 156 weeks. When asked why the treatment was oral and not injected, Atri, a member of the trials鈥� global steering committee, said, 鈥渢here was a lot of debate about that.鈥� Compliance was an issue, he explained, and 鈥渟ome people like shots, some don鈥檛.鈥�

Participants in both trials must have amyloid deposits in their brain鈥攁 hallmark of Alzheimer disease鈥攃onfirmed by positron emission tomography or cerebrospinal fluid. Taking an anti鈥揳myloid-尾 monoclonal antibody鈥� this year, which for now will leave as the only such drug on the market鈥攄oes not exclude people from enrolling in the semaglutide trials, the results of which are expected in 2025.

Patients with type 2 diabetes have an elevated risk of Parkinson disease, but findings about GLP-1 receptor agonists and the neurodegenerative condition have been mixed.

A cohort of approximately 100 000 people with type 2 diabetes, published in 2020, found that the use of GLP-1 receptor agonists or dipeptidyl peptidase 4 inhibitors was associated with a lower rate of Parkinson disease compared with other oral type 2 diabetes drugs.

A newly published involving 156 patients with early Parkinson disease found that the GLP-1 receptor agonist lixisenatide (Adlyxin), which is injected daily, appeared to slow the worsening of symptoms compared with placebo after 1 year of treatment. The drug was associated with adverse gastrointestinal effects.

However, another recent of a GLP-1 receptor agonist found no benefit. Although smaller trials suggested that exenatide might improve Parkinson disease motor features, the more recent larger trial did not confirm this. The trial randomized 255 patients with early, untreated Parkinson disease to injections of a longer-lasting version of exenatide or a placebo for 36 weeks. A subgroup analysis did raise the possibility that the drug might benefit younger people with Parkinson disease, but further study is needed, the authors in January.

There are also hints that GLP-1 receptor agonists might be useful in treating and , , , , and .

Preclinical evidence suggests, for example, that GLP-1 receptor agonists might protect against neuro-ophthalmic conditions such as diabetic retinopathy. 鈥淎t this point, it is an adjuvant benefit for patients with diabetes and/or obesity,鈥� University of Florida neurosurgeon Brandon Lucke-Wold, MD, PhD, said in an email.

As data emerge, though, the drugs might be used to treat glaucoma and other eye conditions in people who don鈥檛 have type 2 diabetes, noted Lucke-Wold, who coauthored an about the protective role of GLP-1 in neuro-ophthalmology.

But if GLP-1 receptor agonists win FDA approval for additional indications, 鈥測ou really need to be making enough drug,鈥� Sloan pointed out. Although they have the same active ingredient, Ozempic isn鈥檛 in short supply, but Wegovy is due to 鈥渄emand increase for the drug,鈥� the FDA.

Both products are semaglutide injections, but while Ozempic is approved to treat type 2 diabetes, Wegovy is indicated for obesity and protection against myocardial infarctions and strokes. Scaling up manufacturing capacity was one of the topics discussed at Novo Nordisk鈥檚 Capital Markets Day for investors on March 7, the company.

Eli Lilly also has 2 brands with the same active ingredient but different indications. Tirzepatide is a dual agonist that activates receptors of 2 hormones secreted from the gut: GLP-1 and glucose-dependent insulinotropic polypeptide. It was as Mounjaro for improving blood glucose in adults with type 2 diabetes, although for weight loss.

As with other GLP-1 receptor agonists, researchers are investigating tirzepatide鈥檚 potential uses beyond treating type 2 diabetes and obesity; for example, a is under way to see whether the drug improves congestive sleep apnea. The availability of some doses of Mounjaro injections was limited from late 2022 through April of this year due to increased demand, the FDA. The agency the other tirzepatide brand, Zepbound, in November 2023 to treat obesity; it was not on the FDA鈥檚 drug shortages list as of early April despite of supply issues.

Probably no one is surprised about the demand for GLP-1 receptor agonists for weight loss, least of all Sloan. He noted that 鈥渢his is the most effective class of medications for treating the number 1 problem that particularly our society has.鈥�

Published Online: April 19, 2024. doi:10.1001/jama.2024.1017

Conflict of Interest Disclosures: Dr Yammine reported receiving research funding from the National Institutes of Health (NIH), the Substance Abuse and Mental Health Services Administration, the UTHealth Houston Center for Clinical and Translational Sciences, PARTNERS Research Awards, the Michael E. DeBakey VA Medical Center, and Novo Nordisk and serving as a consultant for Eli Lilly. Dr Sloan reported receiving research funding from Amgen, Boehringer Ingelheim, Corcept, Eli Lilly, and Merck; serving as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer; and serving on the speakers鈥� bureaus for AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, and Pfizer. Dr Atri reported receiving institutional research grants from the Alzheimer鈥檚 Consortia, Arizona Department of Health Services, Biohaven, Esai, Foundation for NIH, Gates Ventures, Indiana University, Johns Hopkins University, National Institute on Aging, and Washington University; serving as a consultant or member of various boards for Acadia, the Alzheimer鈥檚 Association, Alzheimer鈥檚 Disease International, AZ Therapies, Biogen, Genentech, JOMDD, Life Molecular Imaging, Lundbeck, Merck, Novo Nordisk, Prothena, and Qynapse; and earning royalties from a dementia textbook he wrote. Dr Lucke-Wold reported receiving research funding from the NIH. No other disclosures were reported.