Article In Brief
New research suggests a weekly injection of the drug semaglutide can reduce body weight among obese individuals by an average of 15 percent in 12 months. The drug could be helpful for managing neurologic conditions such as stroke, idiopathic intracranial hypertension, and sleep apnea, that are mediated by obesity.
A once-a-week injection of the drug semaglutide can lower the body weight of obese individuals by an average of 15 percent over one year, according to a phase 3 study published online on February 10 in the New England Journal of Medicine.
That degree of weight loss has the potential to be “a game changer” for reducing risk of stroke, said Seemant Chaturvedi, MD, FAAN, FAHA, the Stewart J. Greenebaum Endowed Professor of Stroke Neurology and stroke program director at University of Maryland School of Medicine, who was not involved in the study. The same drug is currently the focus of a new phase 3 trial in Alzheimer's disease, and it and others in the same class have shown promise in other neurodegenerative diseases.
“There is a growing momentum of interest in this field,” said Thomas Foltynie, MD, PhD, professor of neurology in the department of clinical and movement neurosciences at UCL Queen Square Institute of Neurology. Dr. Foltynie has conducted research on another drug in the same class for Parkinson's disease.
Semaglutide is an analogue of glucagon-like peptide-1 (GLP-1), a hormone released by the large intestine in response to food intake. Acting on receptors in the pancreas, it stimulates insulin release, lowering blood sugar. It also reduces appetite, through mechanisms that are only partially understood, and which may involve action in the central nervous system.
A handful of GLP-1 receptor agonists have been developed and are approved for treatment of diabetes and obesity. An oral form of semaglutide, marketed as Rybelsus, is approved in the United States and Europe.
In the current trial, sponsored by Novo Nordisk, 1,961 participants were enrolled and randomized two to one to receive either semaglutide or placebo subcutaneously delivered by auto-injector, once weekly, for 68 weeks. Participants were eligible if they had a body mass index (BMI) of 30 or more, or a BMI of 27 or more with one or more weight-related co-existing conditions, including hypertension, obstructive sleep apnea, hyperlipidemia, or cardiovascular disease.
“There is a growing momentum of interest in this field.”
—DR. THOMAS FOLTYNIE
All patients were individually counseled every four weeks to encourage maintenance of a reduced-calorie diet and increased physical activity. The primary endpoints were the percent reduction in body weight over the duration of the trial and the loss of 5 percent or more of body weight. Secondary endpoints included loss of 10 and 15 percent of body weight.
“When patients are able to lose 5 percent or 10 percent of their body weight, we start seeing changes in blood pressure, blood sugar, and blood glucose, and changes in quality of life, as patients begin to function better,” said the primary investigator for the trial, Robert Kushner, MD, a professor of medicine (endocrinology) at Northwestern University's Feinberg School of Medicine.
The results of treatment were dramatic, Dr. Kushner said. The mean loss in body weight in the semaglutide group was 14.9 percent versus 2.4 percent in the placebo group. Eighty-six percent of those receiving semaglutide had a 5 percent loss in body weight compared with 31 percent in the placebo group; 69 percent receiving the experimental drug had a 10 percent loss compared with 12 percent in the placebo group; 50 percent had a 15 percent versus 5 percent in those taking placebo.
Weight loss declined steadily throughout the trial, reaching maximal at about 60 weeks. While not a pre-specified endpoint, the data showed that about a third of patients lost 20 percent of their body weight.
“That is really exciting to me,” Dr. Kushner said. For the average patient in the study, who began at a weight of about 230 pounds, “a 15 percent weight loss translates into 34 pounds, and a 20 percent loss into 46 pounds. That is really substantial in reducing medical risk and improving quality of life.”
Two measures of physical function confirmed that conclusion, with significant improvements from treatment on both the Short Form Health Survey (SF-36) and the Impact of Weight on Quality of Life–Lite Clinical Trials Version questionnaire.
The most common adverse were gastrointestinal, including nausea and diarrhea, of mild to moderate intensity that waned over time. Discontinuations due to gastrointestinal events were seen in 4.9 percent of participants receiving semaglutide and 0.8 percent of those receiving placebo.
Other pharmacologic treatments for obesity reduce weight on average by 4- to 6-percent, Dr. Kushner said. Bariatric surgery can lead to about a 20 percent loss, “so for the first time, we are seeing a drug that starts to approach what many patients achieve with bariatric surgery.”
Semaglutide is expected to become a maintenance therapy for those who benefit, Dr. Kushner noted. “We think of obesity as a chronic disease, like hypertension or diabetes, which need to be managed long-term,” he said, adding that injectable semaglutide is currently under review by the Food and Drug Administration.
“Several of the conditions we treat can be linked with obesity,” commented Dr. Chaturvedi of the University of Maryland. “Obesity is a risk factor for stroke, and for diabetes, which itself is an important risk factor for stroke.”
In addition, he said, obesity increases the risk of both obstructive sleep apnea and idiopathic intracranial hypertension. “In many of these conditions, we recommend that people try to lose at least 10 percent of their body weight. Having a more powerful pharmacological option could potentially be very useful because many patients struggle to lose significant weight on their own.”
“The fact that 70 percent of participants in the study lost at least 10 percent of their body weight is extremely impressive,” he added. “This could play an important role for a lot of patients—it could be a game-changer for them.”
GLP-1 receptor agonists may have actions beyond weight loss and may find utility in neurology beyond reducing obesity-related risks, according to Dr. Foltynie of UCL Queen Square. Preclinical data that has accumulated over the past decade has indicated that this class of drugs can offer protection against neurodegeneration in both cells and animal models of Parkinson's disease, potentially through effects on neuroinflammation, insulin signaling, mitochondrial function, or all three, among other hypothesized mechanisms. “There may not be a single pathway, Dr. Foltynie said.
Those effects have found some clinical support as well. In 2017, Dr. Foltynie and colleagues showed in a small double-blind trial that exenatide, another member of the class, improved off-medication motor scores in Parkinson's disease patients over the course of a year of treatment.
Further evidence has come from a study of diabetes patients using a variety of anti-diabetes medications. Dr. Foltynie found that patients using GLP-1 agonists had a dramatically lower risk of developing PD compared to those using other types of medications. “The epidemiology is quite convincing,” he said.
Semaglutide's manufacturer Novo Nordisk is beginning a phase 3 study of oral semaglutide as a way to slow Alzheimer's disease, based on preclinical data, Danish registry data suggesting that treatment reduces the incidence of AD in diabetes patients, and posthoc analysis of company trials, in which fewer patients who received active treatment developed dementia versus those who received placebo in three multi-year trials for people with diabetes.
For the near term, Dr. Chaturvedi said, “We need to see what the reaction to this drug is among our colleagues in the internal medicine and endocrinology communities. If it becomes accepted by them, then we as neurologists should consider its use” for patients for whom weight loss could reduce their risk of stroke or other obesity-related conditions.
Novo Nordisk is also conducting a trial, called SELECT, to examine the potential benefit of semaglutide in obese patients with prior cardiovascular disease, including prior stroke. “It will be very interesting to see if this treatment can reduce the risk of cardiovascular events,” Dr. Chaturvedi said. That trial is expected to finish in 2023.
Dr. Kushner serves on the medical advisory board for Novo Nordisk and receives consultative fees. Dr. Chaturvedi had nothing to disclose. Dr. Foltynie said AstraZeneca is supplying a drug and placebo to an ongoing trial free of charge, but no other payment has been made.